? ? The goal of this proposal is to carry out the preclinical studies and complete regulatory requirements necessary to initiate a clinical trial using an adeno-associated virus to transfer the human CLN2 cDNA to the brain of children with late infantile neuronal ceroid lipofuscinosis (LINCL), a fatal, neurodegenerative lysosomal storage disease. The strategy is based on the concept that persistent expression of the normal CLN2 cDNA in the brain will result in sufficient levels of the CLN2 product tripeptidyl peptidase-I (TPP-I) to slow down or halt neurodegeneration.
The specific aims are:
Aim 1. Demonstrate that the vector, AAV5cuhCLN2, when administered to the brain of experimental animals will result in sufficient distribution, duration and level of functional TPP-I to slow down or halt the progression of the CNS disease in children with LINCL.
Aim 2. Optimize the manufacture of the AAV5cuhCLN2 vector under Good Manufacturing Practice (GMP) conditions and quality control the vector for use in the proof of concept and toxicology studies and in a future clinical study.
Aim 3. To develop the toxicology data, clinical protocol and regulatory documents for the clinical study, and gain approval for a study from the Institutional Review Board ORB), Institutional Biosafety Committee (IBC), NIH Office of Biotechnology Activities/Recombinant DNA Advisory Committee (NIH OBA/RAC) and the Food and Drug Administration (FDA). To achieve these aims and to insure that the milestones developed in conjunction with the NINDS staff are met, five teams with expertise in vector production, in vitro and in vivo analyses, experimental animal studies (proof of concept and toxicology), regulatory affairs and overall management will be used. Our objective is to be ready to commence a clinical study, to be developed as the data evolves, at the end of the 5 yr grant period. ? ?
|Foley, Conor P; Rubin, David G; Santillan, Alejandro et al. (2014) Intra-arterial delivery of AAV vectors to the mouse brain after mannitol mediated blood brain barrier disruption. J Control Release 196:71-78|
|Sondhi, Dolan; Johnson, Linda; Purpura, Keith et al. (2012) Long-term expression and safety of administration of AAVrh.10hCLN2 to the brain of rats and nonhuman primates for the treatment of late infantile neuronal ceroid lipofuscinosis. Hum Gene Ther Methods 23:324-35|
|Piguet, Françoise; Sondhi, Dolan; Piraud, Monique et al. (2012) Correction of brain oligodendrocytes by AAVrh.10 intracerebral gene therapy in metachromatic leukodystrophy mice. Hum Gene Ther 23:903-14|
|de Melo-Martin, Inmaculada; Sondhi, Dolan; Crystal, Ronald G (2011) When ethics constrains clinical research: trial design of control arms in ""greater than minimal risk"" pediatric trials. Hum Gene Ther 22:1121-7|
|Souweidane, Mark M; Fraser, Justin F; Arkin, Lisa M et al. (2010) Gene therapy for late infantile neuronal ceroid lipofuscinosis: neurosurgical considerations. J Neurosurg Pediatr 6:115-22|
|Kiuru, Maija; Boyer, Julie L; O'Connor, Timothy P et al. (2009) Genetic control of wayward pluripotent stem cells and their progeny after transplantation. Cell Stem Cell 4:289-300|
|Sondhi, Dolan; Peterson, Daniel A; Edelstein, Andrew M et al. (2008) Survival advantage of neonatal CNS gene transfer for late infantile neuronal ceroid lipofuscinosis. Exp Neurol 213:18-27|
|Worgall, Stefan; Sondhi, Dolan; Hackett, Neil R et al. (2008) Treatment of late infantile neuronal ceroid lipofuscinosis by CNS administration of a serotype 2 adeno-associated virus expressing CLN2 cDNA. Hum Gene Ther 19:463-74|
|Kiuru, M; Crystal, R G (2008) Progress and prospects: gene therapy for performance and appearance enhancement. Gene Ther 15:329-37|
|Sondhi, Dolan; Hackett, Neil R; Peterson, Daniel A et al. (2007) Enhanced survival of the LINCL mouse following CLN2 gene transfer using the rh.10 rhesus macaque-derived adeno-associated virus vector. Mol Ther 15:481-91|
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