Safety Study of a Gene Transfer Vector for Children With Late Infantile Neuronal Ceroid Lipofuscinosis
Condition: Batten Disease; Late Infantile Neuronal Ceroid Lipofuscinosis
MeSH terms: Neuronal Ceroid-Lipofuscinoses
Study type: Interventional
Phase: Phase 1

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): AAV2CUhCLN2 (3x10^12 particle units)
Intervention type(s): Biological
Intervention description(s): gene transfer; one-time administration via neuro surgery procedure
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: The study will be carried out in two populations of children with LINCL. Group A will include n= 5 children with a total disability score of 0 to 4 (the severe forms of the disease; the staging based on a modification of the scale of Steinfeld et al. Group B will include n=6 children with a total disability score of 5 to 6, a moderate stage of the disease. All of the study population of 11 children (Group A, n= 5 and Group B, n=6) will receive 3x10^12 particle units of the AAV2CUhCLN2 vector divided among 12 locations delivered through 6 burr holes (2 locations at varying depths through each hole), 3 burr holes per hemisphere. The choice of the locations for the burr holes and needle placement will be on a case-by-case basis due to the diffuse and variable nature of the disease presentation.
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Batten Disease; Late Infantile Neuronal Ceroid Lipofuscinosis; LINCL