Gene Therapy

Gene therapy is currently being investigated for MPS VI and other forms of MPS. The concept of gene therapy for MPS is a compelling one—just like enzyme replacement therapy (ERT), it addresses the underlying enzyme deficiency. But at this point, gene therapy remains a very early-stage prospect; current research is ongoing in animal or in vitro models. Human studies have not been performed.

Two general strategies for gene therapy are currently being investigated by various groups:

• Direct administration of adeno-associated virus (AAV) vectors containing the rhASB gene: These viral vectors are intended to transfer the rhASB gene directly into cells of the recipient in the local anatomical area where they are injected. For example, injections into the eye are meant to target cells of the retina, whereas intra-dural injections would target the brain.^1-3
• Ex vivo gene therapy: Cells—for example hematopoietic stem cells, skin fibroblasts, or myocytes—would be removed from the patient, and then cultured and transduced with the rhASB gene using a retroviral vector. The transduced cells, which now produce rhASB enzyme, would then be re-introduced into the patient.^4-6

In either case, the goal is to introduce the rhASB gene into a subset of cells within the patient's body; these cells would then secrete rhASB enzyme into their environment, and the enzyme would be absorbed by other cells that are enzyme-deficient.

1. Hennig AK, Levy B, Ogilvie JM, et al. Intravitreal gene therapy reduces lysosomal storage in specific areas of the CNS in mucopolysaccharidosis VII mice. J Neurosci. 2003;23:3302-3307.
2. Ho TT, Maguire AM, Aguirre GD, et al. Phenotypic rescue after adeno-associated virus-mediated delivery of 4-sulfatase to the retinal pigment epithelium of feline mucopolysaccharidosis VI. J Gene Med. 2002;4:613-621.
3. Fu H, Samulski RJ, McCown TJ, et al. Neurological correction of lysosomal storage in a mucopolysaccharidosis IIIB mouse model by adeno-associated virus-mediated gene delivery. Mol Ther. 2002;5:42-49.
4. Yogalingam G, Muller V, Hopwood JJ, Anson DS. Regulation of N-acetylgalactosamine 4-sulfatase expression in retrovirus-transduced feline mucopolysaccharidosis type VI muscle cells. DNA Cell Biol. 1999;18:187-195.
5. Simonaro CM, Haskins ME, Abkowitz JL, et al. Autologous transplantation of retrovirally transduced bone marrow or neonatal blood cells into cats can lead to long-term engraftment in the absence of myeloablation. Gene Ther. 1999;6:107-113.
6. Yogalingam G, Bielicki J, Hopwood JJ, Anson DS. Feline mucopolysaccharidosis type VI: correction of glycosaminoglycan storage in myoblasts by retrovirus-mediated transfer of the feline N-acetylgalactosamine 4-sulfatase gene. DNA Cell Biol. 1997;16:1189-1194.