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Gene Therapy < Small Molecule Therapy Medical Management >

Gene therapy is the use DNA that encodes a functional, therapeutic gene in order to replace a mutated gene. In gene therapy, DNA that encodes a therapeutic protein is packaged within a "vector", which is used to get the DNA inside cells within the body. Once inside, the DNA becomes expressed by the cell machinery, resulting in the production of therapeutic protein, which in turn treats the patient's disease.

Lysosomal storage disorders are excellent candidates for therapy by gene transfer for they:

represent generally well characterized single gene disorders. are not subject to complex regulation mechanisms, and an enzyme activity of only 15-

20% of the normal level is sufficient for clinical efficacy. There are two ways to deliver a gene into the organism, the in-vivo and the ex vivo technique. The in vivo technique no surgery or even anesthesia. In this process, the therapeutic DNA is injected directly into the body cells, usually via one of two types of viruses. The ex vivo technique, involves surgically removing cells from the affected tissue area, injecting or splicing the new DNA (the DNA that will correct the disease) into the cells and letting them divide in cultures. The new tissues are placed back into the affected area of the patient1. In Vivo Gene Therapy In animal experiments several vehicles such as adenoviral adeno-associated, retroviral and lentiviral vectors were used for efficient organ transduction using the lung and/or liver. The transduced organs produced large amounts of therapeutic enzyme that was secreted into the bloodstream and recaptured by the target organs by the mannose-6- phosphate receptor. In the mouse model of Fabry disease it could be demonstrated that biochemical and functional abnormalities can be corrected by gene therapy using various delivery systems. Li and coworkers used the lung as a depot organ for delivering -galactosidase into the heart and kidney of mice affected by Fabry disease 2. Ogawa et al. examined the possibility of gene therapy in neonatal animals3. AAV vector carrying human -galactosidase cDNA was intravenously administered into neonatal (2 days old) and adult (12 weeks old) Fabry mice. Several investigations were made 25 weeks after the injection. AAV vector preferentially transduced the liver, and in male adults high levels of -galactosidase were found in heart, liver and plasma. In female adult animals, however, AAV-mediated gene expression was suppressed. When the vector was administered to neonates, enzyme activity was found for many weeks in plasma and in the heart, independently from the gender of the mice. From these animal studies it can be concluded that by treatment in the early life major organ failure may be prevented. Ex Vivo Gene Therapy In the mouse model of Fabry disease4 bone marrow mononuclear cells were transduced with a retrovirus encoding -galactosidase and transplanted into irradiated -galactosidase deficient mice. Bone marrow mononuclear cells were then transplanted into secondary recipients. Increased enzyme activity and decreased Gb3 accumulation were found in all organs of all recipient groups. These results indicate that correction of bone marrow cells transduced with the -galactosidase gene via a vector may be able to correct the metabolic defect in Fabry patients. Limitations Although gene therapy in Fabry disease shows promising results additional experiments are required for a concluding treatment strategy. For instance the mouse model of Fabry disease is relatively long-lived and healthy even without corrective intervention. In addition, even in the same animal disease model using similar vectors, completely different results can be obtained5,6. It has also been reported that mice that lack -glucuronidase activity, which were injected with adeno-associated viral vectors containing the human glucuronidase gene, were found to have

hepatocellular carcinomas and angiosarcomas7. The cause of the tumours is presently unclear, although tumour production appears to depend on the over-expression of glucuronidase, as well as the strain of mouse employed. In conclusion more information and additional experiments are required concerning the safety of such vectors and make gene therapy a viable solution in the treatment of Fabry disease.

References: 1. Elstein, Deborah; Altarescu, Gheona; Beck, Michael (Eds.), Fabry Disease, 1st Edition., 2010, XXXVII, 512 p [Springer Book, Scribd] 2. Li C, Ziegler RJ, Cherry M, Lukason M, Desnick RJ, Yew NS, Cheng SH., v, Adenovirustransduced lung as a portal for delivering alpha-galactosidase A into systemic circulation for Fabry disease., Mol Ther. 2002 Jun;5(6):745-54. [PubMed] 3. Ogawa K, Hirai Y, Ishizaki M, Takahashi H, Hanawa H, Fukunaga Y, Shimada T., Long-term inhibition of glycosphingolipid accumulation in Fabry model mice by a single systemic injection of AAV1 vector in the neonatal period., Mol Genet Metab. 2009 Mar;96(3):91-6. Epub 2008 Dec 16. [PubMed] 4. Takenaka T, Murray GJ, Qin G, Quirk JM, Ohshima T, Qasba P, Clark K, Kulkarni AB, Brady RO, Medin JA., Long-term enzyme correction and lipid reduction in multiple organs of primary and secondary transplanted Fabry mice receiving transduced bone marrow cells., Proc Natl Acad Sci U S A. 2000 Jun 20;97(13):7515-20. [PubMed] 5. Takahashi H, Hirai Y, Migita M, Seino Y, Fukuda Y, Sakuraba H, Kase R, Kobayashi T, Hashimoto Y, Shimada T., Long-term systemic therapy of Fabry disease in a knockout mouse by adeno-associated virus-mediated muscle-directed gene transfer., Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13777-82. Epub 2002 Oct 7. [PubMed] 6. Park J, Murray GJ, Limaye A, Quirk JM, Gelderman MP, Brady RO, Qasba P., Long-term correction of globotriaosylceramide storage in Fabry mice by recombinant adeno-associated virus-mediated gene transfer., Proc Natl Acad Sci U S A. 2003 Mar 18;100(6):3450-4. Epub 2003 Mar 6. [PubMed] 7. Donsante A, Vogler C, Muzyczka N, Crawford JM, Barker J, Flotte T. et al. Observed incidence of tumorigenesis in long-term rodent studies of rAAV vectors. Gene Ther. 2001;8:13436. [PubMed]