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

Primary Purpose

Batten Disease, Late Infantile Neuronal Ceroid Lipofuscinosis

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
AAV2CUhCLN2 (3x10^12 particle units)
Sponsored by
Weill Medical College of Cornell University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Batten Disease focused on measuring Batten Disease, Late Infantile Neuronal Ceroid Lipofuscinosis, LINCL

Eligibility Criteria

3 Years - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: 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. Exclusion criteria 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.

Sites / Locations

  • New York Presbyterian Hospital - Weill Medical College of Cornell University

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Group A-Severe Stages of LINCL

Group B-Moderate Stages of LINCL

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

MRI/MRS assessment
The secondary endpoint variable will be the MRI/MRS assessment of the CNS in regions of vector administration. Anatomical measurements of brain parenchymal volume will be combined with proton spectroscopic imaging of the n-acetyl-aspartate (NAA) resonance, a neuronal marker measurable using clinical magnetic resonance techniques.

Full Information

First Posted
September 6, 2005
Last Updated
July 22, 2020
Sponsor
Weill Medical College of Cornell University
Collaborators
Nathan's Battle Foundation
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1. Study Identification

Unique Protocol Identification Number
NCT00151216
Brief Title
Safety Study of a Gene Transfer Vector for Children With Late Infantile Neuronal Ceroid Lipofuscinosis
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
July 2020
Overall Recruitment Status
Completed
Study Start Date
June 2004 (undefined)
Primary Completion Date
June 2019 (Actual)
Study Completion Date
June 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Weill Medical College of Cornell University
Collaborators
Nathan's Battle Foundation

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Batten Disease, Late Infantile Neuronal Ceroid Lipofuscinosis
Keywords
Batten Disease, Late Infantile Neuronal Ceroid Lipofuscinosis, LINCL

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
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)
Allocation
Non-Randomized
Enrollment
10 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Group A-Severe Stages of LINCL
Arm Type
Experimental
Arm Description
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.
Arm Title
Group B-Moderate Stages of LINCL
Arm Type
Experimental
Arm Description
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.
Intervention Type
Biological
Intervention Name(s)
AAV2CUhCLN2 (3x10^12 particle units)
Intervention Description
gene transfer; one-time administration via neuro surgery procedure
Primary Outcome Measure Information:
Title
Neurological assessment using the LINCL clinical rating scale
Description
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.
Time Frame
screening; pre-therapy; and 6 and 18 months post-vector administration
Secondary Outcome Measure Information:
Title
MRI/MRS assessment
Description
The secondary endpoint variable will be the MRI/MRS assessment of the CNS in regions of vector administration. Anatomical measurements of brain parenchymal volume will be combined with proton spectroscopic imaging of the n-acetyl-aspartate (NAA) resonance, a neuronal marker measurable using clinical magnetic resonance techniques.
Time Frame
screening; pre-therapy; and 6 and 18 months post-vector administration

10. Eligibility

Sex
All
Minimum Age & Unit of Time
3 Years
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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. Exclusion criteria 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ronald G. Crystal, MD
Organizational Affiliation
Weill Medical College of Cornell University
Official's Role
Principal Investigator
Facility Information:
Facility Name
New York Presbyterian Hospital - Weill Medical College of Cornell University
City
New York
State/Province
New York
ZIP/Postal Code
10021
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
18473686
Citation
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.
Results Reference
derived

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

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