\r\n\tmolecular and imaging methods for detection and identification of plant diseases have many limitations that will be discussed in this book. This sparked interest in the development of minimally invasive and substrate general spectroscopic \r\n\ttechniques that can be used directly in the field for confirmatory plant disease diagnostics.
\r\n
\r\n\tThis book will also discuss recent progress in development of reflectance, infrared, Raman and surface-enhanced Raman \r\n\tspectroscopy for detection and identification of plant diseases. It will also present advantages and disadvantages of these optical spectroscopy methods compared to the most common molecular and imaging techniques.
\r\n
\r\n\tThe book also aims to discuss specific plant diseases, their symptoms and available methods of treatment.
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1. Introduction
Parkinson’s disease (PD) is a common neurodegenerative disease, with a prevalence of around 250 per 100,000 population and becoming of growing importance in ageing populations. Patients become symptomatic when around 75% of striatal dopamine is lost, with ongoing yearly declines of 5-10% (Brooks 1998, Fearnley 1991). The use of levodopa (L-3,4-dihyroxyphenylalanine ) as a symptomatic therapy was established nearly 50 years ago and continues to be an important approach in early and late disease (Fahn 2006). Although the majority of patients initially respond well to dopaminergic therapies, many eventually develop fluctuations in their therapeutic response, often with associated dyskinesias (Jenner 2000). Additional agents, including catechol O-methyltransferase inhibitors and/or monoamine oxidase inhibitors are often added in to existing medications, with a proportion of patients dependent on infused apomorphine. These therapies are symptomatic, with no effect on the underlying pathogenic processes, particularly the progressive loss of dopaminergic neurons. Novel therapies to either compliment existing approaches, or potentially alter the course of disease, are clearly desirable.
This neuronal loss in Parkinson’s disease is associated with multiple functional abnormalities, including changes in excitatory glutamatergic and inhibitory GABAergic pathways controlling movement (Wichmann 2003). Disinhibited activity in the subthalamic nucleus (STN) correlates with increased activity in excitatory projections to the major nuclei of the basal ganglia – the internal globus pallidus (GPi) and substantia nigra pars reticularis (SNr). The resultant increased inhibitory outflow to the pallidal receiving areas or the thalamus and consequently reduced cortical activity are thought to be responsible for many of the motor features of Parkinson’s disease (Brown 2001). The pathophysiological importance of this overactive subthalamic nucleus activity can be targeted using several approaches, including stereotactic lesioning (Alvarez 2001, Su 2003), high frequency deep brain stimulation (Benabid 1996, The Deep-Brain Stimulation for Parkinson’s Disease Study Group 2001) and pharmacological silencing (Levy 2001), leading to marked improvement in motor function. More recently, these approaches and observations have prompted gene therapy trials to deliver therapeutic vectors into the striatum itself and these will be discussed later. Typically, gene therapy approaches have focused on the restoration or preservation of dopaminergic cell function within the striatum either with neurotrophic factors (Kordower 2000, Marks 2010) or the delivery of enzymes needed for dopamine synthesis (Eberling 2008, Azzouz 2002).
2. Gene delivery to the brain
Gene therapy as a therapeutic approach to central nervous system (CNS) disorders has been theoretically possible for over a decade now, and several recent technical advances have made this avenue increasingly attractive. The method of delivery of the synthetic nucleic acid will fall into one of two groups – nonviral and viral vectors. Nonviral vectors are usually forms of chemically synthesized particles, such as cationic lipids, mixed with recombinant DNA, typically delivered by direct injections. This method is technically relatively straightforward, but usually only produces transient gene expression. Viral vectors, in contrast, are derived from DNA or RNA viruses and can potentially lead to sustained gene expression through genomic integration or the formation of episomes. The past five years have seen major advances in the range of available viral vectors, with individual vector systems having specific advantages and disadvantages for the delivery of therapeutic genes to the CNS. The properties of individual classes of vector are presented here, with a particular focus on adeno-associated virus (AAV), although adenovirus, herpes simplex and lentivirus systems are discussed. With the exception of lentiviruses, retroviral vectors (typically based on murine leukaemia viruses) are unable to infect the post-mitotic cells of the CNS, and are not considered in this review. An additional consideration relates to the method of vector delivery – peripheral systemic injection is clearly not appropriate unless the vector can cross the blood brain barrier with some degree of tissue specificity. Fortunately, deep brain surgical approaches are well developed in the field of movement disorders, making targeted viral injection relatively straightforward.
2.1. Adeno-associated viruses
AAVs are simple, 4.7 kb single stranded DNA viruses (Srivastava 1983) of the Parvoviridae family and Dependovirus genus. Two genes (cap and rep) coding for capsid and viral replication proteins respectively, are flanked by inverted terminal repeats (ITRs). Additional genes are required for replication, potentially derived from either adenovirus or herpes simplex viruses (Atchison 1965, Hoggan 1966, Buller 1981). The AAV serotype 2 (AAV2) was the first to be sequenced, and is the most widely used AAV-based gene therapy vector. Subsequent research has isolated at least 100 AAV variants, with many having different tissue tropisms and apparent transduction efficiencies (Gao 2004). AAV usually persists as monomeric or concatameric episomes (Schnepp 2003), although viral integration can occur, at a defined site on human chromosome 19 (Muzyczka 1992), AAVs are particularly attractive as candidate vectors for gene therapy as they have a high theoretical level of safety (Monahan 2002, Tenenbaum 2003), as wild-type AAV is already replication defective and the virus has not been associated with any known human disease. The weak promoter activity of the terminal repeat sequence reduces the overall risk of insertional mutagenesis and oncogenic activation, so genomic integration is not likely to pose a major risk (McCarty 2004).
Early approaches to the production of recombinant AAVs involved the packing of foreign DNA into viral coats by infecting cells with wild-type AAV and helper adenovirus. This process left residual wild-type viruses contaminating preparations of recombinant AAV, with obvious problems for in vivo applications (Hermonat 1984). More recent systems use a two or three plasmid system (Samulski 1989), in which cells are co-transfected with a plasmid construct coding for the synthetic gene of interest flanked by the 125 base pair viral inverted terminal repeats (ITRs), in combination with further plasmids coding for cap, rep and appropriate adenoviral helper genes. This leads to the production of recombinant virus without the presence of contaminants, further enhancing safety. These advantages mean that AAV has been the predominant vector used in clinical trials.
Some disadvantages with using AAV include the relatively small size of the virus which limits the size of the insert to a maximum of approximately 4 kilobases of foreign DNA. Pre-existing humoral immunity to AAV is found in 80% of the human population, which may be enhanced after vector administration, potentially limiting transgene expression (Peden 2004, Sanftner 2004). The significance of this phenomenon is not clear for CNS based therapies, a site of relative immune privilege, but should prompt further studies into the significance and standardization of neutralising antibody titres during clinical trials.
2.2. Adenovirus
The earlier generations of adenoviral constructs were generally based around the Ad serotype 5 and containing E1 and/or E3 gene region deletions. These found early uses for in vitro work, but were associated with significant in vivo host immune responses and associated toxicity, with cell death leading to transient transgene expression. The deletion of further viral genes in more recent third generation (“gutless”) vectors has reduced these problems significantly (Schiedner 1998), producing long-term gene expression. This class of viruses has several technical advantages, including relative ease in the production of high-titer stocks and generally strong gene expression (Verma 2005). Broader use of this class of vectors is still hampered by immune reactions induced by viral capsid proteins, which are likely to remain a persistent issue (Kafri 1998).
2.3. Herpes simplex virus
Herpes simplex virus has several obvious advantages for CNS delivery, including a large genome size, with resultant high packaging capacity, neurotropism and long lived episomal latency. The virus genome consists of 150 kb of double-stranded DNA, encoding more than 80 genes. Two broad classes of vector systems have been derived – amplicons and recombinant vectors. Amplicon vectors contain only cis-acting sequences (ori and pac) and require a packaging system, usually supplied in trans, from a pac deficient cosmid encoded HSV-1 genome (Cunningham 1993).Vectors with specific deletions in the infected cell polypeptide (ICP)-0 (ICP0), ICP4, ICP22 and ICP47 intermediate early genes retain long lived persistence, apparently without significant cellular toxicity (Samaniego 1998). Some safety concerns remain, however, but this class of vectors looks particularly promising when the delivery of a large DNA construct is required (Lachmann 1999). The use of specific promoters, such as the tyrosine hydroxylase promoter, increases transduction specificity (Cao 2008).
2.4. Lentivirus
Lentiviral vectors are usually considered separately from other retroviruses, as they can efficiently infect both dividing and non-dividing cells, potentially leading to long-term gene expression following chromosomal integration. Most lentiviruses are based on the human immunodeficiency virus (HIV) (Vigna 2000), with transgenes incorporated between elements known as long terminal repeats (LTR), sequences required for host genome integration. The env gene product is typically substituted for sequences from other RNA viruses (frequently the vesicular stomatitis virus glycoprotein VSV-G) to impart a wide cellular tropism, including neurons (Naldini 1996). Further specificity can be given through the use of the human glial fibrillary acidic promoter (hGFAP) or neuron-specific enolase promoter (rNSE), giving glial or neuronal specificities respectively (Jakobsson 2006). This class of vectors certain several advantages, including a relatively large capacity for cloned genes (approximately nine kilobases) (Zhao 2007), but concerns relate to the possibility of recombination events, producing replication-competent virus. The use of two or three plasmid based transfection systems, in which the capsid assembly genes are genetically isolated has increased the safety profile of this class of vectors (Zufferey 1997) and this class looks particularly promising for future studies.
3. Clinical trials with gene therapy vectors
Gene therapy vectors have been used in clinical trials for patients since 1990, with most experience using retroviral vectors (Verma 1997). Initial enthusiasm was tempered, however, following the death of a patient receiving an adenoviral vector as replacement for the enzyme defect ornithine transcarbamylase deficiency (Somia 2000). The patient death – from systemic inflammation and multiorgan failure - led to a temporary suspension of trials in 1999. Since then, technical advances and tighter regulatory frameworks have led to an increase in registered clinical trials using gene therapy and particularly using AAV. Prompted by favourable results in preclinical studies using animals ranging from mice to nonhuman primates, over 40 clinical trials using AAV as a therapeutic vector are currently registered with the US Food and Drug Administration (Mueller 2008).
Early trials, such as the Phase I trial of AAV encoded human factor IX in patients with haemophilia B provided useful safety information (Kay 2000). Following intramuscular vector injection, small but detectable levels of secreted factor IX were produced. No toxicity or chromosomal integration was seen during the time of the study. Unfortunately, cell mediated immunity to AAV was observed, which led to hepatocyte damage and eventual loss of therapeutic gene expression (Manno 2006). Phase I and II studies examined outcomes following intranasal or endobronchial administration of AAV encoded cystic fibrosis transmembrane conductance regulator. Antibody responses to AAV were observed, with limited biological effects. The safety profile appeared good, with no adverse events seen in the 120 patients treated (Mueller 2008).
In addition to the trials for PD there are several other ongoing clinical trials examining AAV mediated gene therapy to the CNS. These include ocular delivery of the RPE65 gene in Leber’s congenital amaurosis, with no reported toxicity in a small number of treated patients despite a transient rise in neutralising antibodies (Simonelli 2009). Also in progress is a phase II trial using AAV to deliver nerve growth factor in patients with Alzheimer’s Disease (Mandel 2010). A recent phase I trial of AAV mediated delivery of aspartoacylase for Canavan disease reported good safety, with detectable antibodies to AAV2 observed in the serum of a minority of patients. In this case, the vector was infused intracranially via burr holes, which may explain the absence of neutralising antibodies in the cerebrospinal fluid of patients and lack of CNS inflammation (McPhee 2006).
4. Gene therapy for Parkinson’s disease
Clearly, several important issues need to be addressed when attempting therapeutic cellular transduction (gene delivery and expression) for Parkinson’s disease. Most obvious is deciding on the therapeutic target – the pathological process underlying PD is widespread and involves multiple brain structures and their relevant cell signaling pathways. Great care needs to be taken with the specific design of the therapeutic gene, including relevant promoters, particularly if the construct is to be constitutively active.
The simplest approach is to restore dopaminergic levels in the basal ganglia, usually through the introduction of genes coding for enzymes important in dopamine production (Azzouz 2002, Hadaczek 2010) or relevant cell signaling proteins (Kaplitt 1994). One early series of experiments examined AAV mediated gene transfer into the CNS, with injection of a virus coding for tyrosine hydroxylase into 6-hydroxydopamine-lesioned rats, finding sustained transgene expression, with no cytopathic effects and no reactive gliosis (Kaplitt 1994). Other strategies aim to slow dopaminergic cell death, usually through the localized production of trophic factors such as brain-derived neurotrophic factor (BDNF) (Hyman 1991, Klein 1999), glial cell line-derived neurotrophic factor (GDNF) (Kordower 2000, Bjorklund 2000) or neurturin(Marks 2008) to promote cell survival and function. Finally, an alternative strategy is targeted at the abnormal activities of the basal ganglia, particularly the subthalamic nucleus and the internal and external segments of the globus pallidus.
4.1. Glutamate decarboxylase
It has been consistently observed that PD is associated with decreased inhibitory activity of the nigrostriatal projections, resulting in overactivity of the subthalamic nucleus and overinhibition of the thalamus. It was therefore hypothesized that, by increasing levels of locally produced γ-aminobutyric acid (GABA) in the subthalamic nucleus, these pathways could be restored to equilibrium and improve patient function. The synthetic pathway for GABA involves the catalytic action of glutamate decarboxylase (GAD) on glutamate, an enzyme found as two genetically distinct isoforms - GAD65 and GAD67 (Erlander 1991, Bu 1992). These have differing enzymatic properties, functional requirements and intracellular distributions. The first experimental study used recombinant AAV (rAAV) encoding the GAD65 and GAD67 isoforms of glutamic acid decarboxylase, with function initially characterized in vitro. Two AAV2 based constructs, AAV/rGAD65 and AAV/rGAD67 were able to productively infect cell lines, with both genes transcribed, leading to the production of enzymatically active GAD65 and GAD67 (Mi 1999).
The cDNAs were then used in a series of in vivo experiments, in which GAD65 or GAD67 were produced by rAAV with bicistronically encoded green fluorescent protein (GFP). Subsequent stereotactic injection of either vector into the STN resulted in prolonged transgene expression (monitored up to five months), with no inflammatory response seen. The cellular distribution of GAD was as expected for each isoform - with membrane restricted GAD65 and cytosolic GAD67. Stimulating electrodes were inserted into the STN, with microdialysis probes inserted into the SNr finding significantly increased release of GABA following STN stimulation in the GAD65 gene treated rats (Luo 2002). Parkinsonian 6-hydroxydopamine (6-OHDA)-lesioned rats were then injected with the viral vectors, leading to a four-fold increase in GABA release following STN stimulation. This was associated with a marked increase in the ratio of inhibitory to excitatory SNr responses. Importantly, controls (injected with GFP or saline) had unchanged responses, indicating that these results were not primarily due to local lesioning effects. GAD67 treated rats, in contrast, had a predominantly excitatory response. Additional effects and outcomes were examined, in particular potential neuroprotective effects of GAD gene administration. By pre-treating with the GAD65 containing construct prior to 6-OHDA lesioning, several functional outcomes (limb use and apomorphine-induced rotations) were significantly improved as compared to control infusions. A corresponding increased survival of tyrosine-hydroxylase positive cells was also seen in the GAD65 treated group, again suggesting a neuroprotective effect.
Subsequent studies examined the properties of the vector when injected in hemiparkinsonian macaques (Emborg 2007). In this model, MPTP is injected into the carotid artery, with subsequent injections of AAV-GAD or GFP control into the ipsilateral STN. Over the course of a 56 week period, 13 macaques (seven on active treatment, six control) were monitored, finding sustained transgene expression, improvement in clinical parameters (bradykinesia, tremor, motor skills) in GAD-treated animals and increased ipsilateral 18F-fluorodeoxyglucose (FDG) PET motor cortical glucose activity. All animals survived to the 1 year end point without significant adverse events.
Prompted by these promising results, an open label phase I trial of unilateral subthalamic viral vector injection, using an AAV2 serotype encoding human GAD65 or GAD67 under the control of a CMV promoter was performed (Kaplitt 2007). Patients recruited for the trial – the first use of gene therapy for an adult neurodegenerative disorder - were reasonably typical for idiopathic Parkinson’s disease, with a disease duration ranging from 6 to 13 years. Exclusion criteria included significant cognitive or psychiatric illness.
The protocol involved a stereotactic frame and MRI guided STN injection of a 50 μl solution of a 1 (low dose) to 10 (high dose) x1011 genomes/ml solution. Unilateral injections were performed into the most symptomatic hemisphere, leaving the contralateral side untreated. Several outcomes were examined, including safety, tolerability, Parkinson’s disease symptoms as rated by the Unified Parkinson’s Disease Rating Scale (UPDRS), and18F-fluorodeoxyglucose (FDG) PET imaging was performed in a blinded manner, at baseline and 12 months post surgery. The procedure was well tolerated, with no deaths or unexpected neurological complications during the study period. Post procedure assessments found an improvement in the UPDRS motor scores from 3 months, sustained through to 12 months post surgery. The change was located primarily to the body side contralateral to the procedure. PET imaging found a significant decline in thalamic metabolism, ipsilateral to the injection. No changes in anti-AAV and GAD65/67 antibodies were seen after surgery (Kaplitt 2007).
Although the study was small and not blinded, the procedure appeared safe and clinical outcomes were encouraging. Some definite benefits over traditional deep brain stimulation procedures include the lack of implanted hardware and theoretical benefits could include a more physiological approach to restoring motor network function through activity dependent GABA release. Findings suggest that GABA release may be subject to autoregulatory pathways involving GABAA receptors of the STN. The full conclusions of the Phase II trial were published recently (LeWitt 2011), confirming a significant improvement in the UPDRS score six months post procedure for the AAV-GAD treated group (decreasing by 8.1 points p<0.0001), although sham treated patients also improved (decreasing by 4.7 points, p<0.003). The improvement seen in AAV-GAD treated subjects was significantly greater than in sham surgery subjects (p=0.04). No additional safety issues were observed. This important trial highlighted not just the importance of including significant patient numbers (22 and 23 in the treatment and control groups respectively) to provide a significant study difference, but also the need for meticulous study design, not least in the placebo group (which included a detailed sham surgery protocol). Several important questions and issues remain to be answered, in particular (i) whether the beneficial effects will be maintained in the medium to long-term; (ii) whether there will be longer term side effects of this therapeutic approach, particularly important in a gene therapy vector in which the agent is constitutively active and; (iii) how this approach compares to more traditional ‘advanced’ therapeutic options, such as deep brain surgery (DBS).
4.2. Glial cell line-derived neurotrophic factor
Glial cell line-derived neurotrophic factor (GDNF) was characterized as a selective neurotrophic factor for dopaminergic neurons from its ability to increase dopamine uptake in midbrain cultures without effect on serotonin or gamma amino butyric acid (GABA) uptake (Lin 1993). In addition, GDNF promoted dopaminergic neuron survival, dopamine uptake, cell body size and neurite outgrowth (Lin 1993), and was therefore identified a potential therapeutic agent in PD.
Early experiments in which GDNF was stereotactically injected into MPTP treated mice (i.e remove comma after mice) found that injection of GDNF into the striatum prior to MPTP treatment was associated with preservation of dopamine levels in the substantia nigra and striatum and preserved striatal TH immunoreactive cells. Treatment with GDNF at any time point was shown to improve the motor function as assessed by locomotion, motility and rearing compared to controls (Tomac 1995).
Initial approaches to delivering sustained in vivo GDNF used a replication deficient adenovirus containing human GDNF in the rat 6-hydroxydopamine (6-0HDA) model (Choi-Lundberg 1997). Adenovirus GDNF significantly increased substantia nigra dopaminergic cell survival compared to controls, although protein and mRNA levels were not sustained and all animals had host reactions around the needle site. Subsequent experiments used stereotactically Injected GDNF encoding lentivirus in MPTP treated rhesus monkeys (Kordower 2000). Again, lentivirally injected substantia nigra displayed increased levels of TH immunoreactive neurons. In a follow-up series of experiments, animals displayed improved functional scores, with a corresponding improvement on FDG PET scanning. Importantly, and in contrast to adenoviral approaches, lentivirally encoded GDNF transgene expression was sustained for up to eight months and inflammatory responses were minimal. Possible idiosyncratic reactions were hinted at, but not detailed, which is an important omission as, for example, cerebellar toxicity has been mentioned as a limiting factor in some cases (Berry 2010). However, this approach shows promise, prompting Amsterdam Molecular Therapeutics to obtain a license to use the GDNF gene delivered via an adeno-associated virus platform.
Future trials of GDNF gene therapy will need to be performed with scrupulous attention to control subjects. Fortunately, there already exists considerable experience using continuous putaminal infusions of recombinant GDNF. Initial open-label trials were encouraging (Gill 2003, Patel 2005), finding significant improvements in UPDRS III OFF and ON scores and statistically improved FDG uptake. It was observed, however, in a separate study that the initial benefits seen at one year had returned to baseline following a one year period of treatment withdrawal (Slevin 2007). Unfortunately, the subsequent randomized control double-blinded phase I/II trial (Lang 2006) did not support the open label findings, finding only improved FDG PET appearances at 6 months compared to baseline and improved mental health as measured by the SF-36 scoring system (frequently used to rate quality of life parameters) in the actively treated group. The reasons for the differences between the results are not clear, but highlight the critical importance of study design and the use of double blinded placebo subjects, including sham operative procedures.
4.3. Neurturin
Neurturin (NTN) was first identified 15 years ago (Creedon 1997), finding sequence homology to GDNF, with similar in vitro neuroprotective properties. These were confirmed by subsequent in vivo experiments, promoting TH positive neuronal survival when injected into the substantia nigra of 6-0HDA treated animals (Horger 1998), with improvements in functional parameters. Stereotactic injection of an NTN encoding AAV vector into the caudate nucleus, putamen and substantia nigra of MPTP treated monkeys found similar benefits (Kordower 2006), with no significant side effects at three months and one year (Herzog 2008, Herzog 2009).
These promising findings led to a Phase I, open-label trial of AAV2-NTN in 2008 (Marks 2008), involving 12 patients (ages 35 to 75) with moderate to severe levodopa responsive PD. In this cohort the diagnosis was established for a minimum of 5 years, patients were on stable doses of antiparkinsonian medications, but without good control with at least 3 hours of “off” time per day. The participants were divided between low and high treatment groups and received stereotactic guided injections bilaterally throughout the putamen. Participants experienced a significant improvement in UPDRS Part III motor score in the practically defined “off” period as compared to baseline, on average an improvement of 36%. Other than a presumed air embolus, which did not lead to complications, there were no clinically important operative adverse events.
This was followed up by the first double blind randomised Phase 2 trial of gene therapy for Parkinson’s disease, published in late 2010 (Marks 2010). The 58 participants met similar eligibility criteria as the open-label study, with groups were divided 2:1 to receive either AAV-NTN or sham surgery respectively, with assessments at baseline and 1, 3, 6, 9 and 12 months and every 3 months thereafter until the final patient had been seen at 12 months. At each visit the patients were assessed with the UPDRS in the practically defined “off” state and the best “on” state. Home diary and quality of life questionnaires were also employed. The primary outcome - UPDRS Part III score in the “off” state was not significantly improved at 12 months. A range of secondary outcomes, including the mental score (Part I) in the “off” state and activities of daily living score (Part II) in the “on” state were significantly improved.
For the small number of patients followed up until 18 months the UPDRS Part III “off” score was significantly improved. Histological analysis of two patients’ brains in the treatment group revealed only limited expression of the neurturin protein in the putamen and even more modest expression in the substantia nigra. Three patients in the active treatment group developed tumours: one glioblastoma, one adenocarcinoma of the prostate and one oesophageal adenocarcinoma. Quantitative PCR of biopsied tissue was negative for AAV-NTN and retrospective reanalysis of pre-procedure MRI suggested that the glioblastoma predated the intervention. There were two deaths in the treatment group one from myocardial infarction and one from a pulmonary embolus. Headache, nausea, post-procedural pain, dyskinesa, insomnia and worsening of PD were the most commonly reported adverse events and occurred more frequently in the active treatment compared to sham surgery groups. Serious adverse events secondary to surgery occurred in both groups without subsequent lasting neurological sequelae. Neurturin protein and antibodies were not detected in patient sera.
Although the trial failed to show a significant difference in the primary endpoint, the data gathered from the study was generally informative. The reasons underlying the therapeutic failure are not clear, potentially relating to inadequate levels of neurturin at the site of pathology. Planned future work, currently recruiting, will also include direct injection into the substantia nigra as well as increased dosing (Clinical trials.gov identifier NCT00985517).
4.4. Aromatic-L-amino decarboxylase (AADC)
Production of dopamine from either endogenous or exogenous levodopa is dependent on aromatic-L-amino decarboxylase (AADC). As PD progresses, patients typically require increasing doses of L-dopa and are therefore at increased risk of medication induced side effects. It is postulated that AADC activity is depleted in PD and that therapeutic restoration of this activity may lead to clinical improvement and allow reduced doses of levodopa (Bankiewicz 2000).
In a series of in vivo experiments using MPTP-induced hemiparkinsonian rhesus monkeys, AAV-AADC was injected throughout the caudate and putamen (Bankiewicz 2000). This led to increased in vivo AADC tracer activity and immunohistochemical staining, with partial restoration of to the ability to convert levodopa to dopamine in an ex vivo assay. Improvement on a range of functional scores was seen at 24 months and a subsequent imaging experiment found increased AADC levels up to 72 months (Bankiewicz 2006).
The work prompted an ongoing clinical trial in which five patients, with levodopa responsive Parkinson’s disease and intractable motor fluctuations despite optimised medical therapy (Hoehn and Yahr stage III-IV), received bilateral putaminal infusions of 9 x 1010 vector genomes by stereotactic infusion. No adverse events were reported that were attributable to AAV-AADC infusions. FDG PET uptake was significantly increased at 6 months compared to baseline. The absence of controls in this safety study makes secondary clinical outcome interpretation difficult, although there were significant increases in 6 month total UPDRS scores on and off medication and 3 participants were able to take lower doses of levodopa (Eberling 2008).
This cohort was then compared with 5 patients who received a higher dose (3 x 1011 vector genomes) of AAV-AADC (Christine 2009). Of concern, three patients had intracranial haemorrhages, and four patients developed a transient increase in dyskinesias. In both cohorts the total UPDRS and UPDRS III scores improved at 6 months when assessed “off” medication, but no significant improvements were seen “on” medication in the UPDRS IIII score. This is odd, as the effect of AAV-AADC is thought to be dependent on levodopa therapy, although all patients in the high dose group were able to manage on lower doses of levodopa, hinting at efficacy. The study is ongoing and is expected to be completed in 2013 at which point 60 months of efficacy and safety data will be available.
4.5. Prosavin
Parkinson’s disease potentially results from deficiencies in several steps of the dopaminergic synthetic pathway in which L-tyrosine is converted to levodopa by the enzyme tyrosine hydroxylase (TH). GTP cyclohydrolase 1 (CH1) is the rate-limiting enzyme for the generation of tetrahydrobiopterin which is a co-factor for TH. Levodopa is then converted to the biologically active dopamine by AADC. In an attempt to reconstitute these steps, genes coding for TH, CH1 and AADC were combined into a single lentiviral vector for administration to the striatum (Azzouz 2002).
Functional improvements were seen in stereotactically injected 6-0HDA lesioned rats, despite an apparently relatively modest increase in dopamine levels (Azzouz 2002). Subsequent in vivo microdialysis measurement in the MPTP macaque model demonstrated a greater increase in extracellular levels, so the therapeutic efficacy may have been greater than first thought (Jarraya 2009). Treated macaques exhibited restoration of the firing rate and pattern of neurons within the basal ganglia and reduced metabolic activity within the subthalamic nucleus, coupled with functional improvements. No safety issues were noted.
Although peer reviewed data has not yet been published, preliminary results of an ongoing Phase I/II clinical trial of Prosavin have been announced. Nine patients have now received Prosavin in three cohorts of 1x dose, 2x dose and 2x dose with an improved delivery method. The first cohort has had a 20% functional motor improvement at 24 months and the second cohort a 29% improvement at 12 months. The third cohort has had a 26% improvement at 3 months. All cohorts have had in improved “ON” time, stable or improved quality of life assessments and stable or reduced levodopa dosing. Whilst these are preliminary announcements the results are encouraging and have prompted the initiation of a 5x dose cohort commencing early in 2011.
5. Conclusions
Despite decades of research, Parkinson’s disease is a chronic progressive neurodegenerative condition of unknown aetiology and the underlying pathogenesis remains unclear. Despite understandable reservations about using a gene therapy approach for the condition, several Phase I and II clinical trials have now reported their clinical findings, providing a wealth of experience and data. The use of adeno-associated vectors for gene therapy, with trials including several hundred patients, appears to be generally safe, with little procedure related morbidity.
Although there are definite concerns relating to the development of immunity to systemically administered AAV, leading to destruction of transduced tissues, this phenomenon has not been observed with CNS administration, suggesting a degree of immune privilege which may lead to more sustained therapeutic effects. Ongoing concerns relate primarily to the specific choice of therapeutic agent, site of action and levels of production. The use of non selective (particularly constitutively ‘on’) mammalian promoters such as CMV, do not permit adjustment of therapeutic effects. Current models suggest that autoregulation may occur through homeostatic feedback pathways, but this has not been demonstrated formally and long term effects on cellular phenotypes are unknown.
Ongoing monitoring of patients recruited into Phase I and II studies will be essential to establish whether initially observed benefits are sustained and to look for long term complications. Further randomized double blinded studies, with appropriate longitudinal follow-up will be necessary to properly evaluate the therapeutic effectiveness of this novel class of agents.
Further technological developments are likely, particularly involving the use of more sophisticated AAV-based viral vectors. These could use more neuron-specific promoters (eg neuron specific enolase or synapsin 1 gene promoters) and regulate protein production through the use of inducible systems (eg ecdysone-based) to control therapeutic activity in a more directed fashion. Although still in its infancy, this technology still shows great promise as a novel therapeutic approach for this devastating disease.
\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/22887.pdf",chapterXML:"https://mts.intechopen.com/source/xml/22887.xml",downloadPdfUrl:"/chapter/pdf-download/22887",previewPdfUrl:"/chapter/pdf-preview/22887",totalDownloads:1434,totalViews:260,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,dateSubmitted:"October 20th 2010",dateReviewed:"May 26th 2011",datePrePublished:null,datePublished:"November 2nd 2011",dateFinished:null,readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/22887",risUrl:"/chapter/ris/22887",book:{slug:"towards-new-therapies-for-parkinson-s-disease"},signatures:"Michael Douglas and Jonathan Hazlehurst",authors:[{id:"28309",title:"Dr.",name:"Michael",middleName:null,surname:"Douglas",fullName:"Michael Douglas",slug:"michael-douglas",email:"m.r.douglas.1@bham.ac.uk",position:null,institution:null},{id:"138116",title:"Dr.",name:"Jonathan",middleName:null,surname:"Hazlehurst",fullName:"Jonathan Hazlehurst",slug:"jonathan-hazlehurst",email:"jonathan_hazlehurst@intechweb.com",position:null,institution:{name:"University of Birmingham",institutionURL:null,country:{name:"United Kingdom"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Gene delivery to the brain",level:"1"},{id:"sec_2_2",title:"2.1. Adeno-associated viruses",level:"2"},{id:"sec_3_2",title:"2.2. Adenovirus",level:"2"},{id:"sec_4_2",title:"2.3. Herpes simplex virus",level:"2"},{id:"sec_5_2",title:"2.4. Lentivirus",level:"2"},{id:"sec_7",title:"3. Clinical trials with gene therapy vectors ",level:"1"},{id:"sec_8",title:"4. Gene therapy for Parkinson’s disease",level:"1"},{id:"sec_8_2",title:"4.1. Glutamate decarboxylase",level:"2"},{id:"sec_9_2",title:"4.2. Glial cell line-derived neurotrophic factor ",level:"2"},{id:"sec_10_2",title:"4.3. Neurturin",level:"2"},{id:"sec_11_2",title:"4.4. Aromatic-L-amino decarboxylase (AADC)",level:"2"},{id:"sec_12_2",title:"4.5. Prosavin",level:"2"},{id:"sec_14",title:"5. Conclusions",level:"1"}],chapterReferences:[{id:"B1",body:'AlvarezL.et al.\n\t\t\t\t\t2001\n\t\t\t\t\tDorsal subthalamotomy for Parkinson’s disease. 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K.et al.\n\t\t\t\t\t2005 Intraputamenal infusion of glial cell line-derived neurotrophic factor in PD: a two-year outcome study. Annals of Neurology, 57, 298302 .'},{id:"B60",body:'PedenC. S.et al.\n\t\t\t\t\t2004 Circulating anti-wild-type adeno-associated virus type 2 (AAV2) antibodies inhibit recombinant AAV2 (rAAV2)-mediated, but not rAAV5-mediated, gene transfer in the brain. Journal of Virology, 78, 63446359 .'},{id:"B61",body:'SamaniegoL. A.NeiderhiserL.De LucaN. A.\n\t\t\t\t\t1998 Persistence and expression of the herpes simplex virus genome in the absence of immediate-early proteins. Journal of Virology, 72, 33073320 .'},{id:"B62",body:'SamulskiR. J.ChangL. S.ShenkT.\n\t\t\t\t\t1989 Helper-free stocks of recombinant adeno-associated viruses: normal integration does not require viral gene expression. Journal of Virology, 63, 38223828 .'},{id:"B63",body:'SanftnerL. M.et al.\n\t\t\t\t\t2004 Striatal delivery of rAAV-hAADC to rats with preexisting immunity to AAV. 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Nature Biotechnology, 15, 871875 .'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Michael Douglas",address:null,affiliation:'
Department of Neurology, Dudley Group of Hospitals NHS Foundation Trust, Dudley, UK
School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
Department of Neurology, Dudley Group of Hospitals NHS Foundation Trust, Dudley, UK
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Ibrahimagic",authors:[{id:"79783",title:"MSc.",name:"Zikrija",middleName:null,surname:"Dostovic",fullName:"Zikrija Dostovic",slug:"zikrija-dostovic"}]},{id:"25522",title:"Employment and Mental Illness",slug:"employment-and-mental-illness",signatures:"Mary Ditton",authors:[{id:"83520",title:"Dr.",name:"Mary",middleName:"Jane",surname:"Ditton",fullName:"Mary Ditton",slug:"mary-ditton"}]},{id:"25523",title:"Workplace Functional Impairment Due to Mental Disorders",slug:"workplace-functional-impairment-due-to-mental-disorders",signatures:"Charl Els, Diane Kunyk, Harold Hoffman and Adam Wargon",authors:[{id:"88250",title:"Dr.",name:"Diane",middleName:null,surname:"Kunyk",fullName:"Diane Kunyk",slug:"diane-kunyk"},{id:"88336",title:"Dr.",name:"Charl",middleName:null,surname:"Els",fullName:"Charl Els",slug:"charl-els"},{id:"127699",title:"Dr.",name:"Harold",middleName:null,surname:"Hoffman",fullName:"Harold Hoffman",slug:"harold-hoffman"}]},{id:"25524",title:"Early Intervention in Psychiatry Challenges & Opportunities",slug:"early-intervention-in-psychiatry-challenges-opportunities",signatures:"Mamdouh El-Adl",authors:[{id:"78667",title:"Dr.",name:"Mamdouh",middleName:null,surname:"El-Adl",fullName:"Mamdouh El-Adl",slug:"mamdouh-el-adl"}]},{id:"25525",title:"Lost in the Social World: How Social Cognitive Deficits Affect Social Functioning of People with Asperger Syndrome",slug:"lost-in-the-social-world-how-social-cognitive-deficits-affect-social-functioning-of-people-with-aspe",signatures:"Mónica Figueira, Inmaculada Fuentes and Juan C. Ruiz",authors:[{id:"79146",title:"Dr.",name:"Inma",middleName:null,surname:"Fuentes",fullName:"Inma Fuentes",slug:"inma-fuentes"},{id:"81271",title:"Prof.",name:"Mónica",middleName:"Martins",surname:"Figueira",fullName:"Mónica Figueira",slug:"monica-figueira"},{id:"81272",title:"Prof.",name:"Juan Carlos",middleName:null,surname:"Ruiz",fullName:"Juan Carlos Ruiz",slug:"juan-carlos-ruiz"}]},{id:"25526",title:"Bibliotherapy for Chinese Patients with Depression in Rehabilitation",slug:"bibliotherapy-for-chinese-patients-with-depression-in-rehabilitation",signatures:"Yang Wang",authors:[{id:"82369",title:"MSc.",name:"Yang",middleName:null,surname:"Wang",fullName:"Yang Wang",slug:"yang-wang"}]},{id:"25527",title:"Suicidal Cut Throat Injuries: Management Modalities",slug:"suicidal-cut-throat-injuries-management-modalities",signatures:"Adeyi A. Adoga",authors:[{id:"77636",title:"Dr.",name:"Adeyi",middleName:"A.",surname:"Adoga",fullName:"Adeyi Adoga",slug:"adeyi-adoga"}]},{id:"25528",title:"Selfhood: A Theory-Derived Relational Model for Mental Illness and Its Applications",slug:"selfhood-a-theory-derived-relational-model-for-mental-illness-and-its-applications",signatures:"Luciano L’Abate and Mario Cusinato",authors:[{id:"77359",title:"Prof.",name:"Luciano",middleName:null,surname:"LAbate",fullName:"Luciano LAbate",slug:"luciano-labate"},{id:"108745",title:"Dr.",name:"Mario",middleName:null,surname:"Cusinato",fullName:"Mario Cusinato",slug:"mario-cusinato"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"65634",title:"Newer Modalities in the Treatment of Type 2 Diabetes Mellitus: Focus on Technology",doi:"10.5772/intechopen.84285",slug:"newer-modalities-in-the-treatment-of-type-2-diabetes-mellitus-focus-on-technology",body:'\n
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1. Introduction
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During the past 30 years, there has been significant advances in technology for the treatment of patients with Diabetes Mellitus. Most of these advances have focused on patients with Type 1 diabetes mellitus. The perception has been that individuals with Type 2 diabetes mellitus have not needed these advances or that they are not appropriate for a population that does not always require insulin.
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Type 2 diabetes mellitus is a disease which is multifactorial: linked to metabolic derangements, Obesity, dietary behavior along with lifestyle issues particularly those individuals who are Sedentary [1, 2]. Given these factors, technology has been considered as adjunct therapeutic modalities to use in addition modification of diet, education, medications and lifestyle changes.
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2. Insulin pump therapy (CSII)
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Continuous Subcutaneous Insulin Infusion (CSII) has been utilized since the 1970s for the treatment of Diabetes Mellitus. The first insulin pumps were extremely large and bulky. Dr. Arnold Kadish devised a backpack insulin pump in the 1960s, but it proved to be less than optimal for everyday use. Dean Kamen in the late 1970s developed a more practical portable insulin pump which was eventually produced by Baxter called the Auto Syringe. This was the initial insulin pump that this author utilized in the early 1908s. Insulin pumps have evolved significantly over the past 40 years becoming smaller, more precise in the delivery of insulin doses and more reliable than their older versions [3]. During the 1980s to early 2000s, there were several companies providing insulin pumps to the public. Due to varying factors, these companies ceased production and in the late 2000s, there were only 4–5 companies in the US. As of 2018, there are only three large companies still functioning in the USA: Medtronic Diabetes, Omnipod and Tandem. There are several more companies in Europe that are providing insulin pumps. In the future there may be additional entries into the US market from other companies. Patch pumps are of particular interest to many individuals with DM.
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The use of continuous subcutaneous insulin infusion as a primary therapy for Type 2 DM patients has been investigated for the past 40 years. It has been utilized in various patient groups, including those who have newly diagnosed Type 2 DM. It is noted that individuals with Type 2 DM have poor to average control [4].
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Multiple uncontrolled studies from 2008 to 2013 evaluated insulin pump therapy (CSII) in patients with Type 2 diabetes mellitus. The various studies indicated switching to CSII therapy led to improved glucose control generally, reduction in daily insulin doses compared with conventional Multiple Dose Injection therapy (MDI) and improved patient satisfaction [5]. These studies were conducted in various entities- Clinical Research Centers, Hospital outpatient clinics and small private outpatient offices.
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Random Clinical Trials evaluating the efficacy of CSII therapy versus conventional MDI have been conducted and published since 1991 [6, 7, 8, 9, 10, 11, 12, 13]. Many of these earlier studies were shorter ranging from 16 to 32 weeks and showed minimal benefit of one modality over the other.
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The OpT2mise trial included a large heterogeneous population noted significant benefit compared with MDI with lower HbA1C levels, decrease in insulin requirement and no significant change in weight and no change in hypoglycemic events. This was a large scale multi center international trial which compared the efficacy of CSII therapy to intensive MDI therapy in patients who were not able to reach HbA1C goals despite intensified MDI regimens. This was a randomized parallel group study encompassing a run-in phase, 6-month randomized phase and a 6-month continuation phase. To continue in the trial a minimum of 3 measurements of glucose per day was required [14].
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The study noted that CSII therapy significantly improved blood glucoses in patients when compared with MDI regimens (~ mean difference was 0.7%). There was a 20% decrease in the total insulin dose per day with little or no change in hypoglycemic events or weight gain. Additionally, these results also indicate that selection of the proper individual for CSII treatment is paramount. The study also noted that ~ 38% of patients in the CSII treatment arm had mild cognitive impairment. Patients with such impairments can successful implement CSII therapy with proper training and education.
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This landmark study of CSII in Type 2 DM individuals does has some notable limitations. Patients with insulin resistance utilizing greater than 220 units per day were excluded. This is a large population which is increasing, and further large studies need to be considered. The study did not include individuals utilizing concentrated forms of insulin (U-200 and U-500).
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Additionally, the study does not take in account the availability of continuous glucose monitoring and depended on serum blood glucose (SBG) monitoring. With the advent of flash glucose monitoring and advances in continuous glucose monitoring (CGM) discussed in another part of this chapter, additional studies comparing CSII and MDI in these patients may be warranted.
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At present, the CSII systems available for patients with Type 2 DM include pumps with sensor combinations that have the ability to suspend delivery if the sensor notes low glucose [15].
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These systems are presently the only ones approved for patients with Type 2 DM.
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Future advances in CSII use for Type 2 DM could include the use of the hybrid closed loop system which now available for Type 1 DM individuals. The Medtronic hybrid closed loop system is the only one currently available. This system automatically adjusts the basal delivery every 5 minutes based on sensor readings. The system attempts to maintain glucose levels to an assigned target [16]. This form of CSII therapy functions with two different modes: Auto mode which uses an algorithm to respond to glucose levels. Manual mode is similar to previous pump-sensor combinations and requires preset basal rates by the individual in conjunction with his/her physician. Both systems still require manual meal bolus (MB) administration and manual correction for consistently elevated glucoses. Other companies are presently testing their versions of closed loop hybrid systems which may be available in the near future [17].
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Patient with extreme insulin resistance have been at a disadvantage utilizing CSII therapy due to the restricted capacity of the pumps (either 180 units, 200 units, 300 units). One company in Europe has developed small insulin pumps with 500 unit and 800-unit capacity though this system is presently not available in the United States [18]. Physicians have resorted to utilizing U-500 in the pumps to decrease the frequency of site and pump changes. Several studies have noted the efficacy and improvement in quality of life with the use of U-500 in CSII therapy [19, 20]. Additional attempts to improve glucose control, quality of life, decreasing insulin requirements for Type 2 patients has led to use of so called “double pump” systems, utilizing insulin in 1 pump and pramlintide in an additional pump. Results in a small non-double-blind placebo-controlled observational study indicated a 10–20% decrease in insulin requirements, improvement in glucose control, weight loss and significant improvement in quality of life [21]. Limitations included the ability to obtain supplies for two separate pumps and utilization of pramlintide as this medication in vials was discontinued by the manufacturer at the direction of the FDA.
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CSII therapy has been considered an improvement over traditional MDI therapy due to multiple factors: (1) There is predictable absorption of insulin. MDI which traditional requires injection of larger doses of insulin will form a depot and generally less efficacious in absorption and metabolic activity compared with CSII which involves smaller volumes [13]. Both the basal rate and meal bolus with CSII can be utilized with more precise insulin increments (tenths or hundredths of units). (2) Patients using CSII therapy appear to have increased satisfaction with this form of insulin therapy compared with traditional MDI injections. Based on personal observation and previous studies, patients find CSII more convenient for their lifestyle, easier to utilize after being trained and more likely to adhere to the treatment regimen. There is less likelihood of omitting (forgetting) their dose of insulin as compare with MDI. Peyrot et al. noted that patients record regular omission of insulin injections [22]. Personal observation of patients within my practice regularly indicates individuals utilizing MDI regularly admit missing meal time insulin injections. Those using CSII therapy note that since the insulin pump is attached and readily available, along with various alarm reminders missing doses is minimal. (3) The ability to download information from insulin pumps to websites (each pump has its own download capability which can cause increase work for the physician) can facilitate more efficient data collection and an ability to change the treatment regimen between patient visits.
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Given the advantages of CSII therapy over MDI therapy, it would appear that CSII therapy should be considered for individuals with Type 2 DM as it is now considered for patients with Type 1 DM. However, cost effectiveness in several health systems has not been completely demonstrated. Current policies in many health systems are varied and the ability for patients to obtain access to CSII therapy may be limited.
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3. Continuous glucose monitoring (CGM)
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Continuous glucose monitoring or CGM was first available for research projects in the 1970s.
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Miles Laboratories in the late 1970s developed the Biostator which was large, bulky and required IV access. It had little use in everyday clinical practice, due to its size, need for constant supervision, IV access and waste of blood in order to measure glucose levels [23, 24].
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In 2002, the GlucoWatch Biographer was introduced. It was shaped like a watch, similar to the Apple Watches of today. It adhered to the skin and used interstitial fluid to measure glucose levels every 10 minutes for 13 hours. [25]. See Figure 1.
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Figure 1.
GlucoWatch Biographer 2.
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Due to its process reverse iontophoresis, the GlucoWatch had significant drawbacks. It was painful for many individuals, had accuracy issues and was difficult particularly in warmer climates with individuals sweating. The Autosensor, which was replaced every 13 hours had caused skin changes and irritation in many patients. Eventually the GlucoWatch was discontinued in late 2007. It did, however, pave the way for the CGM systems of today.
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The current CGM systems use an enzymatic modality that reacts with interstitial fluid glucose and transfers it to an electrode. The electrical current that is generated is then relayed to a reader via Bluetooth wireless or an app on a smart phone which displays the results to the individual. The data can also be downloaded to a computer. Additionally, the information can be stored to the cloud and relayed to the physician or caregiver via a secure website [26].
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It must be noted that interstitial glucose measurements can lag 5–15 minutes behind blood glucose measurements particularly if there is rapid variability [27, 28]. Previously, CGM systems required calibrations twice per day which introduced a perceived limitation particularly for individuals who wished to limit “finger sticks” as an incentive to move to CGM systems.
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The newer versions of CGM to include the DEXCOM G6, Guardian 3 and a flash form of CGM, the FreeStyle Libre (10-day and 14-day systems) have decreased the necessity of frequent calibrations.
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In recent years, there have multiple studies with CGM involving individuals with Type 2 diabetes mellitus. The focus has been efficacy, the effect of CGM with regards to hypoglycemia and glucose variability [29]. A study conducted by Vigersky et al. with patients utilizing diet, lifestyle vs. other combinations of oral agent therapy with or without basal insulin noted a reduction of mean unadjusted HbA1C of 1.0% vs. 0.5% in the SMBG group at week 12 and 0.8% vs. 0.2% at week 52. This occurred without intensification of medication or an increase in hypoglycemic episodes [29]. An additional study by Fonda et al. noted even an intermittent use of CGM may be appropriate for motivating individuals or helping to avoid “burnout” [30, 31].
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The DiaMonD study (Daily Injections and Continuous Glucose Monitoring in Diabetes) study was a 6-month randomized control trial that compared the effectiveness of CGM to SMBG in individuals using MDI (multiple daily injections). This included both Type 1 and Type 2 DM patients. The results of the 6-month trial for Type 2 patients was published in 2017 and noted the following: Type 2 DM individuals after 24 weeks using CGM had an average 0.8% reduction in HbA1C levels compared with baseline. Those with higher A1C levels noted the greatest reduction with a group starting with A1C levels greater than 9.0% noting an average 1.4% reduction from baseline. Those using CGM had an increase in time spent in the target range compared with the control group (those only using SMBG). The A1C reductions occurred with minimal changes in insulin doses, little or no change in regimen or addition of non-insulin medications [32].
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CGM has also been useful in recognizing previously undetectable episodes of hypoglycemia. Studies conducted by Zick et al.; Pazos-Couselo et al.; Klimontov and Myakina all noted a significant higher percentage of hyperglycemic episodes observed with the use of CGM compared with SMBG use.
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The use of CGM particularly in older individuals utilizing insulin therapy has noted significantly higher incidences of nocturnal hypoglycemia compared with those utilizing only CGM. This indicates that CGM can be useful in high-risk Type 2 DM populations such as the elderly, those with special needs and individuals that have difficulty utilizing HGM such as severe arthritic conditions, vascular issues, etc. [33, 34, 35, 36].
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CGM is also a tool to assess glucose variability. This has become important in outcome measurements recently in addition to the standard A1C levels. The INITIATION study which tested an insulin initiation algorithm in Type 2 DM patients used CGM in 78 patients who were followed for 24 weeks. The results noted that insulin initiation reduced hyperglycemia but not glucose variability [37, 38]. The FLAT-SUGAR study which randomized 102 patients who were on metformin and basal/bolus insulin to either maintenance with basal/bolus therapy for changing the basal insulin to GLP-1 therapy. The drug used with this study of 26 weeks was exenatide BID. Using CGM it was noted that the GLP-1 group had lower variability of glucose as measured by the coefficient of variation. Of note with this study, A1C levels or episodes of hypoglycemia did note change significantly between the treatment groups [39, 40, 41].
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These studies and others both past and presently being conducted have shown the CGM use in patients with Type 2 DM can improve A1C levels, detect risk of hypoglycemia which is not clinically apparent, particularly nocturnally and may be able to assess and address glucose variability.
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There are two forms of CGM presently available for use in clinical practice: (1) Professional CGM and (2) Personal CMG. Professional CGM is placed in the physician office and does not require the patient to obtain or purchase a system. It is a blinded system in many instances, that is, the patient has no access to the results immediately and must wait for the CGM to be downloaded in the physician’s office, analyzed and then informed of the results. These systems can be worn for 3, 7 or 14 days, though generally the 7- or 14-day systems are more popular today. The systems available today in the United States for professional use are: the DEXCOM Professional system, the FreeStyle Libre Pro system, Medtronic iPro 2 system. Most of these systems do require additional calibration. Once the study is completed, the data is downloaded to either the cloud or a specific program on the computer and then can be reviewed by the physician or allied health provider in conjunction with the physician and then shared with the patient. The blinded system can be helpful in regards that the patient is not responding during the time of the study but continuing their usual habits to include diet, activity and medications. Reimbursement for use of Professional CGM has improved over the past several years particularly in the United States. Requirements as the reporting of CGM results can vary among the different health plans which can lead to limitations in its use.
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Personal CGM consists of an individual obtaining a system which is unblinded and provides blood glucoses every 5+ minutes for DEXCOM and Guardian 3 systems. These systems are placed subcutaneously and have alarms with notify the patient when certain patterns or thresholds are detected. There are multiple threshold alarms, rate of change alarms, predictive alarms. Predictive alarms are useful in that it permits the individual to take preventative action rather than corrective action. However, the downside of these alarms is that there can be false positives and false negatives. This can lead to so-called “alarm fatigue” [42]. Individuals will in many instances either ignore or silence the systems due to the multitude of alarms. In some cases, they will abandon CGM altogether. The DEXCOM G5–6 system is the only CGM device at present that is approved by the FDA for a non-adjunctive indication. It can be considered a therapeutic CGM, allowing individuals and physicians to modify therapy based solely on the readings and trends.
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The FreeStyle Libre system utilizes a flash monitoring system. It is placed like the other CGM systems subcutaneously but provides glucose results when the CGM is scanned. Thus, the results are intermittent depending on the frequency of scanning by the patient [43]. The newest of the FreeStyle Libre systems, the 14-day unit improves over the older 10-day system with a 1-hour warm up period compared with 12 hours. Several randomized controlled trails note that the use of flash CGM with the Libre system reduced hypoglycemia, increased the time in target range and reduced glucose variability [44, 45] Studies and personal observation have also shown higher device utilization. This may be due to the simplicity of application and ease of use. The use of this system in increasing and may prove to be an asset particularly in individuals who may not need the sophistication of the more complex CGM system but want the benefit of CGM and not have to consistently perform SMBG or finger sticks.
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Additional studies in Europe have shown the cost effectiveness of CGM in the management of patients with Type 2 DM receiving intensive MDI regimens and also improvement in the detection and avoidance of hypoglycemia in individuals with Type 2 DM [46, 47].
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Another technological advance in CGM has been the development and approval of the implantable CGM system by Senseonics called the Eversense System. The system consists of an implantable cylindrical sensor 3.5 mm × 18.3 mm in size. This is implanted by the physician every 90 days in the upper arm area under the skin. When the system in activated, it measures interstitial glucose levels every 5 minutes. The data is transferred to a battery powered transmitter that is worn externally over the sensor. The external transmitter also provides alerts similar to other CGM systems for impending hypo or hyperglycemia. The transmitter needs to be recharged for ~15 minutes every other day. The sensor is explanted, and a new sensor implanted every 90 days. A 180-day sensor is being developed for the future.
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Several studies have shown the accuracy and acceptability of an implantable glucose sensor. The PRECISE and PRECISE II studies noted that the Eversense system was safe and provided accurate glucose results during the 90-day sensor life [48, 49]. An additional study in the UK and Germany comprising a subgroup of individuals in the PRECISE trial who were administered quantitative psychosocial assessments that included the Diabetes Distress Scale (DDS), CGM Impact Scale and a bespoke device satisfaction questionnaire. The results of the sub study indicated that an implantable CGM was acceptable to most of the participants and the majority of users both first time to CGM or previous CGM users would continue to use an implantable CGM to manage their glucoses and DM more effectively [50].
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As the accuracy of CGM improves, particularly in the hypoglycemia range, the acceptance should also increase. However, at this time, CGM still does not, in the eyes of the regulatory agencies substitute fully for conventional SBGM. With continued development and use, it appears that eventually CGM, with or without CSII therapy will become the “standard of care” for both Type 1 and Type 2 diabetes mellitus.
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4. Smart pen systems
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Most individuals with DM, particularly Type 2 DM, who utilize insulin therapy are using insulin pen systems to deliver their daily insulin dose. Previous administration of insulin via syringe and vial has been difficult to administer and master. Additionally, accuracy of dose has been questioned. Insulin pens are one of the most widely used devices worldwide in DM treatment and care [51].
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A recent review of the literature and meta-analysis noted that insulin pen devices noted improvement in patient adherence and persistence with their treatment regimen. Hypoglycemia was noted to be reduced, with a possible improvement in dose accuracy in pen devices. However, these studies were limited, and the authors of the meta-analysis recommended additional larger scale studies [52].
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Additionally, there is the issue of documentation of insulin doses. Many patients do not record the time and dose of insulin consistently. Many will state that they took their insulin with meals, nighttime, for correction of their glucose, etc. but will not be able to provide accurate documentation. Therefore, this can be a significant barrier to glycemic control. Guidelines developed by various organizations make no mention of the need to record insulin dose administered and timing of injection whether the patient uses pen or syringe/vial.
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In December 2017, the FDA approved the first smart pen system in the US. This insulin pen system records the dose of insulin and time of injection and transmits the data via Bluetooth to a mobile application that is downloaded on the patient’s smart phone. The mobile app has the capability of dose calculation and less than whole number units which conventional insulin pens are not able to deliver.
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It can also inform the individual how much insulin is on board (IOB) similar to CSII devices. This data is stored on the individuals’ smart phone and can be brought easily to the clinical visit for analysis by the physician/health care provider.
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There may an additional entry in this area. Bigfoot Biomedical is developing an insulin smart pen that will connect to the FreeStyle Libre system. It will be controlled with a mobile app and hopefully adjust long and short acting insulin doses without manual input [53].
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The benefits of a smart pen system in the treatment of individuals with DM can be summarized as follows:
Improvement in poor adherence to the treatment regimen and omission of insulin doses.
Having the data readily available and reminders on their phone can provide an extra incentive to be more compliant with their regimen.
Improvement with the risk of insulin dose errors. Access to dosing and timing of insulin can facilitate more accurate doses and limit the risk of accidental overdose or under dosing.
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This being a relatively new technology, these devices will need to demonstrate improvement in clinical and QOL (Quality of Life) outcomes, cost effectiveness, ease of training and use. However, many of the technologies discussed above have underwent the same scrutiny. The issue of cybersecurity as with any connected DM devices will need to be resolved to maintain patient confidentiality and integrity of the data. Smart pens may be an alternative to individuals who do not want CSII therapy for a multitude of reasons but would like to intensify their regimen and have access to appropriate dosing and timing of insulin to improve their glucose control.
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5. Mobile and computer applications (apps)
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Data Management software for diabetes has been available since the late 1980s to early 1990s. However, acceptance and adoption by both patients and physicians has been slow. The issues have been the ability to download or upload data with each device having its own set of software and cable connections. In many cases, physician offices had upwards of 6–10 different connections to obtain data from SMBG meters and other devices.
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Over the past two decades, a number of innovations were developed that “streamlined” the ability to obtain data from patient devices. There has been an improvement in device connectivity with most devices now able to utilize Bluetooth technology thus eliminating the need for multiple cables or hubs. Additionally, smartphone technology has decreased the cost and complexity of data sharing. The use of automated uploads from devices to the “cloud” has allowed both patient and physician to have almost real-time access to data [53].
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Proprietary cloud data platforms from multiple device manufacturers have been able to provide secure data and have developed common formats, easing the burden on physicians and their offices to maintain multiple programs. Also, many of the device companies, including those manufacturing SMBG devices have developed complex reporting capabilities that have been designated as Ambulatory Glucose Reports or Profiles.
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The multitude of apps for the patient with DM has led to concerns of quality and safety. Apps available at both the Google Play store and Apple App Store may little or no oversight. A recent study in 2016 found that the majority of apps from the Google Play store did not meet the minimum requirements or did not work appropriately [54, 56] Additional studies are needed to fully investigate the efficacy and utility of mobile applications with regard to the treatment of individuals with Type 2 DM.
\n
Another approach is to combine the mobile application, the cloud with a remote coaching system. Studies are now ongoing to assess the effect of individuals using a smart phone-based glucose monitoring system which automatically moves data to a secure cloud-based site [55]. A designated “diabetes coach” which is a health care provider (RN, NP or physician) then reviews the data several times per week and remotely connects with the patient to provide recommendations or discussion. Results are pending in these studies and hopefully preliminary results will be available in 2019. (Personal Observation).
\n
The use of Artificial Intelligence (AI) in the treatment of patients with Diabetes is emerging and advancing at significant pace. Multiple programs are being developed to improve adherence and personalize the individual’s regimen. Studies are ongoing to determine whether pattern recognition and the ability of machine learning can provide the patient with diabetes mellitus a unique, individualize model which is automated and can assist with predictions and decisions. At this time, AI cannot and does not substitute for patient – physician interaction and communication.
\n
\n
\n
6. Conclusion
\n
This chapter attempted to briefly outline the technological advances in the treatment of Type 2 diabetes mellitus. It is noted the technology has improved the quality of life, blood glucose control and possibly decreased the risk of complications. However, it must be pointed out to the reader that technology, no matter how advanced, does not substitute for personal interaction with patients. The ability to know your patient, his/her lifestyle, stressors, etc. plays an important role in designing the proper treatment regimen. Continued advances in technology will in the future make the physician/healthcare provider and the patient’s ability to control his/her blood glucoses less complicated but ultimately the decisions to maintain diet, exercise, monitoring of glucoses remains with the individual.
\n
\n
Conflicts of interest
The author notes that he is a member of the DSMB and CEC for Medtronic Diabetes and serves on the Speaker’s Bureau for Sanofi and Astra Zeneca.
\n
Notes/thanks/other declarations
\n
The author wishes to thank his wife for assisting in the research for this chapter and his associate and staff for permitting him to devote extra time from the practice to complete this endeavor.
\n
\n',keywords:"CSII-continuous subcutaneous insulin infusion, CGM-continuous glucose monitoring, HbA1C, MDI-multiple dose injection, smart pen",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/65634.pdf",chapterXML:"https://mts.intechopen.com/source/xml/65634.xml",downloadPdfUrl:"/chapter/pdf-download/65634",previewPdfUrl:"/chapter/pdf-preview/65634",totalDownloads:628,totalViews:0,totalCrossrefCites:0,dateSubmitted:"September 7th 2018",dateReviewed:"January 10th 2019",datePrePublished:"February 21st 2019",datePublished:null,dateFinished:null,readingETA:"0",abstract:"This chapter will focus on the technological advances for individuals with Type 2 diabetes mellitus and their effect on treatment, control of blood glucoses and possible improvement in lifestyle and decreasing complications. This is a general overview of technological improvements and not an outline for specific patient care. 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Comparison of continuous blood glucose measurement with conventional documentation of hypoglycemia in patients with type 2 diabetes on multiple daily insulin injection therapy. Diabetes Technology & Therapeutics. 2007;9:483-492\n'},{id:"B34",body:'Pazos-Couselo M, Garcia-Lopez JM, Gonzalez-Rodriquez M, et al. High incidence of hypoglycemia in stable insulin treated type 2 diabetes mellitus: Continuous glucose monitoring vs. self-monitored blood glucose. Observational prospective study. Canadian Journal of Diabetes. 2015;39:428-433. DOI: doi.org/10.1016/j.jcjd.2015.05.007\n'},{id:"B35",body:'Klimontov VV, Myakina NE. Glucose variability indices predict the episodes of nocturnal hypoglycemia in elderly type 2 diabetic patients treated with insulin. Diabetes and Metabolic Syndrome: Clinical Research and Reviews. 2017;11:119-124\n'},{id:"B36",body:'Gomez AM, Umpierrez GE, Munoz OM, et al. 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Flat Sugar Trial Investigators: Glucose variability in a 26-week randomized comparison of mealtime treatment with rapid-acting insulin versus GLP-1 agonist in participants with type 2 diabetes at high cardiovascular risk. Diabetes Care. 2016;39:973-981. DOI: 10.2337/dc15-2782\n'},{id:"B40",body:'Xu F, Zhao L-H, Su J-B, et al. The relationship between glycemic variability and diabetic neuropathy in type 2 diabetes with well controlled HbA1c. Diabetology & Metabolic Syndrome. 2014;6:139\n'},{id:"B41",body:'Sartore G, Chilelli NC, Burlina S, Lapolla A. Association between glucose variability as assessed by continuous glucose monitoring (CGM) and diabetic retinopathy in type 1 and type 2 diabetes. Acta Diabetologica. 2013;50:437-442\n'},{id:"B42",body:'Shivers JP et al. “Turn it off!”; diabetes device alarm fatigue considerations for the present and the future. Journal of Diabetes Science and Technology. 2013;7(3):789-794\n'},{id:"B43",body:'Kudva YC, Ahmann AJ, Bergenstal RM, Gavin JR III, Kruger DF, Midyett LK, et al. Approach to using trend arrows in the FreeStyle Libre flash glucose monitoring Systems in Adults. Journal of the Endocrine Society. 2018;2(12):1320-1337. DOI: 10.1210/js.2018-00294\n'},{id:"B44",body:'Bolinder J, Antuna R, Geelhowed-Duijvestijn P, Kroder J, Weitgasser R. Novel glucose-sensing technology and hypoglycaemia in type 1 diabetes. A multicenter, non-masked randomized controlled trial. Lancet;388(10057):2254-2263. DOI: 10.1016/S0140-6736(16)31535-5\n'},{id:"B45",body:'Haak T, Hanaire H, Ajjan R, Hermanns N, Riveline JP, Rayman G. Flash glucose-sensing technology as a replacement for blood glucose monitoring for the management of insulin-treated type 2 diabetes: A multicenter open-label randomized controlled trial. Diabetes Therapy. 2017;8(1):55-73. DOI: 10.1007/s13300-016-0223-6\n'},{id:"B46",body:'Bilir SP, Hellmund R, Wehler E, Li H, Munakata J, Lamotte M. The cost-effectiveness of flash glucose monitoring system for management of patients with type 2 diabetes receiving intensive insulin treatment in Sweden. European Endocrinology. 2018;14(2):80-85. DOI: 10.17925/EE.2018.14.2.80\n'},{id:"B47",body:'Adolfsson P, Rentoul D, Klinkenbiji PCG. Hypoglycemia remains the key obstacle to optimal Glycemic control-continuous glucose monitoring is the solution. European Endocrinology. 2018;14(2):50-56. DOI: 10.17925/EE.2018.14.2.50\n'},{id:"B48",body:'Kropff J, Choudhary P, Neupane S, Barnard K, Bain S, Kapitza C, et al. Accuracy and longevity of an implantable continuous glucose sensor in the PRECISE study: A 180-day, prospective, Multicenter, pivotal Trial. Diabetes Care. 2017;40:1-6. DOI: 10.2337/dc16-1525\n'},{id:"B49",body:'Christianson MP, Klaff LJ, Brazg R, Chang AR, Levey CJ, Lam D, et al. 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DOI: 10.1177/1932296816633721\n'},{id:"B53",body:'Baily TS, Walsh J, Stone JY. Emerging technologies for diabetes care. Diabetes Technology & Therapeutics. 2018;20(s2):78-84. DOI: 10.1089/dia.2018.0115\n'},{id:"B54",body:'Coughlin SS. Mobile technology for self-monitoring of blood glucose among patients with type 2 diabetes mellitus. mHealth. 2017;3:47-50. DOI: 10.21037/mhealth.2017.10.03\n'},{id:"B55",body:'Brzan PP, Rotman E, Pajnkihar M, et al. Mobile applications for control and self-management of diabetes; a systematic review. Journal of Medical Systems. 2016;40:210. DOI: 10.1007/s10916-016-0564-8\n'},{id:"B56",body:'Huang Z, Soljak M, Boehm BO, Car J. Clinical relevance of smartphone apps for diabetes management: A global overview. Diabetes/Metabolism Research and Reviews. 2018;34:e2990. DOI: 10.1002/dmrr.2990\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Alan B. Schorr",address:"abs@sugardoc.com",affiliation:'
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