Safety Study of a Gene Transfer Vector (Rh.10) for Children With Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL)
Condition: Batten Disease; Late-Infantile Neuronal Ceroid Lipofuscinosis
MeSH terms: Neuronal Ceroid-Lipofuscinoses
Study type: Interventional
Phase: Phase 1

Summary: 
      This is a proposed follow up study on the investigators previous gene transfer human clinical
      trial entitled "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" (Weill Cornell IRB# 0401007010). As in the previous study,
      the investigators propose to administer a biologic by direct gene transfer into the brain and
      assess its safety on children with a fatal genetic disease of the central nervous system
      (CNS). The disease is Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL, a form of Batten
      disease). This will be accomplished by using delivery of a gene (method called gene transfer)
      to administer to the brain an experimental drug called AAVRh.10CUhCLN2, a gene transfer
      vector.
    

Detailed description: 
      The investigators propose to assess a new drug to treat children with a form of Batten
      Disease called Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL). These children are born
      with genetic changes called mutations in their CLN2 gene that result in the inability of the
      brain to properly recycle proteins. The recycling failure leads to death of the nerve cells
      in the brain and progressive loss of brain function. Children with Batten disease are normal
      at birth but by age 2 to 4 have motor and vision problems which progress rapidly to death at
      age approximately 10 years old. There are no therapies available to treat the disease.

      The experimental gene transfer procedure treatment the investigators propose consists of
      augmenting the abnormal gene by a good copy. A virus is used to deliver the good gene to the
      nerve cells. Since the disease is due to an abnormal CLN2 gene, the aim of this study is to
      add a normal copy of the CLN2 gene to the brain of affected children to try to reverse death
      of cells in the brain. Previously the investigators have used a virus called adeno-associated
      virus 2 (AAV2) as the gene delivery system. That study showed that viral delivery of the gene
      was safe. We now propose to use a slightly different virus called AAVrh.10 as a gene delivery
      system and use 2 different doses of the virus. Children with Batten disease will get the drug
      injected into the brain and will receive extensive neurological assessment at intervals to
      determine if the transfer slows the rate of progress of the disease.

      The primary aims of the study are: (1) to assess the hypothesis that direct administration of
      AAVrh.10CUhCLN2 to the brain of children with LINCL can be achieved safely and with minimal
      toxicity; and (2) to evaluate the hypothesis that direct administration of AAVrh.10CUhCLN2 to
      the brain of children with LINCL will slow down or halt progression of the disease as
      assessed by neurological rating scales and quantitative MRI (primary variables).

      The investigators have recently completed a study in which the normal copy of the gene was
      surgically delivered to 12 locations in the brain in 10 children with LINCL. The children
      were assessed by a number of neurological and imaging parameters prior to and after gene
      transfer. The data demonstrated that the gene transfer was well tolerated and had a small
      impact on the progression of the disease and suggested that higher doses and a better
      delivery system may provide greater benefit. The previous study used the viral gene transfer
      vector adeno-associated virus type 2 (AAV2) at a dose of 2,000,000,000,000 molecules of the
      drug (2 x 10^12 particle units). The investigators now propose a very similar study with
      delivery of the identical payload with a slightly different viral gene delivery system based
      on the virus AAVrh.10.
    

Intervention name(s): AAVrh.10CUhCLN2 vector 9.0x10^11 genome copies; AAVrh.10CUhCLN2 vector 2.85x10^11 genome copies
Intervention type(s): Biological; Biological
Intervention description(s): The experimental drug for this second generation study has a genome identical to that used in our previous study and delivers the same gene, but instead of an AAV2 capsid (protein shell of the virus), the new vector has the capsid of AAVrh.10, a clade E AAV derived from rhesus macaque (a species of Old World monkeys). The first dose that was given to the first 6 subjects is 9.0x10^11(900,000,000,000 molecules of the drug) genome copies/subject. In regards to drug administrations, we propose to perform 2 series of 6 simultaneous administrations of vector for 75 min each. Each subject will receive the assigned dose of AAVrh.10CUhCLN2, divided among 12 locations delivered through 6 burr holes (2 locations at 2 depths through each hole), 3 burr holes per hemisphere.; The experimental drug for this 2nd generation study has a genome identical to that used in our previous study and delivers the same gene but instead of an AAV2 capsid (protein shell of the virus), the new vector has the capsid of AAVrh.10, a clade E AAV derived from rhesus macaque (a species of Old World monkeys). Group B will receive a dose of 2.85x10^11 genome copies (285,000,000,000 molecules of the drug). In regards to drug administration, we propose to perform 2 series of 6 simultaneous administrations of vector for 75 min each. Each subject will receive the assigned dose of AAVrh.10CUhCLN2, divided among 12 locations delivered through 6 burr holes, 3 burr holes per hemisphere.
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: We chose an initial dose two fold lower of 9.0x10^11 genome copies/subject (Group A). Initially, the study plan was to proceed to Group B, which would receive a higher dose of 1.8x10^12 genome copies if the initial dose was well tolerated. However, after assessing the MRI images of the first 6 children who received the dose of 9.0x10^11 gc, we discovered that 4 of the 6 subjects at 6 months and 1 of the 6 subjects at 12 months exhibited varying degrees of T2 hyperintensities related to diffusion restriction at the sites of vector deposition. Although there are no clinical correlates to these MRI findings, we have decided to lower the dose by ½ log to 2.85x10^11 gc for the remaining subjects to be enrolled in protocol #0810010013. The volume of the drug solution will be the same as in Group A, but the concentration of the vector will be ½ log less.
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Batten Disease; Late Infantile Neuronal Lipofuscinosis; gene transfer