The aim of this study is to treat the signs and symptoms of late infantile neuronal ceroid lipofuscinosis (LINCL), a fatal inherited disease in the brain. This will be accomplished by using delivery of a gene (method called gene transfer) to administer to the brain an experimental drug called AAV2CUhCLN2, a gene transfer vector.
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
10
gene transfer; one-time administration via neuro surgery procedure
New York Presbyterian Hospital - Weill Medical College of Cornell University
New York, New York, United States
Neurological assessment using the LINCL clinical rating scale
The neurological examination will be carried out using a standard format with input from the parents/legal guardians as relevant. The clinical rating scale, referred to as a "CNS disability scale" is made up of individual sum of 4 point scales for each of 3 activities; the ratings for each activity are summed, giving a "CNS disability score". Each of the activities are rated 0 to 3, where 0 is the most severe form of the disease. This scale, developed by Steinfeld et al, originally included the four major functional problems in LINCL (loss of motor performance, seizure activity, loss of vision, and loss of language). In this modified clinical rating system, these are now 3 categories.
Time frame: screening; pre-therapy; and 6 and 18 months post-vector administration
MRI/MRS assessment
The secondary endpoint variable will be the MRI/MRS assessment of the CNS in regions of vector administration. Anatomical measurements of brain parenchymal volume will be combined with proton spectroscopic imaging of the n-acetyl-aspartate (NAA) resonance, a neuronal marker measurable using clinical magnetic resonance techniques.
Time frame: screening; pre-therapy; and 6 and 18 months post-vector administration
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