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Report for Clinical Trial NCT01414985

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 LINCL With Uncommon Genotypes and/or Moderate to Severe Impairment

The investigators propose to assess the safety and efficacy of a new administration method to deliver a biologic to children with a form of Batten disease using an experimental gene transfer procedure. This gene transfer procedure consists of delivering a good copy of the mutated gene to the nerve cells via a virus. These children are born with genetic changes called mutations 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 investigators previous clinical trial 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 and showed small, but significant benefits to the recipient. The investigators currently have an IRB approved protocol which uses a slightly different virus called AAVrh.10 as the gene delivery system. This 3rd protocol proposes to use the same virus AAVrh.10 as the gene delivery system and has expanded the eligibility criteria.

NCT01414985 Late Infantile Neuronal Ceroid Lipofuscinosis Batten Disease
MeSH:Neuronal Ceroid-Lipofuscinoses

1 Interventions

Name: AAVrh.10CUCLN2

Description: There will be 2 dose cohorts in this study. Group A consists of 2 subjects who have received 9.0x10^11 genome copies (900,000,000,000 molecules) of the study drug, AAVrh.10CUCLN2. Group B will consist of 6 subjects who will receive a lower dose of 2.85x10^11 genome copies (285,000,000,000 molecules) of the study drug, AAVrh.10CUCLN2.
Type: Biological
Group Labels: 2

Group A Group B


Primary Outcomes

Description: The Weill Cornell LINCL scale, a 12 point scale which combines assessment of feeding, gait, motor and language to give an overall assessment of various CNS functions (Appendix II for the paper describing the scale and Appendix VI for the scale)27. The lowest possible score is 0 (less progressed in disease) and the highest possible score is 12 (more progressed in disease). This rating scale evaluation will be performed by 2 independent pediatricians, on the basis of a videotaped evaluation. If the 2 independent scores differ by 1 or less they will be averaged and if they differ by greater than 1 point, a consensus will be obtained by a 3rd pediatrician. This outcome measure will look at changes over time.

Measure: Change in CNS function, as measured by the Weill Cornell LINCL Scale

Time: Screening, Pre-transfer, Months 1, 6, 12 and 18

Description: 3 imaging parameters (% gray matter volume, % ventricular volume and cortical apparent diffusion coefficient) correlate with age and the Weill Cornell LINCL scale. These 3 imaging parameters will be used to assess disease progression (control protocol) and safety of the gene transfer vector (vector protocol) over time. In addition to these imaging parameters we will also perform magnetic resonance spectroscopy (MRS) but the data obtained from this will be for information only for method development. This outcome measure will look at changes over time.

Measure: Safety, as measured by MRI

Time: Screening, Pre-transfer, Months 6, 12 and 18

Secondary Outcomes

Description: The CHQ or ITQoL, a quality of life questionnaire which will be completed by at least one parent/legal guardian at the time of the LINCL patients' visits to Weill Cornell. The survey will be administered independently to each parent to minimize observer bias if both parents are present. This outcome measure looks at a change over time.The lowest possible score is 0 (corresponds to lower health-related quality of life) and the highest possible score is 100 (corresponds to better health-related quality of life).

Measure: Change in Quality of Life, as measured by the Child Health Questionnaire (CHQ) or Infant Toddler Quality of Life (ITQoL) (depending on age)

Time: Screening, Pre-transfer (optional) and Month 18

Description: The Mullen scale, a pediatric developmental psychological rating scale, will be administered by a developmental psychologist, and be videotaped. This outcome measure will look at changes over time. The lowest possible score is 0 (corresponds to less psychological development) and the highest possible score is 197 (corresponds to better psychological development).

Measure: Change in psychological development, as measured by the Mullen Scale

Time: Screening, Pre-transfer (optional) and Month 18

Purpose: Treatment

Allocation: Non-Randomized

Parallel Assignment


There are 6 SNPs

SNPs


1 C3670T

3. Subjects will have an average total score of less than 4 but at least 1, and/or an uncommon genotype defined as any genotype that does not include at least one of the 5 most common mutant CLN2 genotypes: C3670T (nonsense Arg208 to stop), G3556C (intron 7 splice), G5271C (Gln422His), T4396G (aberrant splicing, intron8), and G4655A. --- C3670T ---


2 G3556C

3. Subjects will have an average total score of less than 4 but at least 1, and/or an uncommon genotype defined as any genotype that does not include at least one of the 5 most common mutant CLN2 genotypes: C3670T (nonsense Arg208 to stop), G3556C (intron 7 splice), G5271C (Gln422His), T4396G (aberrant splicing, intron8), and G4655A. --- C3670T --- --- G3556C ---


3 G4655A

3. Subjects will have an average total score of less than 4 but at least 1, and/or an uncommon genotype defined as any genotype that does not include at least one of the 5 most common mutant CLN2 genotypes: C3670T (nonsense Arg208 to stop), G3556C (intron 7 splice), G5271C (Gln422His), T4396G (aberrant splicing, intron8), and G4655A. --- C3670T --- --- G3556C --- --- G5271C --- --- Gln422His --- --- T4396G --- --- G4655A ---


4 G5271C

3. Subjects will have an average total score of less than 4 but at least 1, and/or an uncommon genotype defined as any genotype that does not include at least one of the 5 most common mutant CLN2 genotypes: C3670T (nonsense Arg208 to stop), G3556C (intron 7 splice), G5271C (Gln422His), T4396G (aberrant splicing, intron8), and G4655A. --- C3670T --- --- G3556C --- --- G5271C ---


5 Q422H

3. Subjects will have an average total score of less than 4 but at least 1, and/or an uncommon genotype defined as any genotype that does not include at least one of the 5 most common mutant CLN2 genotypes: C3670T (nonsense Arg208 to stop), G3556C (intron 7 splice), G5271C (Gln422His), T4396G (aberrant splicing, intron8), and G4655A. --- C3670T --- --- G3556C --- --- G5271C --- --- Gln422His ---


6 T4396G

3. Subjects will have an average total score of less than 4 but at least 1, and/or an uncommon genotype defined as any genotype that does not include at least one of the 5 most common mutant CLN2 genotypes: C3670T (nonsense Arg208 to stop), G3556C (intron 7 splice), G5271C (Gln422His), T4396G (aberrant splicing, intron8), and G4655A. --- C3670T --- --- G3556C --- --- G5271C --- --- Gln422His --- --- T4396G ---



HPO Nodes