Clinical protocol. Administration of a replication-deficient adeno-associated virus gene transfer vector expressing the human CLN2 cDNA to the brain of children with late infantile neuronal ceroid lipofuscinosis.

摘要: Late infantile neuronal ceroid lipofuscinosis (LINCL) is a fatal childhood neurodegenerative lysosomal storage disease with no known therapy. There are estimated to be 200 300 children in the United States at any one time disease. LINCL genetic resulting from deficiency of tripeptidyl peptidase I (TPP-I), proteolytic enzyme encoded by CLN2, gene that mutated individuals LINCL. The subjects chronically ill, progressive CNS disorder invariably results death, typically age 8 12 years. strategy this clinical study based on concept persistent expression normal CLN2 cDNA production sufficient amounts TPP-I should prevent further loss neurons, and hence limit progression. To assess concept, an adeno-associated virus vector (AAV2CUh-CLN2) will used transfer express human brain consists AAV2 capsid enclosing 4278-base single-stranded genome consisting two inverted terminal repeats AAV serotype 2 cassette composed cytomegalovirus (CMV) enhancer, chicken beta-actin promoter/splice donor 5' end intron, 3' rabbit P-globin intron splice acceptor, optimized Kozak translation initiation signal, polyadenylation/transcription stop codon 3-globin. proposed include 10 divided into parts. Group A, studied first, four severe form B trial six moderate After direct intracranial administration vector, there neurological assessment rating scale magnetic resonance imaging/magnetic spectroscopy regions administration. data generated help evaluate hypotheses: (1) it safe carry out AAV2cuhCLN2 LINCL, (2) slow down or halt progression central nervous system.