Safety Study of a Gene Transfer Vector for Children With Late Infantile Neuronal Ceroid Lipofuscinosis

Late infantile neuronal ceroid lipofuscinosis (LINCL) is a fatal childhood neurodegenerative lysosomal storage disease with no known therapy. There are estimated to be 200 to 300 children in the USA at any one time with the disease. LINCL is a genetic disease resulting from mutations in the CLN2 gene. The CLN2 gene encodes a protein tripeptidyl peptidase-I (TPP-I) which is absent/deficient in children with LINCL. This absence/deficiency of TPP-I results in lysosomal storage and subsequent cell death (especially neurons). The children with LINCL are chronically ill, with a progressive CNS disorder that invariably results in death, typically by age 8 to 12. This clinical study will evaluate the concept that persistent expression of the normal CLN2 cDNA in the CNS will result in the production of sufficient amounts of TPP-I to prevent further loss of neurons, and hence limit disease progression. To assess this concept, an adeno-associated virus vector encoding the normal human CLN2 gene (AAV2CUhCLN2) will be used as a vehicle to deliver and express the human CLN2 cDNA in the brain of children with LINCL. The proposed study will include 11 individuals and will be divided into two parts. Group A, to be studied first, will include 5 individuals with the severe form of the disease. Group B of the trial will include 6 individuals with a moderate form of the disease. Following direct intracranial administration of the vector, there will be neurological assessment using the LINCL clinical rating scale and magnetic resonance imaging/magnetic resonance spectroscopy assessment of the CNS in regions of vector administration. The data generated will help evaluate two hypotheses: (1) that it is safe to carry out direct intracranial administration of the AAV2CUhCLN2 vector to the CNS of individuals with LINCL; and (2) that administration of the AAV2CUhCLN2 vector will slow down or halt the progression of the disease in the central nervous system.