Characteristics of viral vectors for gene therapy
\\n\\n
Dr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\\n\\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\\n\\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\\n\\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\\n\\nThank you all for being part of the journey. 5,000 times thank you!
\\n\\nNow with 5,000 titles available Open Access, which one will you read next?
\\n\\nRead, share and download for free: https://www.intechopen.com/books
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Preparation of Space Experiments edited by international leading expert Dr. Vladimir Pletser, Director of Space Training Operations at Blue Abyss is the 5,000th Open Access book published by IntechOpen and our milestone publication!
\n\n"This book presents some of the current trends in space microgravity research. The eleven chapters introduce various facets of space research in physical sciences, human physiology and technology developed using the microgravity environment not only to improve our fundamental understanding in these domains but also to adapt this new knowledge for application on earth." says the editor. Listen what else Dr. Pletser has to say...
\n\n\n\nDr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\n\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\n\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\n\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\n\nThank you all for being part of the journey. 5,000 times thank you!
\n\nNow with 5,000 titles available Open Access, which one will you read next?
\n\nRead, share and download for free: https://www.intechopen.com/books
\n\n\n\n
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Ashraf",coverURL:"https://cdn.intechopen.com/books/images_new/8268.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"199287",title:"Dr.",name:"Ghulam Md",middleName:null,surname:"Ashraf",slug:"ghulam-md-ashraf",fullName:"Ghulam Md Ashraf"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"9536",leadTitle:null,title:"Education at the Intersection of Globalization and Technology",subtitle:null,reviewType:"peer-reviewed",abstract:"
\r\n\tOur rapidly shrinking, interconnected world is experiencing an unprecedented change in the face of digital innovation and emerging globalization. As the world’s population spirals beyond 7.7 billion, international economies are becoming more integrated and mutually dependent upon one other. These interconnected economies are subject to political, social, and cultural expectations unimagined in past decades. Employee skill sets that were in high demand only a few decades ago are now considered obsolete and unnecessary. New occupations are evolving in the face of digital advancement only to be quickly replaced by other emerging occupations more suitable to satisfying transitioning expectations. The changes are endless. Educational systems can no longer educate for today’s jobs. They must educate for tomorrow’s jobs. They must empower the future of their national economies while remaining mindful of the needs of tomorrow’s global economy. They stand at the intersection of globalization and technology. The only thing certain is change.
\r\n\r\n\tThis book is intended to examine the educational issues encountered in such an environment. The book aims to afford a fresh examination of theory, research, and practice into this field of study and to provide the reader with an insight into the challenges, successes, and opportunities encountered by today’s educational institutions.
",isbn:"978-1-83962-470-4",printIsbn:"978-1-83962-469-8",pdfIsbn:"978-1-83962-471-1",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"0cf6891060eb438d975d250e8b127ed6",bookSignature:"Dr. Lee Waller, Dr. Sharon Waller, Dr. Vongai Mpofu and Dr. Mercy Kurebwa",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/9536.jpg",keywords:"Global Skill Sets, Career Development, International Networking, Adult Education, World Education Culture, Modernization, International Standards, Educator Preparation, Educational Technology, Educational Impact, Curriculum Development, Sociocultural Issues",numberOfDownloads:613,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"June 10th 2020",dateEndSecondStepPublish:"July 1st 2020",dateEndThirdStepPublish:"August 30th 2020",dateEndFourthStepPublish:"November 18th 2020",dateEndFifthStepPublish:"January 17th 2021",remainingDaysToSecondStep:"7 months",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:"Prof. Lee Waller completed a Ph.D. in Higher Education Administration from the University of North Texas, he spent 17 years in the American community college system and served for 9 years at Texas A&M University-Commerce before joining the AURAK family.",coeditorOneBiosketch:"Dr.Sharon Waller spent 13 years at a Sherman Independent School District where she served as an educational diagnostician, curriculum coordinator, and teacher, her teaching and research focus on special education, strategic educational leadership, and effective assessment of student learning.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"263301",title:"Dr.",name:"Lee",middleName:null,surname:"Waller",slug:"lee-waller",fullName:"Lee Waller",profilePictureURL:"https://mts.intechopen.com/storage/users/263301/images/system/263301.png",biography:"Prof. Lee Waller completed a Ph.D. in Higher Education Administration from the University of North Texas. He earned his BS in Education and MS in Mathematics from Stephen F. Austin State University in Nacogdoches, Texas. Prof. Lee spent 17 years in the American community college system and served for 9 years at Texas A&M University Commerce before joining the AURAK family. Prof. Waller’s teaching and research focus on digital learning, strategic educational leadership, and effective assessment of student learning. Prof. Waller was recently awarded (2014) the Effective Practice Award for Excellence in the Utilization of Emerging Technology by the Online Learning Consortium (formerly Sloan-C). He was also awarded (2012) the Excellence in Teaching Award by Sigma Alpha Pi, The National Society of Leadership and Success.",institutionString:"American University of Ras Al Khaimah",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:null}],coeditorOne:{id:"263302",title:"Dr.",name:"Sharon",middleName:null,surname:"Waller",slug:"sharon-waller",fullName:"Sharon Waller",profilePictureURL:"https://mts.intechopen.com/storage/users/263302/images/system/263302.png",biography:"Dr. Sharon Waller completed a Ph.D. in Special Education from the Texas Woman’s University in Denton, Texas. She earned her Master of Education in Special Education from the University of North Texas and her BBA from Texas Woman’s University. Both institutions are located in Denton, Texas. Dr. Sharon spent 13 years a Sherman Independent School District where she served as an educational diagnostician, curriculum coordinator, and teacher. She joined the AURAK family as Manager of Counseling, Testing, and Disability Services in 2105. Dr. Waller’s teaching and research focus on special education, strategic educational leadership, and effective assessment of student learning.",institutionString:"American University of Ras Al Khaimah",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:null},coeditorTwo:{id:"299343",title:"Dr.",name:"Vongai",middleName:null,surname:"Mpofu",slug:"vongai-mpofu",fullName:"Vongai Mpofu",profilePictureURL:"https://mts.intechopen.com/storage/users/299343/images/system/299343.jpg",biography:"Dr. Vongai Mpofu is a seasoned Science teacher educator with a strong background in school leadership and science teaching. She holds a Ph. D. in Science Education from the University of Witswatersrand in South Africa and have twelve years of University teaching experience at Bindura University of Science Education (BUSE). She joined University service at BUSE with a wealth of experience of heading several high schools in Zimbabwe. She has been in university leadership as a chairperson of the Department of Science and Mathematics Education as well as the acting Dean of the Faculty of Science Education. Dr. Vongai has a good record for teaching, research, and community engagement as well as qualities of good leadership. She is also engaged in journal editorship and peer reviews. She is actively involved in research and leadership related events inclusive of presenting conference papers and facilitating in research and leadership events. Her school management experiences have been enhanced by several professional development courses in leadership she has attended.",institutionString:"Bindura University of Science Education",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Bindura University of Science Education",institutionURL:null,country:{name:"Zimbabwe"}}},coeditorThree:{id:"324485",title:"Dr.",name:"Mercy",middleName:null,surname:"Kurebwa",slug:"mercy-kurebwa",fullName:"Mercy Kurebwa",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00002x7lPRQAY/Profile_Picture_1592997052286",biography:"Mercy Kurebwa is a Full Professor in Education. She is a goal-getter, hardworking and committed individual who has worked as a teacher in the Primary schools and a Senior Assistant Registrar, Registrar and Lecturer in Universities. Her work experience spans over 34 years. Currently, she is working in the Zimbabwe Open University’s Faculty of Education and Department of Educational Studies teaching courses in Educational management at both Bachelors and Masters levels. Mercy Kurebwa holds a Certificate in Education (Morgenster Teachers College), Bachelor’s Degree in Educational Administration, Planning and Policy Studies and a Master’s Degree in Administration, Planning and Policy Studies (University of Zimbabwe) and a Doctor of Philosophy Degree in Education (Zimbabwe Open University). Mercy Kurebwa has published 53 journal articles and has also presented over 20 papers at local and international conferences. The focus of the publications and presentations was on Assessment, Open and Distance Learning (ODel), Early Childhood Education, issues in schools, leadership and a few social issues. Mercy supervises Doctorate candidates, participates in university committees; has written and reviewed modules, reviewed journal articles and is an internal and external examiner for Doctorate candidates. Her passion is in research and publication in an endeavor to find solutions to educational problems and bring awareness to the academic arena.",institutionString:"Zimbabwe Open University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Zimbabwe Open University",institutionURL:null,country:{name:"Zimbabwe"}}},coeditorFour:null,coeditorFive:null,topics:[{id:"23",title:"Social Sciences",slug:"social-sciences"}],chapters:[{id:"73237",title:"Beyond Teaching: School Climate and Communication in the Educational Context",slug:"beyond-teaching-school-climate-and-communication-in-the-educational-context",totalDownloads:106,totalCrossrefCites:0,authors:[null]},{id:"73216",title:"Addressing Sustainability Planning in Higher Education Research",slug:"addressing-sustainability-planning-in-higher-education-research",totalDownloads:58,totalCrossrefCites:0,authors:[null]},{id:"73159",title:"Learning Is Visual: Why Teachers Need to Know about Vision",slug:"learning-is-visual-why-teachers-need-to-know-about-vision",totalDownloads:61,totalCrossrefCites:0,authors:[null]},{id:"74001",title:"Globalization, Technological Advancement and the Traditional Library System: Implications for Information Utilization and Learning",slug:"globalization-technological-advancement-and-the-traditional-library-system-implications-for-informat",totalDownloads:62,totalCrossrefCites:0,authors:[null]},{id:"73194",title:"Limitations and Proposals for Improvement of the Bilingual Program of the Community of Madrid in Public Primary Schools",slug:"limitations-and-proposals-for-improvement-of-the-bilingual-program-of-the-community-of-madrid-in-pub",totalDownloads:42,totalCrossrefCites:0,authors:[null]},{id:"73290",title:"Indian Education: Ancient, Medieval and Modern",slug:"indian-education-ancient-medieval-and-modern",totalDownloads:186,totalCrossrefCites:0,authors:[null]},{id:"74087",title:"Community Learning Centres as Podia for Technology Enhanced Ubiquitous Learning: A Botswana Case",slug:"community-learning-centres-as-podia-for-technology-enhanced-ubiquitous-learning-a-botswana-case",totalDownloads:56,totalCrossrefCites:0,authors:[null]},{id:"74356",title:"Online Career Guidance Systems for PK-12 School Students: Compliments to a Comprehensive School Counseling Program",slug:"online-career-guidance-systems-for-pk-12-school-students-compliments-to-a-comprehensive-school-couns",totalDownloads:39,totalCrossrefCites:0,authors:[null]},{id:"74808",title:"Development Strategies towards a Reputable International Program: Special Focus at International Program for Islamic Economics and Finance, Universitas Muhammadiyah Yogyakarta",slug:"development-strategies-towards-a-reputable-international-program-special-focus-at-international-prog",totalDownloads:3,totalCrossrefCites:0,authors:[{id:"316229",title:"Dr.",name:"Dimas",surname:"Wiranatakusuma",slug:"dimas-wiranatakusuma",fullName:"Dimas Wiranatakusuma"}]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"247041",firstName:"Dolores",lastName:"Kuzelj",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/247041/images/7108_n.jpg",email:"dolores@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"17769",title:"Gene Therapy in Urology",doi:"10.5772/22235",slug:"gene-therapy-in-urology",body:'The application of gene therapy in the field of Urology is not limited to cancer therapy but is also being evaluated for non-cancer related bladder dysfunctions as well as erectile dysfunction (ED). This article will review the use of gene therapy for these conditions; the vectors used and limitations associated with different gene delivery systems and the attempts to overcome these shortcomings.
Bladder cancer is the 7th most common cancer worldwide. It has a natural history of superficial recurrences and local progression. It is estimated that within 18 months of first diagnosis approximately 50% of patients will have a recurrence (Anderson & Naish 2008). Thus there is a need for frequent monitoring of these patients. In the US the estimated life-time cost of therapy for bladder cancer patients with non-muscle invasive disease was US $21.03 million based on a Medicare database (Cooksley et al. 2008). The majority of this is spent on surveillance and the treatment of recurrences. Tumors occur on the luminal surface of the bladder and the architecture of the bladder permits topical intravesical therapies. The bladder is isolated from other organs and tissues and intravesical therapy permits contact with the entire internal surface of the bladder with minimal systemic side-effects.
The present gold standard therapy for superficial bladder cancers is immunotherapy with Mycobacterium bovis, Bacillus Calmette Guerin (BCG) following local transurethral resection of the bladder tumor (TURBT). BCG induces a mononuclear and neutrophilic infiltrate in the bladder wall which results in an inflammatory response as measured by cytokine production that causes sloughing of both tumor and normal cells (Herr and Morales 2008). The presence of IL-2, IL-8 and IL-18 in the urine of patients has been reported to correlate with response to therapy (Thalmann et al. 1997; Thalmann et al. 2000; Saint et al. 2003). Unfortunately, BCG has several shortcomings: it is a live vaccine and commonly causes side effects and occasionally septicemia. In addition some patients (20-42%) do not respond to therapy (Kamat and Lamm 2000). In place of BCG, recombinant cytokines such as IFN-, TNF-, and IL-2 have been used in a number of clinical trials with encouraging results (Glazier et al. 1995; Den Otter et al. 1998; Stavropoulos et al. 2002). However, recombinant cytokines are costly, unstable in urine and have poor permeability across the glycosaminoglycan (GAG) layer of the urothelium. Gene therapy is a natural alternative approach to ensure cytokine production in the bladder environment.
Initially replication defective viruses were generated with the sole purpose of gene delivery (Thomas et al. 2003). The viruses evaluated included: Adenovirus (type 2 and 5), Adeno-associated virus (Parvoviridae family), Herpes simplex virus, Retrovirus (Dumey et al. 2005), Canary pox virus and Vaccinia virus (Lee et al. 1994). Table 1 lists their characteristics.
However, because of the limited transduction capability of some viruses, replicating and conditionally replicating viruses were developed. These viruses amplify the transfection efficiency, as virus transduced cells produce more viruses that can infect the surrounding cells. Replication of wild type viruses also induces cytolysis of infected cells.
Siemens et al. compared adeno-, canary pox and vaccinia viruses in terms of their ability to transfect tumor cells after intravesical delivery in a murine model of bladder cancer (Siemens et al. 2003). The vaccinia and avian pox viruses were better at transfecting tumor cells than adenoviruses but all three resulted in transfection of extravesical tissue (e.g. kidney, liver, spleen). In contrast Wood et al reported only sporadic extravesical transfection after intravesical adenovirus instillations (Wood et al. 1999).
To reduce non specific viral transduced gene expression, oncolytic adenoviruses have been engineered to express the E1A and E1B genes under the control of the uroplankin II gene promoter (Zhang et al. 2002; He et al. 2009) which limits expression to urothelial cells. Another strategy to target viral replication to tumor cells is to place the adenovirus E1A gene under the control of the telomerase promoter (Lanson et al. 2003), the midkine gene promoter (Terao et al. 2007) or the Cox-2 promoter (Shirakawa et al. 2004). All these genes are highly expressed in tumor cells.
Bladder cancer cells often over-express the epidermal growth factor receptor (EGFR) and targeting EGFR with bi-specific antibodies improved the delivery of adenovirus to cancer cells (van der Poel et al. 2002). A gammaretrovirus carrying a chimeric envelope protein containing a single chain variable fragment (scFv) antibody to the human epidermal growth factor receptor 2 (HER2) was shown to specifically target cells expressing Her2 (Tsai et al. 2010).
The internal surface of the bladder is covered by uroplakin proteins and the GAG layer which together provide a barrier to transfection of urothelial cells. Agents that disrupt this protective layer such as ethanol, HCl, dodecyl-B-d-maltoside and sodium dodecyl sulphate have been shown to improve viral transduction of the bladder (Engler et al. 1999; Lin et al. 2002; Ramesh et al. 2004).
Though adenoviruses are the most popular viruses for gene therapy they require adhesion with the cellular coxsackie-adenoviral receptor (CAR) for transduction of mammalian cells. Neoplastic tissue unlike normal bladder cells have reduced CAR expression (Buscarini et al. 2007) as a result of epigenetic control mechanisms (Pong et al. 2003).
Virus | Transfection efficiency | Immunogenicity | DNA inserts | Gene expression |
Adenovirus | High with CAR receptor | high | 8kb | Transient expression, DNA remains episomal |
Adeno-associated virus | Good, no receptor | low | 4.5kb | Stable, DNA episomes found |
Herpes simplex virus | High in neurons | high | "/>30kb | Stable in neurons and transient in others, episomal |
Moloney murine leukemia virus | High in dividing cells | low | 8kb | Stable expression, DNA integration into host genome Hematopoietic cells |
Lentivirus | Non dividing cells | low | 8kb | Stable expression, Integration in host chromosome, |
Canary pox virus | Most cells | low | 25kb | Transient expression, Viral DNA limited to cytoplasm |
Vaccinia virus | Most cells | high | Up to 25kb | Transient expression, Viral DNA limited to cytoplasm |
Characteristics of viral vectors for gene therapy
To circumvent the need for receptor mediated uptake, polymers have been used to enhance adenovirus transfection of bladder cells (Kasman et al. 2009) or even small molecule excipients such as Syn3 (Connor et al. 2001; Yamashita et al. 2002; Nagabhushan et al. 2007). A recent study has shown that CAR receptor expression and thus adenoviral expression can be increased by treatment with histone deacetylase inhibitors (HDACI) such as trichostatin A and sodium phenylbutyrate (Sachs et al. 2004).
Vaccinia viruses have long been used in man as vaccines against smallpox. This raised the issue of whether previous immunization would block the effectiveness of these viruses as gene delivery vehicles. Intravesical instillation of vaccinia viruses was successfully demonstrated in pre-immunized mice (Lee et al. 1994). The immunogenicity of adenoviruses is a major limitation in most therapeutic strategies. However it may be advantageous in bladder cancer therapy where non-specific inflammation as a consequence of BCG instillation has been associated with tumor removal.
Adenovirus genes expressed from a CMV promoter induced better gene expression than those expressed using a RSV promoter (Freund et al. 2000). But quite often the CMV promoter is inactivated in vivo. It has been found that adenoviral transfection together with HDAC inhibitor trichostatin or retinoic acid improved CMV promoter activity. Treatment with these drugs could improve and prolong adenoviral transgene expression (Gaetano et al 2000). The development of tissue specific promoters as described above may resolve this problem.
The strength and weakness of non-viral vectors is the transient expression of the delivered genes. For non-viral gene delivery the genes are encoded on plasmid DNA of bacterial origin. Non-viral delivery agents include liposomes (N-[1-(2,3-Dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride, DOTAP), polyethylenimine (PEI), viral envelopes (with fusogenic properties) conjugated to liposomes (Hemagglutinating Virus of Japan (HVJ) liposomes), chitosans as well as physical means such as the use of an electrogun or ultrasound (Harimoto et al. 1998; Lawrencia et al. 2001; Ogawa et al. 2004; Bonnet et al. 2008; Tsai et al. 2009; Zaharoff et al. 2009). Plasmid DNA delivery systems result in cellular entry via the endosomes (Al-Dosari & Gao 2009). Endosomal escape is often difficult and when successful the plasmid DNA is mainly restricted to the cytoplasm. A small amount may make it to the nucleus and exist as episomal DNA molecules that can be lost during replication (Al-Dosari & Gao 2009). Besides the delivery agents, the plasmid DNA sequence can also modulate the efficiency of transfection as discussed below.
It has been reported that the CMV promoter often used for plasmid gene expression does not always result in good gene expression (Loser et al. 1998) as a consequence of promoter inactivation. This can be overcome by using a HDAC inhibitor, as demonstrated with OSU-HDAC42 (Lai et al. 2010). An alternative strategy is to utilize tissue/cancer cell specific promoters such as the COX-2, H19 and human IGF2-P4 gene promoters (Ohana et al. 2002; Zhang et al. 2008; Amit & Hochberg 2010).
The primary focus of improving plasmid DNA transfection is improving escape from the endosomes and this is achieved by developing new additives and lipoplexes or even polyplexes that use either acidification or osmotic pressure changes or membrane fusogenic molecules to allow DNA escape (Al-Dosari and Gao 2009). We developed a formulation comprised of DOTAP and Methyl--cyclodextrin solubilized cholesterol (MBC) that transfects urothelial cells in vivo within 2 hours of exposure. Transfection was confined to the bladder (Lawrencia et al. 2001) and occurred in the superficial and deeper layers of the urothelial tumours (Wu et al. 2003).
Antibodies have been used to target delivery of plasmids to tumor cells. ScFv antibody to Her-2 (Tsai et al. 2009) or transferrin have been demonstrated to successfully target plasmids to tumor cells (Pirollo et al. 2008). The latter strategy targets both primary and metastatic disease when delivered systemically. Targeting of plasmid DNA to the nucleus can also be induced by introducing mammalian transcription factor binding sites in the plasmid and this increased the duration of expression (Gill et al. 2009).
Plasmid DNA expression is transient because of the episomal nature of transfected DNA. In bladder cancer therapy this can be overcome by repeated intravesical instillations. Another strategy to improve gene expression is to add a scaffold matrix attachment region (S/MAR) to the plasmid DNA. S/MAR serve both to ensure prolonged gene expression, by reducing the silencing of plasmid DNA as well as to ensure plasmid DNA replication as episomes (Gill et al. 2009).
Integration of plasmid DNA into chromosomal DNA is achievable now. The techniques used include retroviral integrase (Tanaka et al. 1998), sleeping beauty (SB) transposons (Hackett et al. 2010) or phage recombinase mediated integration (Olivares et al. 2002). Thus in the future a single intravesical instillation may be sufficient for prolonged therapeutic effects.
For small molecules such as CpG oligodeoxynucleotides (ODN), intravesical delivery to urothelial cells can be achieved without a transfection agent (Ninalga et al. 2005). But plasmid DNA requires a delivery agent. Nanoparticles (10-100nm in size) with bound plasmid DNA are recognized by cell surface nucleolin on HeLa cells and this results in DNA transport to the nucleus (Chen et al. 2008) and avoidance of endosomal entrapment.
The CpG sequences on plasmid DNA induce inflammation that could reduce gene expression by either destruction of transfected cells or promoter inactivation (Yew et al. 2000). Minicircle DNA (mcDNA), are supercoiled DNA with only the therapeutic gene cassette. They are generated in vivo by site specific recombination in E coli and exhibit improved gene expression in terms of the level and duration of gene expression (Darquet et al. 1997).
The different categories of genes used successfully in animal studies are listed in Table 2. Both Sub-cutaneous (sc) and orthotopic models of bladder cancer have been used to evaluate gene therapy. While the data from sc studies have shown the efficacy of the expressed genes, it is the orthotopic models that best reflect clinical disease and therapeutic gene delivery. In general regardless of the delivery system or gene delivered tumor growth reduction or even eradication has been reported in murine models of bladder cancer. Most therapeutic schedules used in the animal studies require repeated instillations of the gene delivery vehicle whether it is a viral or non-viral vector. However, a recent study of viral gene delivery of IFN indicated that a high dose could reduce the need for increased intravesical instillations (Tao et al. 2006). Transfection using transposons may also reduce the need for repeated transfection of plasmid DNA.
New therapies aim to combine several strategies at once. These include the use of oncolytic viruses and immune modulation using GMCSF (Cozzi et al. 2001; Ramesh et al. 2006); wild type p53 and ribozyme erb-2 (Irie et al. 2006) and Rb94 or oncolytic viruses and chemotherapeutic drugs (Zhang et al. 2002; Pirollo et al. 2008). In vitro studies have shown that combining AdHSVTK, ganciclovir and chemotherapy may have therapeutic benefit (Freund et al. 2003). Further the beneficial effect of 5-FU and adenovirus cytosine deaminase gene therapy could be enhanced by irradiation (Zhang et al. 2003). Such multi-factor therapies may be better at eradicating tumor cells. Another strategy is to modify immune cells in vitro for cancer therapy. Dendritic cell manipulation by transfection with adenovirus carrying the survivin gene has been shown to induce cytotoxic T lymphocytes ( CTLs) (Kikkawa et al. 2009).
Table 3 lists several Phase I trials that have been carried out for bladder cancer. However, results from only a few of these trials are published.
Genes demonstrated to cause tumor reduction in murine models of bladder cancer.
Clinical trials for bladder cancer gene therapy. NCT designation indicates data obtained from http://www.who.int/ictrp/en/; Other alphabet and number designations are for data obtained from http://www.wiley.com/legacy/wileychi/genmed/clinical where the alphabets indicate country of registration and the numbers only designation are for data obtained from http://www.gemcris.od.nih.gov/Contents/GC_HOME.asp. Note some trials were registered on more than one web-site.
Information about completed, on-going and planned trials were obtained from the following sources: gene therapy clinical trials world wide web-site
A Phase I trial on vaccinia virus instillation showed increased lymphocyte recruitment and the induction of an inflammatory response in the bladder (Gomella et al. 2001). There were no clinical manifestations of vaccinia toxicity indicating the safety and therapeutic potential of this virus as a gene therapy vector. Adenovirus delivery of p53 was also shown to successfully deliver p53 gene to bladder cells but there was no change in immunohistochemical detection of p53 in bladder tissue (Pagliaro et al. 2003). However, adenovirus therapy was safe and well tolerated (Pagliaro et al. 2003). Delivery of adenovirus carrying p53 with a transduction enhancing agent improved p53 gene delivery and protein expression was found in patient tissue samples (Kuball et al. 2002). Though higher doses of the virus were administered, no dose toxicity was observed (Kuball et al. 2002). Similarly no serious adverse effects were reported by Malmstrom et al. from a recently concluded Phase I/IIa trial using AdCD40L (Malmstrom et al. 2010). They observed gene transfer in biopsies and the infiltration of T lymphocytes (Malmstrom et al. 2010).
A plasmid was used to deliver the diphtheria toxin gene under the control of the H19 gene regulatory sequence in a Phase I/IIa trial for non–muscle invasive bladder cancer (Sidi et al. 2008). They reported mild toxicity and observed complete and partial response in some patients. Thus based on these Phase I trials, both non viral and viral vectors appear to be well tolerated in man.
Several new trials are either in progress or about to commence. These use non-viral and viral delivery vectors as listed in Table 3. A proposal for a Phase I trial for intravesical therapy in bladder cancer patients using plasmid DNA carrying the IFN- gene and our liposome based delivery system is being evaluated by the Health Sciences Authority, Singapore.
Though not covered here several clinical trials are on-going, evaluating gene therapy for prostate and renal cancers. In general the vectors and genes used are similar though tissue specific promoters may differ. Information on these trials can be obtained from the web-sites listed above. Unlike bladder cancer however, gene delivery to these tissues is not as simple. Thus tissue specific targeted gene expression has been developed. Another strategy is the use of macrophages transfected ex vivo with a plasmid carrying the E1A/B construct under the control of the hypoxia response element (HRE) as well as a replication competent adenovirus with the E1A under the control of the prostate specific antigen promoter. At the hypoxic tumor site the E1A protein is produced and the adenoviruses released infect tumor cells and cause their lysis (Muthana et al. 2011). Such a strategy prevents virus neutralization in vivo.
The bladder is made up of a reservoir and an outlet (bladder neck, urethra and urethral sphincter) whose activities are controlled by smooth and striated muscles. There are more patients with bladder dysfunctions related to its primary function of urine storage and voiding than cancer. These include: lower urinary tract symptoms (LUTS), interstitial cystitis (IC), overactive bladder (OAB), spinal cord injuries affecting micturition and urinary incontinence (UI). It is estimated that by 2018, some 2.3 billion people worldwide will be affected by at least one LUTS, OAB, UI and LUTS suggestive of bladder obstruction (Irwin et al. 2011). LUTS is an umbrella term that encompasses urine storage (increased frequency, at least one episode of nocturia per night, urgency and UI), voiding and post-micturition symptoms (Abrams et al. 2003). Another urological problem is erectile dysfunction (ED). Both LUTS and ED are increased with aging and in patients with diabetes (Brown et al. 2005). With the worldwide increase in the incidence of diabetes the incidence of these urological problems will increase.
Most current therapies for the above mentioned conditions are palliative rather than therapeutic. Gene therapy however, may provide a way to cure the disease and the recent review by Christ lists some of these strategies (Christ 2011). Most of the bladder related problems seem to be linked to muscle and neuronal defects and because of the latter the most common vectors used for animals studies of bladder dysfunctions are HSV vectors.
Urinary incontinence is a general term used to cover three types of incontinence namely stress, urge and overflow (Chancellor et al. 2001). Stress incontinence occurs when the urinary sphincter muscle is unable to prevent urine leakage following jumping or coughing. This is more common in women than men. Treatment approaches include exercise, surgery and collagen injections into the sphincter muscle. Often multiple injections are required which adds to the cost of treatment and some patients are allergic to bovine collagen. Tissue engineering and ex vivo gene therapy are alternative therapeutic strategies that are being evaluated (Shokeir et al. 2010). Phase I trials of the delivery of autologous myoblasts and fibroblasts from muscle biopsies to female patients with stress incontinence have shown some benefit (Mitterberger et al. 2007). In mice, combining myoblast and gene therapy such as the ex vivo transformation of myoblasts with the VEGF gene resulted in improved volume and function of muscle cells (Delo et al. 2008).
Urge incontinence is characterized by increased urinary urgency and frequency caused by involuntary bladder contractions leading to uncontrollable urine leakage. One study has evaluated intravesical non-viral delivery of a cDNA for the K+ channel and showed that this resulted in increased K+ channels in the smooth muscle of the bladder and amelioration of bladder overactivity (Christ et al. 2001).
\n\t\t\t\tOverflow incontinence results from nerve damage such that patients cannot urinate. One common cause is diabetes related neuropathy. Diabetes related cystopathy is often irreversible and restoring bladder functions to diabetic patients is difficult (Sasaki et al. 2002). Animal studies have identified nerve growth factor (NGF) as a good candidate for gene therapy for diabetes induced incontinence (Apfel et al. 1994). HSV delivery of NGF increased NGF in the bladder wall and dorsal root ganglion and improved voiding function in streptozotocin (STZ) induced diabetic rats (Goins et al. 2001; Sasaki et al. 2004).
Interstitial cystitis or painful bladder syndrome occurs predominantly in females (Persu et al. 2010). It is believed to result from underlying inflammation in the bladder. It cannot be adequately treated by drugs and prolonged drug therapy can lead to dependency and tolerance to drugs that may require dose escalation to remain effective. Thus it is a candidate for gene therapy. Delivery of the preproenkephalin gene by HSV (Yokoyama et al. 2009) has been shown to be beneficial in reducing pain. A HSV vector carrying the ionotropic glycine receptor (GlyR) whose expression was induced by glycine had an analgesic effect (Goss et al. 2011). This vector when inoculated into the bladder wall of an inflammation model of IC/PBS in rats was activated by systemic glycine delivery.
Overactive bladder (OAB) is defined as “urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary incontinence” (Haylen et al. 2010) Detrusor over activity is considered a single marker for OAB. It can occur as a result of spinal injury and could result in a lack of control of micturition. This has been demonstrated in animal models of spinal injury. HSV vector delivery of glutamic acid decarboxylase has shown benefit in a rat model of spinal injury (Miyazato et al. 2009; Miyazato et al. 2010).
Approximately 150 million men are projected to suffer from ED and the incidence of ED increases with age. Normal erectile function occurs as a result of 3 synergistic events namely: neurological mediated penial arterial inflow increase; cavernosal smooth muscle relaxation and restriction of venous outflow from the penis (Andersson & Wagner 1995). In ED one or more of these events may be impaired. The penis is an excellent candidate for gene therapy because it is easily accessible, has limited blood flow and a slow cellular turnover (Bivalacqua & Hellstrom 2001). Though therapy is available for erectile dysfunction there are a significant number of patients who do not respond to available therapy (Yoshimura et al. 2010). The recent review by Harraz et al. provides an excellent overview of gene therapy strategies used in animal models of ED that have been shown to resolve this problem (Harraz et al. 2010). Rather than reproducing that information only recent publications not included in that review are mentioned here. Over expression of the transient receptor potential (TRP) channels 6 (dominant negative) by transfection with a plasmid caused a decrease in calcium levels in the corporal smooth muscle and improved erectile function in diabetic rats (Jung et al. 2010). Using a STZ induced diabetes model to evaluate erectile dysfunction, it was found that implantation of mesenchymal stem cells transfected with VEGF improved erectile function compared to implantation of mesenchymal stem cells alone (Qiu et al. 2011).
Only two clinical trials are listed on the
One major issue is the safety of gene therapy in terms of its impact on the environment as well as long term safety in patients. Schenk-Braat et al found that only half of all registered clinical trials included viral shedding data (Schenk-Braat et al. 2007) and what data was available was primarily for the time after virus delivery and not at the time of delivery. These questions should also be raised for plasmid based gene therapy. Long term follow-up data on patients who have received gene therapy may further ameliorate the safety concerns of this therapy. This will result in gene therapy being more readily applied to other non-malignant conditions. The development of better plasmids and ways to integrate plasmids into the chromosome may lead to the greater use of plasmid rather than viral vectors for urological gene therapy.
MicroRNAs (MiRNA) are new targets for cancer therapy. These are small non-coding RNA molecules that bind to complementary sequences in the protein coding regions of mRNA and block their translation. Their expression levels vary in cancer and normal tissues (Catto et al. 2011). MiRNA-203 and MiRNA-221 have been shown to modulate the growth and apoptosis of human bladder cancer cell lines (Lu et al. 2010; Bo et al. 2011) and these could be new targets for therapy. Given the function of miRNA it is possible that these molecules could also be targets for non-cancer related bladder dysfunctions. This has not yet been explored and identifying such molecules may improve our knowledge of the development of these conditions.
The application of gene therapy for urological conditions is being evaluated in many preclinical disease models. In general the results obtained are encouraging and soon these therapies may move to Phase I trials.
Sickle cell anemia (SCA) is the commonest hemoglobin disorder among the black population worldwide [1, 2]. As a genetic defect with the Mendelian autosomal-recessive inheritance, children with the sickle cell hemoglobin genes in the homozygous form have reversibly sickled and irreversibly sickled red blood cells. These abnormal red cells, which become rigid having lost their deformability, consequently block the microvasculature resulting in vasoocclusion. They are also prone to damage which leads to chronic hemolysis. Most of the clinical features of SCA are essentially related to these two events.
\nChildren with SCA may eventually end up with end-organ complications: the kidneys being one of the most frequently affected organs. The renal complications arise from medullary ischemia and infarction leading to features of tubular dysfunction such as hyposthenuria and renal tubular acidosis [3]. As early as 3 years of age, children with SCA may present with hyposthenuria: one of the earliest renal defects in the disease which results in an obligatory urine output of more than 2 l in a day [4]. The symptomatic manifestation as nocturnal polyuria is thought to be the reason for the observed nocturnal enuresis in these children. In spite of the more prevalent occurrence of nocturnal enuresis in children with SCA than in their normal colleagues, the precise underlying mechanisms have not yet been resolved. Research on the subject has led to divergent conclusions about the pathogenesis; one report had earlier suggested that hyposthenuria was a major determinant of enuresis in the disease [5], while other authors not only controverted this observation but had reported disparate etiopathogenic factors [6, 7, 8]. In fact, a recent review of published evidence on the subject indicates similar determinants of nocturnal enuresis for both SCA and non-SCA patients [9]. Thus, the role of hyposthenuria as the exclusive determinant of nocturnal enuresis in children with SCA remains debatable although the consensus is now tilting towards a multifactorial etiopathogenesis in affected children.
\nThis book chapter aims to discuss the epidemiologic perspectives of nocturnal enuresis in SCA, as well as the current hypotheses on the etiopathogenesis of this complication.
\nNocturnal enuresis has been defined as the persistence of urination in the bed (bedwetting) at night, two or more times per week after the age of 5 years, for a period of at least 3 months [10]. It can present as a primary form (no previous dry period) or a secondary form (previous dry period), and as monosymptomatic (absence of daytime symptoms) or non-monosymptomatic (presence of daytime symptoms) [9]. Studies which show that children with SCA have a tendency for nocturnal enuresis more than children with normal hemoglobin however reported different prevalence rates and epidemiologic patterns, depending on study methods and definition criteria (Table 1).
\nStudy authors (Country) | \nStudy method (age bracket) | \nNE definition | \nPrevalence rates (N) | \nSex predominance | \nEffect of socioeconomic status | \n
---|---|---|---|---|---|
Eneh et al. (Nigeria)† | \nProspective parental interview (5–11 years) | \nDSM-IV criteria | \n31.4% (70) | \nMale | \nNot significant | \n
Akinyanju et al. (Nigeria)‡ | \nProspective parental interview (4–20 years) | \nInvoluntary passage of urine during sleep>1/month | \n41.6% (209) | \nMale | \nNot reported | \n
Ogunrinde et al. (Nigeria)†† | \nProspective parental interview (5–16 years) | \n≥3 bedwetting episodes/ month (5–6 year old) or 1 episode/month (>6 year old) | \n47.1% (360) | \nMale | \nNot significant | \n
Mabiala Babela et al. (Congo Brazzaville) | \nCross-sectional study (5–20 years) | \nMicturition during sleep in a child aged >5 years | \n51% (456) | \nFemale | \nNot reported | \n
Portocarrero et al. (Brazil) | \nProspective questionnaire (5–17 years) | \nNot stated | \n32% (155) | \nNot reported | \nNot reported | \n
Barakat et al. (USA) | \nProspective phone interview (5–22 years) | \nNocturnal urinary incontinence >5 years of age (>2/week for 3 months) | \n39.2% (217) | \nMale | \nNot reported | \n
Jordan et al. (USA) | \nProspective interview (5–17 years) | \nUrinary incontinence >5 years of age (>2/week for 3 months) | \n25% (126) | \nNot reported | \nNot reported | \n
Figueroa et al. (USA) | \nProspective screening questionnaire (6–21 years) | \nBed wetting at least 2/week | \n30% (91) | \nNot reported | \nNot reported | \n
Field et al. (USA) | \nProspective questionnaire (6–20 years) | \nRecurrent bed wetting | \n33% (213) | \nNot reported | \nNot reported | \n
Lehmann et al. (USA) | \nProspective questionnaire (4–19 years) | \nPre-sleep bed wetting/month | \n39% (221) | \nNot reported | \nNot reported | \n
Readett et al. (Jamaica) | \nProspective interview (8 years) | \nBed wetting 2 nights/week | \n45% (175) | \nMale | \nNot significant | \n
Ekinҫi et al. (Turkey) | \nProspective questionnaire (6–40 years) | \nBed wetting at night >1/week for 3 months | \n26.4% (55) | \nNot reported | \nNot reported | \n
Nocturnal enuresis (NE) in children with sickle cell anemia: epidemiologic perspectives.
South East Nigeria.
South West Nigeria.
North West Nigeria.
N = study population, DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, Fourth edition, USA = United States of America.
For instance, the possible effect of sex and socioeconomic status on enuresis in children has been well documented in several studies [7, 11, 12, 13, 14, 15, 16]. Firstly, male predominance was noted among children with SCA in some of the studies [7, 11, 13, 14, 15], whereas a female predominance was reported in one study [12]. Although the disparity could be due to study selection bias, a similar trend of male predominance has also been reported among non-SCA children [15, 17]. This gender bias suggests that contributory factors to nocturnal enuresis in non-SCA children such as slower maturation and reduced responsiveness to toilet training in boys [18], and more frequent developmental delays [19], may also apply to children with SCA. Secondly, there appears to be no significant impact of socioeconomic status on the prevalence of nocturnal enuresis in both SCA children [7, 14], and their non-SCA counterparts [16]. However, a previous report indicates that enuresis in non-SCA children was more frequent in those from lower socioeconomic classes [17], whereas another study noted a higher prevalence among non-SCA children from higher socioeconomic classes [20].
\nThere is a wide variation in the global prevalence rates of nocturnal enuresis among children with SCA (Table 1). Prevalence rates vary from 25–51% depending on methodology and definition of nocturnal enuresis adopted in each study. In the West African sub-region, prevalence rates of 41.6, 31.4 and 47.1% were reported in south-west [11], south-east [14], and north-west [15] regions of Nigeria respectively. The study in south-east of the country prospectively interviewed parents of SCA subjects aged 5–11 years and parents of age- and sex-matched non-SCA controls; using the Diagnostic and Statistical Manual of Mental Disorders, Fourth edition (DSM-IV) criteria to define nocturnal enuresis [14]. In South West Nigeria, the authors also used prospective parental interview for subjects and controls aged 4–20 years, but defined nocturnal enuresis as ‘involuntary micturition during sleep which occurred more often than once in a month’ [11]. Conversely, the study in North West Nigeria used a structured questionnaire to obtain information from parents of enrolled 5- to 16-year-old subjects and controls; defining nocturnal enuresis as ‘3 or more episodes of bedwetting per month in a child aged 5 to 6 years and at least, once monthly in an older child’ [15]. In Central Africa, a prevalence rate of 51% was reported in a cross-sectional study of 5- to 20-year-old SCA patients (with age- and sex-matched controls) in Congo-Brazzaville which used the defining criteria for nocturnal enuresis as ‘complete act of urination most often during sleep in a child over 5 years’ [12]. Elsewhere in South America, a Brazilian study which was conducted on 5- to 17-year-old Negroid children and adolescents with SCA reported a prevalence rate of 32% [21]. The authors prospectively administered a questionnaire on the caregivers of these subjects and their age-matched controls. In North America, studies in the United States conducted among African-Americans documented prevalence rates of 39% [6], 39.2% [13], 25% [22], 30% [23], and 33% [24]. In these studies, there was disparity in the age bracket of the study population and the definition adopted for nocturnal enuresis. A prospective phone interview was used in one study, which defined nocturnal enuresis as ‘incontinence of urine at night after 5 years of age, more than twice a week for at least 3 months,’ while the study population were aged 5–22 years [13]. Another study employed a prospective interview of parents whose children were aged 5–17 years, and defined nocturnal enuresis as ‘incontinence of urine at night after 5 years of age, more than twice a week for at least 3 months’ [22]. Two of the studies utilized prospective questionnaires [6, 24], but interviewed primary caregivers of subjects who were aged 6–20 years [6], and 4–19 years [24]; defining nocturnal enuresis as ‘recurrent problem with bedwetting’ [6], and ‘wet bed in 1 month before sleep study’ [24]. In the last of the studies, nocturnal enuresis was defined ‘as wetting bed at least twice per week’ [23]; primary nocturnal enuresis was studied among subjects aged 6–21 years with a prospective screening questionnaire. In the Caribbean, a Jamaican study which used the prospective interview method reported a prevalence rate of 45% among 8-year-old SCA patients [7]. The authors’ definition of nocturnal enuresis was ‘being wet for at least 2 nights per week.’ A study in Turkey which adopted the definition criterion of nocturnal enuresis as ‘wet bed at night more than once a week for at least 3 months,’ reported a prevalence rate of 26.4% [25]. The investigators conducted semi-structured interviews with caregivers of pediatric and adult patients. Perhaps, the combination of SCA and thalassemia patients in the study population (with preponderance of the latter) as well as the wide age-bracket of 6–40 years accounted for this comparatively lower prevalence rate. Furthermore, it has been established that the prevalence of nocturnal enuresis decreases with advancing age, although this finding was essentially noted among non-SCA subjects [26, 27].
\nThere are now several hypotheses on the etiopathogenesis of enuresis in children [9, 28, 29]. In fact, it is believed that children with SCA may have a tendency to develop nocturnal enuresis because of the common general etiopathogenic factors in childhood, SCA-related etiopathogenic factors or a combination of both [9]. Specifically, the unresolved questions include the following: What is the exact role of hyposthenuria in SCA-related nocturnal enuresis? What are the contributory bladder-specific factors? Is there any relationship between sleep disordered breathing (SDB) and nocturnal enuresis in SCA? and Is there a difference in arousability threshold in normal subjects with nocturnal enuresis and those with SCA? [9]. Interestingly, the current hypotheses on the etiopathogenesis of SCA-related nocturnal enuresis revolve around these posers.
\nFirstly, the nocturnal polyuria resulting from hyposthenuria has long been suggested as the cause of nocturnal enuresis in SCA patients [5]. This hypothesis is supported by the fact that hyposthenuria is one of the commonest and earliest infarction-related renal complications, as intravascular sickling occurs more readily in the kidneys than in any other organs [30]. The microvasculature of the renal medulla is particularly susceptible to hypoxia induced by sickling and vasoocclusion [31]. Medullary ischemia and infarction result in the impairment of the urine-concentrating ability of the vasa recta and juxtamedullary nephrons, as failure of this function is thought to manifest as polyuria and enuresis [32, 33]. Although the ‘hyposthenuria hypothesis’ has been disputed by some authors who failed to establish a causal link between SCA and enuresis [7, 34], it has later been observed that both urine osmolality and overnight urine volume after fluid restriction were similar in enuretic and non-enuretic children with SCA; making the authors to conclude that low maximum functional bladder capacity and high overnight urine volume to maximum functional bladder capacity ratio were the determinants of nocturnal enuresis in affected children rather than low urine osmolality and high overnight urine volume [8].
\nSecondly, another hypothesis on nocturnal enuresis in the general population is that it results from an interaction of detrusor instability, delayed arousal from sleep and nocturnal polyuria [28]. Other authors also observed that in enuretic children, the nocturnal bladder capacity during sleep was significantly smaller than the diurnal functional capacity; thus highlighting the role of the inability to hold urine during sleep as an important etiopathogenic mechanism for nocturnal enuresis [29]. Nocturnal polyuria, nocturnal detrusor over-activity and high arousal thresholds are now regarded as crucial factors in the pathogenesis of enuresis, with an underlying mechanism on the brainstem level probably common to these pathogenic mechanisms [35]. In a review which appraised the possible etiopathogenic factors of primary nocturnal enuresis, the partly proven mechanisms were listed as maturational delay of the central nervous system, genetic factors, sleep disorders and SDB, and low levels of nocturnal anti-diuretic hormone (ADH) secretion [36]. Among these hypotheses, delayed functional maturation of the central nervous system is thought to be the most plausible mechanism for nocturnal enuresis as it reduces the child’s ability to inhibit nocturnal bladder emptying [36]. This theory is supported by the observation of spontaneous improvement in enuresis which occurs with advancing age [26]. Despite bladder filling, the non-perception of the sensory output emanating from its stretching removes the cortical control on the contraction of the urethral sphincter. Failure of the sleep arousal mechanism due to high arousal thresholds may also contribute to this inability to inhibit nocturnal bladder emptying. Presumably, these hypotheses on etiopathogenesis also apply to nocturnal enuresis in children with SCA. For instance, in these children a strong link between nocturnal enuresis and urinary bladder dysfunction has been reported by several authors [8, 37, 38]. Another recent postulation is that SCA-related enuresis may be due to atonic detrusor muscle which results in an underactive bladder with defective emptying mechanism. This abnormality is thought to be a consequence of chronic bladder ischemia caused by recurrent cycles of ischemia-perfusion injury triggered by vasoocclusion [39]. Evidence for this hypothesis was reported by some authors who studied the urinary bladder function in a transgenic sickle cell disease murine model and found these pathophysiologic changes: reduced urine output, inability to produce the typical bladder contraction and emptying, lower detrusor muscle, small bladder contraction and reduced urethral contraction [40].
\nThirdly, the role of sleep disorders and SDB in the etiopathogenesis of nocturnal enuresis has also been advanced as a sleep-related study show that patients with nocturnal enuresis have difficulties in waking, and are thus considered as ‘deep sleepers’ [41]. In addition, nocturnal enuresis is associated with SDB as a result of upper airway obstruction in children; surgical relief by tonsillectomy, adenoidectomy or both was reported to have reduced nocturnal enuresis in up to 76% of patients [42]. In a recent study, enuresis has not only been linked to SDB in children with SCA but the severity of SDB has been observed to have a strong correlation with frequency of nocturnal enuresis [6]. Notably, SDB is a common sleep disorder comprising a spectrum from snoring to obstructive sleep apnea syndrome (OSAS) which may worsen nocturnal enuresis through disrupted sleep and neurologic dysregulation [9]. While the finding of a study suggests that SDB is more prevalent in children with SCA than in the general population [43], overwhelming evidence also shows that a significant relationship exists between SDB and nocturnal enuresis among non-SCA children [44, 45, 46].
\nFurthermore, the role of low levels of some vitamins in the etiopathogenesis of nocturnal enuresis has been highlighted in recent studies. For instance, enuretic children were observed to have lower serum vitamin B12 and folate levels than their non-enuretic counterparts [47, 48]. The reduced vitamin levels are believed to be associated with slow cortical maturation which has been linked to enuresis. Interestingly, significantly lower or deficient vitamin B12 levels have equally been reported in children with SCA compared to non-SCA controls [49, 50]. In addition, increased risk of nocturnal enuresis has been observed in vitamin D-deficient children as this vitamin deficiency directly correlated with severity of enuresis [51]. In a recent systematic review, the prevalence of vitamin D deficiency was reported to vary from 56.4% to 96.4% in children with SCA [52]. This link between vitamin D deficiency and nocturnal enuresis can be explained partly by its influence on SDB and nocturnal polyuria. Reports indicate that low level of serum 25 (OH) D was associated with increased risk of developing OSAS [53], as well as primary snoring [54]. The association of low vitamin levels with OSAS is reportedly mediated through promotion of adenotonsillar hypertrophy, chronic rhinitis and/or myopathy of airway muscle [55]. Better still, low vitamin D levels may result in nocturnal enuresis through obstructive sleep apnea, sleep fragmentation and nocturnal polyuria, which all occur in children with SCA [39].
\nAnother etiologic consideration for nocturnal enuresis seen in SCA is its association with some involuntary movements such as periodic limb movement syndrome and restless leg syndrome. The prevalence of periodic limb movement syndrome in SCA has been documented as 20.5–29% [56, 57, 58], which was significantly higher than the rates of 1.2–8% reported for non-SCA children [59, 60]. Similarly, a prevalence rate of 11.1% has been observed for children with restless leg syndrome [56]. Notably, both involuntary movements are associated with sleep disruption [60]. Given that enuretic children have higher incidence of periodic limb movement and sleep fragmentation [59] and the higher rate of periodic limb movement syndrome associated nocturnal enuresis and sleep disruption in SCA patients, it is therefore not surprising to observe a high prevalence rate of nocturnal enuresis in them. To underscore the nexus between these aforementioned etiologic factors (low serum vitamin D level and restless leg syndrome), it has been observed that Vitamin D supplementation also improved the severity of this involuntary movement [61].
\nIn summary, the etiopathogenic mechanisms involved in nocturnal enuresis among SCA and non-SCA children are multifactorial and not mutually exclusive, and they include hyposthenuria-related nocturnal polyuria, decreased bladder capacity or nocturnal bladder over-activity, high sleep arousal thresholds and SDB [9] (Figure 1).
\nThe proposed etiopathogenic mechanisms for nocturnal enuresis. SDB, sleep-disordered breathing; nocturnal polyuria, induced by hyposthenuria. Concept and design: by SNU (one of the authors).
Although nocturnal enuresis appears more prevalent in children with SCA than in their non-SCA counterparts, the exact etiopathogenesis of enuresis is not completely understood. In fact, the suggested mechanisms for nocturnal enuresis in SCA children are also applicable to their non-SCA counterparts. Moreover, the multiregional variations in prevalence rates may be due to differences in definition criteria and study methods. Male predominance in enuretic children has been somewhat established, but there is no unanimity yet on the influence of socioeconomic status on prevalence rates. Perhaps, adopting standardized definitions and study methods may in future minimize the disparities in the reported prevalence rates. More importantly, further research is still required to establish the precise etiopathogenesis of nocturnal enuresis in children with SCA.
\nThe authors acknowledge the invaluable information obtained from the articles Uwaezuoke et al. [62] and Wolf et al. [9].
\nThe authors declare that there are no conflicts of interest.
\nIntechOpen implements a robust policy to minimize and deal with instances of fraud or misconduct. As part of our general commitment to transparency and openness, and in order to maintain high scientific standards, we have a well-defined editorial policy regarding Retractions and Corrections.
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\\n\\n4. FINAL REMARKS
\\n\\nIntechOpen wishes to emphasize that the final decision on whether a Retraction, Statement of Concern, or a Correction will be issued rests with the Academic Editor. The publisher is obliged to act upon any reports of scientific misconduct in its publications and to make a reasonable effort to facilitate any subsequent investigation of such claims.
\\n\\nIn the case of Retraction or removal of the Work, the publisher will be under no obligation to refund the APC.
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\n\nA formal Retraction will be issued when there is clear and conclusive evidence of any of the following:
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\n\n1.2. REMOVALS AND CANCELLATIONS
\n\n2. STATEMENTS OF CONCERN
\n\nA Statement of Concern detailing alleged misconduct will be issued by the Academic Editor or publisher following a 3rd party report of scientific misconduct when:
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\n\n3. CORRECTIONS
\n\nA Correction will be issued by the Academic Editor when:
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\n\n4. FINAL REMARKS
\n\nIntechOpen wishes to emphasize that the final decision on whether a Retraction, Statement of Concern, or a Correction will be issued rests with the Academic Editor. The publisher is obliged to act upon any reports of scientific misconduct in its publications and to make a reasonable effort to facilitate any subsequent investigation of such claims.
\n\nIn the case of Retraction or removal of the Work, the publisher will be under no obligation to refund the APC.
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