1. Introduction
Lysosomes are organella involving the catabolism of biomolecules extracellularly and intracellularly incorporated, which contain more than 60 distinct acidic hydrolases (lysosomal enzymes) and their co-factors. Lysosomal storage diseases (LSDs) are caused by germ-line gene mutations encoding lysosomal enzymes, their activator proteins, integral membrane proteins, cholesterol transporters and proteins concerning intracellular trafficking of lysosomal enzymes [1,2]. The LSDs associate with excessive accumulation of natural substrates, including glycoconjugates (glycosphingolipids, oligosaccharides derived from glycoproteins, and glycosaminoglycans from proteoglycans) as well as heterogeneous manifestations in both visceral and nervous systems [1,2]. LSDs comprise greater than 40 diseases, of which incidence is about 1 per 100 thousand births, and recognized as so-called ‘Orphan diseases’.
In the biosynthesis of lysosomal matrix enzymes, newly synthesized enzymes are N-glycosylated in the endoplasmic reticulum (ER) and then phosphorylated in the Golgi apparatus on the 6 position of the terminal mannose residues (M6P) via two step reactions catalyzed by Golgi-localized phosphotransferase and uncovering enzyme necessary to expose the terminal M6P residues [3,4]. The M6P-carrying enzymes then bind the cation-dependent mannose 6-phosphate receptor (CD-M6PR) at physiological pH in the Golgi. The enzyme–receptor complex is then transported to late-endosomes where the M6P-carrying enzymes dissociate from the receptor at acidic pH, while the CD-M6PR then traffics back to the Golgi as a shuttle. M6P-carrying enzymes are delivered to lysosomes via fusion with late-endosomes. A small percentage of lysosomal enzymes is known secreted from the cell. The secreted M6P-carrying enzymes or the dephosphorylated enzyme with terminal mannose residues can then bind either cation-independent M6P/IGFII receptor (CI-M6PR) or mannose receptor (MR) on the plasma membrane [4,5]. Thus, the extracellular lysosomal enzymes can be endocytosed via both glycan receptors to be delivered to the lysosomes where the captured enzymes can exhibit their normal catabolic functions.
Many therapeutic approaches developed for LSDs, including bone marrow transplantation (BMT), stem cell-based therapy (SCT), enzyme replacement therapy (ERT) and
On the other hand, the gene replacement therapy (GT) [21-24] has advantages, including i) long-lasting therapy by a single transduction utilizing recombinant viral gene transfer vectors [25-29], ii) cross-correction effects, and iii) possible CNS-directed application to LSDs involving neurological symptoms [23,24,30-33], whereas GT has disadvantages, including i) low levels and persistence of expression in all tissues of patients, ii) incomplete response to therapy dependent on clinical phenotypes, and iii) insertional mutagenesis resulting in neoplasia. GT is one of the promising therapeutic approaches, especially toward LSDs involving CNS symptoms. In this review, we focus on the challenges to develop the CNS-directed GT for LSDs including GM2 gangliosidoses.
2. GM2 gangliosidoses
Lysosomal β-hexosaminidase (Hex, EC 3.2.1.52) is a glycosidase that catalyzes the hydrolysis of terminal N-acetylhexosamine residues at the non-reducing ends of oligosaccharides of glycoconjugates [34,35]. There are two major Hex isozymes in mammals including man, HexA (αβ, a heterodimer of α- and β-subunits) and HexB (ββ, a homodimer of β-subunit), and a minor unstable isozyme, HexS (αα, a homodimer of α-subunit). All these Hex isozymes can degrade terminal β-1,4 linked N-acetylglucosamine (GlcNAc) and N-acetylgalactosamine (GalNAc) residues, while only HexA and HexS prefer negatively charged substrates and cleave off the terminal N-acetylglucosamine 6-sulfate residues in keratan sulfate. Hex A is essential for cleavage of the GalNAc residue from GM2 ganglioside (GM2) in co-operation with GM2 activator protein (GM2A) [34,35].
Tay-Sachs disease (TSD) (MIM 272800) and Sandhoff disease (SD) (MIM 268800) are autosomal recessive GM2 gangliosidoses caused by germ-line mutations of
GM2 gangliosidoses including TSD and SD exhibit a spectrum of clinical phenotypes, which vary from the severe infantile form (classical type), which is of early onset and fatal culminating in death before the age of 4 years, to the late-onset and less severe form (atypical type), which allows survival into childhood (subacute form) or adulthood (chronic form) [34,35,37,38]. Many mutations have been identified for each gene, including missense, deletion and insertion mutations [34,39-41]. Structural information on the basis of the crystal structures of human Hex B [42,43] and HexA [44] allowed us to predict the effects of missense mutaitons identified in TSD [34,39,40] and SD [34,39,41] on the protein structures of mutated gene products. According to these reports, the β-subunit of Hex comprises two domains (domain I and II). Domain I has an α/β topology, and domain II is folded into a (β/α)8-barrel with the active site pocket at the
3. General aspects of gene therapy for LSDs
Gene therapy (GT) utilizing various vectors for gene transfer has been preclinically and clinically applied for LSDs in recent years [21-33]. Recombinant viral vectors including retroviruses [25,32], adenovirus [26-28], herpes simplex virus (HSV) [33], adeno-associated virus (AAV) [29,46-48] and lentiviruses [24,49-51] are utilized currently as the effective means of gene transfer and enzyme expression. The retroviruses have been used primarily in
The application of recombinant viral vectors varies dependently on several factors, including ease of vector delivery, expression level in cell types and target tissues and organs mainly affected with LSD. At initial stage of development of GT for LSDs, the
The lentiviral vector based on human immunodeficiency virus had been expected to overcome the limitation of early generation of murine-based retroviral vectors in
Direct
The AAV vector has been also developed as an alternative gene transfer tool for direct
As mentioned above, GT has therapeutic potency for LSDs involving neurological symptoms superior to that of clinically applied intravenous ERT, in which the enzyme cannot cross the BBB. Several CNS-directed
4. Gene therapy for GM2 gangliosidoses
4.1. Experimental and preclinical gene therapy using animal models
GM2 gangliosidoses, including Tay-Sachs disease (TSD), Sandhoff disease (SD) and the AB variant disorder, are characterized by excessive accumulation of GM2 and neurological symptoms due to progressive neurodegeneration and gliosis, as described above. However, there is no effective therapy for GM2 gangliosidoses at present, although we have reported and proposed the clinical potential of the intrathecal ERT using recombinant modified human HexA [73] and HexB [74,75] in recent years. It is crucial for treatment of GM2 gangliosidoses to develop the CNS-directed molecular therapy including such intrathecal ERT,
At early stage of development of GT for GM2 gangliosidoses, gene transduction of cultured cells was performed by utilizing recombinant vectors (virus or plasmids), and examined the effect of cross correction due to the secreted Hex isozymes. Guidotti, JE.
On the other hand, Martino
We transfected an expression vector plasmid coding the human
Yamaguchi
These findings suggested that brain-directed
4.2. CNS-directed in vivo gene therapy
Bourgoin
Martino
Caillaud and co-workers reported that mono and bicistronic lentiviral vectors based on a simian immunodeficiency virus (SIV) containing the human
Cachon-Gonzalez
4.3. CNS-directed ex vivo gene therapy
Lacorazza HD
Tsuji D.
Mesenchymal stem cells (MSCs) derived from bone marrow stromal cells are one of the candidates for autologous donor cells for ex vivo GT, and have the multipotency to differentiate under specific culture conditions into other cell types such as osteoblasts, adipocytes, and chondrocytes [93,] as well as into neural lineages [94]. Recently, we established MSCs derived from bone marrow of adult
Lee J-P.
5. Conclusion
A number of preclinical and therapeutic approaches for GM2 gangliosidoses, including stem cell therapy, substrate deprivation therapy, gene therapy, and enzyme replacement therapy, are being examined and evaluated with disease model mice, although there is no effective therapy for treatment of the patients with GM2 gangliosidoses at present. However, according to the preclinical results obtained by using animal disease models, CNS-directed
Acknowledgments
Recent our research was supported by NIBIO (Osaka, Japan). We would appreciate Ms. Mayuko Oe for assisting us to prepare this review.References
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