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The neuronal ceroid-lipofuscinoses (NCLs) constitute one of the most common groups of inherited neurodegenerative disorders in children but may also occur in adults. The childhood forms of NCL show an autosomal recessive inheritance, and are clinically characterized by progressive mental and motor deterioration and loss of vision, often accompanied by epileptic seizures and myoclonus. The rare adult forms usually present as dementia. The common denominator of all forms of NCL is the lysosomal accumulation of abnormal lipofuscin-like material in nerve cells, associated with progressive and selective neuronal loss. The NCLs are caused by more than 400 mutations in at least 13 different genes. The diagnosis is based on the characteristic clinical picture and/or biopsy, and verified by enzyme tests and molecular genetic methods. Prenatal and carrier testing is increasingly available. Current research aims at bridging the gap between the multiple genomic defects and the strikingly uniform pattern of neurodegeneration, and developing new therapies.

This chapter describes a program to assess gene transfer as a therapeutic approach to delay the neurological decline in children with the late infantile form of neuronal ceroid lipofuscinosis (LINCL). The disease arises from autosomal recessive inheritance of rare mutations in the CLN2 gene leading to a deficiency in the lysosomal protease tripeptidyl peptidase I (TPP-I). The challenge for a potential treatment is to obtain a therapeutic level of the target protein throughout the brain over the long term. Direct injection into the brain of a gene transfer vector derived from AAV serotype 2, AAV2CUhCLN2, was chosen as the most easily implemented approach to begin a human clinical study. Limited pre-clinical efficacy studies were performed in rats and monkeys to demonstrate feasibility. Upon proof of concept, a toxicology study and a manufacturing program were executed providing the supporting data for commencing a clinical study in June 2004. This ongoing study is providing an insight on the feasibility of this approach in slowing the neurodegeneration in children with LINCL as well as potentially using similar approaches to treat other neurodegenerative diseases of lysosomal storage.