Gene Therapy in the Central Nervous System
Neurodegenerative diseases represent a substantial burden for society in terms of both patient suffering and socio-economic costs. For example, in Europe nearly 3 million persons suffer from stroke, over 3 5 million from dementia (with a higher proportion of women than men) and about 1 million from Parkinson’s disease (PD). Overall, diseases of the nervous system, includingeyediseases, account for approximately 25% of all health costs in the EU, which in money terms translates into hundreds of billions of Euros. With increasing life expectancy, this cost is likely to greatly increase, since the prevalence of dementia is 18% of the population between 80 and 85 years of age and 32% between 85 and 90. Similarly, PD affects more than 10% of the population after the age of 85. There is no cure for most of the neurodegenerative diseases, and the very few available treatments are unsatisfactory. The urgent need to develop therapies will rely on the unravelling of the pathophysiological mechanisms underlying these afflictions and on the development and use of post-genomics and cell/gene transfer technologies.
KeywordsToxicity Dementia Retina Neurol Gravel
Unable to display preview. Download preview PDF.
- Bilang-Bleuel A, Revah F, Colin P, Locquet I, Robert JJ, Mallet J, Horellou P (1997) Intrastriatal injection of an adenoviral vector expressing glial-cell-line-derived neurotrophic factor prevents dopaminergic neuron degeneration and behavioral impairment in a rat model of Parkinson disease. Proc Natl Acad Sci USA 94: 8818–8823.PubMedCrossRefGoogle Scholar
- Bruijn LI, Becher MW, Lee MK., Anderson KL, Jenkins NA, Copeland NG, Sisodia, SS, Rothstein JD, Borchelt DR, Price DL, Cleveland DW (1997) ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing indusions. Neuron 18,; 327–338.PubMedCrossRefGoogle Scholar
- Fan DS, Ogawa M, Fujimoto KI, Ikeguchi K, Ogasawara Y, Urabe M, Nishizawa M, Nakano I, Yoshida M, Nagatsu I, Ichinose H, Nagatsu T, Kurtzman GJ, Ozawa K (1998) Behavioral recovery in 6-hydroxydopamine-lesioned rats by cotransduction of striatum with tyrosine hydroxylase and aromatic L- amino acid decarboxylase genes using two separate adeno-associated virus vectors. Human Gene Ther 9: 2527–2535.CrossRefGoogle Scholar
- Kordower J.H, Emborg ME, Bloch J, Ma SY, Chu Y, Leventhal L, McBride J, Chen EY, Palfi S, Roitberg BZ, Brown WD, Holden JE, Pyzalski R, Taylor,MD, CarveyP, Ling, Z, Trono D, Hantraye P, Deglon N, Aebischer P (2000) Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson’s disease. Science 290: 767–773.PubMedCrossRefGoogle Scholar
- Le Gal La Salle G, Robert JJ, Berrard S, Ridoux V, Stratford-Perricaudet LD, Perricaudet M, Mallet J (1993) An adenovirus vector for gene transfer into neurons and glia in the brain. Science 25+9: 988–990.Google Scholar
- Morelli AE, Larregina AT, Smith-Arica J, Dewey RA, Southgate,TD, Ambar B, Fontana A, Castro MG, Lowenstein PR (1999) Neuronal and glial cell type-specific promoters within adenovirus recombinants restrict the expression of the apoptosis-inducing molecule Fas ligand to predetermined brain cell types, and abolish peripheral liver toxicity. J Gen Virol 80: 571–583.PubMedGoogle Scholar
- Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O’Regan JP, Deng HX, Rahmani Z, Krizus A, McKenna-Yasek D, Cayabyab SM, Berger R, Tanzi RE, Halperin J, Herzfeldt B, Van den Bergh R, Hung W-Y Hung, Bird T, Deng G, Mulder DW, Smyth C, Laing NG, Soriano E, Pericak-Vance MA, Haines J, Rouleau GA, Gusella JS, Horvitz HR, Brown Jr RH (1993). Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362, 59–62.PubMedCrossRefGoogle Scholar
- Tu PH, Raju P, Robinson KA, Gurney ME, Trojanowski JQ, Lee VM (1996) Transgenic mice carrying a human mutant superoxide dismutase transgene develop neuronal cytoskeletal pathology resembling human amyotrophic lateral sclerosis lesions. Proc Natl Acad Sci USA 93,: 3155–3160.PubMedCrossRefGoogle Scholar
- Wong PC, Pardo CA, Borchelt DR, Lee MK, Copeland NG, Jenkins NA, Sisodia, SS, Cleveland DW, Price DL (1995). An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron 14: 1105–1116.PubMedCrossRefGoogle Scholar