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Report for Clinical Trial NCT01161576

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

Direct CNS Administration of a Replication Deficient Adeno-associated Virus Gene Transfer Vector Serotype rh.10 Expressing the Human CLN2 cDNA to Children With Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL)

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.

NCT01161576 Batten Disease Late-Infantile Neuronal Ceroid Lipofuscinosis
MeSH:Neuronal Ceroid-Lipofuscinoses

2 Interventions

Name: AAVrh.10CUhCLN2 vector 9.0x10^11 genome copies

Description: 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.
Type: Biological
Group Labels: 1

Group A

Name: AAVrh.10CUhCLN2 vector 2.85x10^11 genome copies

Description: 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.
Type: Biological
Group Labels: 1

Group B


Primary Outcomes

Description: A clinical rating, 12 point scale which combines assessment of feeding, gait, motor and language to give an overall assessment of various CNS functions.

Measure: Change in Weill-Cornell LINCL scale from Baseline to 18 months

Time: 18 Months

Description: Based on previous analyses, we have determined that 3 imaging parameters (% grey matter volume, MRI Assessment, % ventricular volume and cortical apparent diffusion coefficient) correlate best with age and with the Weill Cornell LINCL scale and will be used to assess disease progression and the effect of the gene transfer.

Measure: Disease progression based on change in MRI imaging parameter (% grey matter volume) from Baseline to 18 Months

Time: 18 Months

Description: Based on previous analyses, we have determined that 3 imaging parameters (% grey matter volume, MRI Assessment, % ventricular volume and cortical apparent diffusion coefficient) correlate best with age and with the Weill Cornell LINCL scale and will be used to assess disease progression and the effect of the gene transfer.

Measure: Disease progression based on change in MRI imaging parameter (% ventricular volume) from Baseline to 18 Months

Time: 18 Months

Description: Based on previous analyses, we have determined that 3 imaging parameters (% grey matter volume, MRI Assessment, % ventricular volume and cortical apparent diffusion coefficient) correlate best with age and with the Weill Cornell LINCL scale and will be used to assess disease progression and the effect of the gene transfer.

Measure: Disease progression based on change in MRI imaging parameter cortical apparent diffusion coefficient) from Baseline to 18 Months

Time: 18 Months

Secondary Outcomes

Description: The quality of life survey that will be completed by at least one parent/legal guardian at the screening visit and the month 18 visit will be either the Infant Toddler Quality of Life (ITQoL) questionnaire or the Child Health Questionnaire (CHQ), depending on the age of the subject. The ITQoL is administered to subjects up to the age of five and the CHQ is administered to subjects from age 5-18.

Measure: Change in Quality of Life Survey from Baseline to 18 Months

Time: 18 months

Description: Averaging the scores from the Mullen Scale

Measure: Mullen Scale (developmental assessment) from Baseline to 18 Months

Time: 18 months

Purpose: Treatment

Allocation: Non-Randomized

Parallel Assignment


There are 8 SNPs

SNPs


1 C365Y

The genotype must include at least one of the 5 most common CLN2 mutant genotypes: C3670T (nonsense Arg208 to stop), G3556C (intron 7 splice), G5271C (Gln422His), T4396G (aberrant splicing, intron 8) and G4655A (Cys365Tyr). --- C3670T --- --- G3556C --- --- G5271C --- --- Gln422His --- --- T4396G --- --- G4655A --- --- Cys365Tyr ---


2 C3670T

The genotype must include at least one of the 5 most common CLN2 mutant genotypes: C3670T (nonsense Arg208 to stop), G3556C (intron 7 splice), G5271C (Gln422His), T4396G (aberrant splicing, intron 8) and G4655A (Cys365Tyr). --- C3670T ---


3 G3556C

The genotype must include at least one of the 5 most common CLN2 mutant genotypes: C3670T (nonsense Arg208 to stop), G3556C (intron 7 splice), G5271C (Gln422His), T4396G (aberrant splicing, intron 8) and G4655A (Cys365Tyr). --- C3670T --- --- G3556C ---


4 G4655A

The genotype must include at least one of the 5 most common CLN2 mutant genotypes: C3670T (nonsense Arg208 to stop), G3556C (intron 7 splice), G5271C (Gln422His), T4396G (aberrant splicing, intron 8) and G4655A (Cys365Tyr). --- C3670T --- --- G3556C --- --- G5271C --- --- Gln422His --- --- T4396G --- --- G4655A ---


5 G5271C

The genotype must include at least one of the 5 most common CLN2 mutant genotypes: C3670T (nonsense Arg208 to stop), G3556C (intron 7 splice), G5271C (Gln422His), T4396G (aberrant splicing, intron 8) and G4655A (Cys365Tyr). --- C3670T --- --- G3556C --- --- G5271C ---


6 Q422H

The genotype must include at least one of the 5 most common CLN2 mutant genotypes: C3670T (nonsense Arg208 to stop), G3556C (intron 7 splice), G5271C (Gln422His), T4396G (aberrant splicing, intron 8) and G4655A (Cys365Tyr). --- C3670T --- --- G3556C --- --- G5271C --- --- Gln422His ---


7 R447H

If either parental allele is R447H, the patient will not be included in the study. --- R447H ---


8 T4396G

The genotype must include at least one of the 5 most common CLN2 mutant genotypes: C3670T (nonsense Arg208 to stop), G3556C (intron 7 splice), G5271C (Gln422His), T4396G (aberrant splicing, intron 8) and G4655A (Cys365Tyr). --- C3670T --- --- G3556C --- --- G5271C --- --- Gln422His --- --- T4396G ---



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