Safety Study of a Gene Transfer Vector for Children With Late Infantile Neuronal Ceroid Lipofuscinosis

NCT00151216 | Completed Phase 1 DMC FDA Drug

• 2 other identifiers: 0401007010OBA-RAC 0312-619
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Batten Disease; Late Infantile Neuronal Ceroid Lipofuscinosis

Keywords

Batten Disease; Late Infantile Neuronal Ceroid Lipofuscinosis; LINCL

Outcome Measures

Primary Outcomes (1)

• 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.

  screening; pre-therapy; and 6 and 18 months post-vector administration

Secondary Outcomes (1)

• MRI/MRS assessment

  screening; pre-therapy; and 6 and 18 months post-vector administration

Study Arms (2)

Group A-Severe Stages of LINCL

EXPERIMENTAL

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. All subjects will receive 3x10\^12 particle units of the AAV2CUhCLN2 vector.

Biological: AAV2CUhCLN2 (3x10^12 particle units)

Group B-Moderate Stages of LINCL

EXPERIMENTAL

Group B will include n=6 children with a total disability score of 5 to 6, a moderate stage of the disease. All subjects will receive 3x10\^12 particle units of the AAV2CUhCLN2 vector.

Biological: AAV2CUhCLN2 (3x10^12 particle units)

Interventions

AAV2CUhCLN2 (3x10^12 particle units) BIOLOGICAL

gene transfer; one-time administration via neuro surgery procedure

Group A-Severe Stages of LINCL; Group B-Moderate Stages of LINCL

Eligibility Criteria

• Age: 3 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• A definitive diagnosis of late infantile neuronal ceroid lipofuscinosis, based on clinical phenotype and genotype, with CLN2 gene mutations known to be associated with the disease.
• All subjects will be naive, i.e., they have not previously participated in a gene therapy study for LINCL.
• Parents of study participants must agree to comply in good faith with the conditions of the study, including attending all of the required baseline and follow-up assessments.
• Both parents or legal guardians must give consent for their child's participation in the research study.
• For group A, subjects will have a LINCL average total disability score 0 to 4, the severe form of the disease.
• For group B, subjects will have a LINCL average total disability score 5 to 6, a moderate form of the disease.

You may not qualify if:

• Other significant medical or neurological conditions may disqualify the patient from participation in this study, particularly those which would create an unacceptable operative risk or risk to receiving the AAV2CUhCLN2 vector. Examples include malignancy (other than skin cancer), congenital heart disease, liver or renal failure, or seropositive for HIV. Each case will be individually reviewed and the final decision shall rest with the Eligibility Committee comprised on three physicians other than the Principal Investigator, including a pediatric neurosurgeon, pediatric neurologist and general pediatrician.
• Individuals without adequate control of seizures (i.e., a seizure score \<3 on the CNS Disability Scoring System for Late Infantile Neuronal Ceroid Lipofuscinosis).
• Individuals with heart disease that would be a risk for anesthesia.
• History of hemorrhage or major risk factors for hemorrhage (e.g., abnormally low platelet counts).
• Concurrent participation in any other FDA approved Investigational New Drug clinical protocol is not allowed, although the Principal Investigator will work with other doctors to accommodate specific requests (e.g., a study of nutritional supplements probably would not be a disqualification).
• Individuals who have a (1) heart pacemaker and/or related implants, (2) metal fragment/chip in the eye or other sites, (3) an aneurysm clip in their brain, and (4) metallic inner ear implants.

Sponsors & Collaborators

• Weill Medical College of Cornell University: lead
• Nathan's Battle Foundation: collaborator

Study Sites (1)

New York Presbyterian Hospital - Weill Medical College of Cornell University

New York, New York, 10021, United States

Location

Related Publications (2)

• Sondhi D, Kaminsky SM, Rosenberg JB, Rostami MR, Hackett NR, Crystal RG. Twenty-Year Survival Analysis of Adeno-Associated Virus Vector Serotype 2-Mediated Gene Therapy to the Central Nervous System for CLN2 Disease. Hum Gene Ther. 2024 Jan;36(1-2):28-35. doi: 10.1089/hum.2024.182. Epub 2025 Jan 2.

  PMID: 39745261 DERIVED

• Worgall S, Sondhi D, Hackett NR, Kosofsky B, Kekatpure MV, Neyzi N, Dyke JP, Ballon D, Heier L, Greenwald BM, Christos P, Mazumdar M, Souweidane MM, Kaplitt MG, Crystal RG. Treatment of late infantile neuronal ceroid lipofuscinosis by CNS administration of a serotype 2 adeno-associated virus expressing CLN2 cDNA. Hum Gene Ther. 2008 May;19(5):463-74. doi: 10.1089/hum.2008.022.

  PMID: 18473686 DERIVED

MeSH Terms

Conditions

Neuronal Ceroid-Lipofuscinoses

Condition Hierarchy (Ancestors)

Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lipidoses; Lipid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• Ronald G. Crystal, MD

  Weill Medical College of Cornell University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: September 6, 2005
• First Posted: September 8, 2005
• Study Start: June 1, 2004
• Primary Completion: June 1, 2019
• Study Completion: June 1, 2019
• Last Updated: July 24, 2020

Record last verified: 2020-07

Locations

US (1)