Trial record 2 of 2 for:    CEROID LIPOFUSCINOSIS, NEURONAL, 10

Safety Study of a Gene Transfer Vector (Rh.10) for Children With Late Infantile Neuronal Ceroid Lipofuscinosis

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2013 by Weill Medical College of Cornell University
Sponsor:
Information provided by (Responsible Party):
Weill Medical College of Cornell University
ClinicalTrials.gov Identifier:
NCT01161576
First received: March 22, 2010
Last updated: November 5, 2013
Last verified: November 2013
  Purpose

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 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.


Condition Intervention Phase
Batten Disease
Late Infantile Neuronal Lipofuscinosis
Genetic: AAVrh.10CUhCLN2 vector
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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)

Resource links provided by NLM:


Further study details as provided by Weill Medical College of Cornell University:

Primary Outcome Measures:
  • Rating on the Weill-Cornell scale [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  • MRI Parameters [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • CHQ/ITQoL questionnaire [ Time Frame: 18 months ] [ Designated as safety issue: No ]
    Quality of Life questionnaire to be filled out by parents.

  • Mullen Scale (developmental assessment) [ Time Frame: 18 months ] [ Designated as safety issue: No ]

Estimated Enrollment: 16
Study Start Date: August 2010
Estimated Study Completion Date: August 2032
Estimated Primary Completion Date: August 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group A
The first dose cohort consists of 6 subjects who received 9.0x10^11 genome copies (gc) total dose. This is equal to 900,000,000,000 molecules of the drug.
Genetic: AAVrh.10CUhCLN2 vector
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.
Other Name: Adeno-associated virus expressing the CLN2 gene.
Experimental: Group B
The second dose cohort consists of 10 subjects, who will receive 2.85x10^11 genome copies (gc) total dose. This is equal to 285,000,000,000 molecules of the drug.
Genetic: AAVrh.10CUhCLN2 vector
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.
Other Name: Adeno-associated virus expressing CLN2 gene.

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.

  Eligibility

Ages Eligible for Study:   2 Years to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Definitive diagnosis of LINCL, based on clinical phenotype and genotype. The genotype must be some combination 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). These account for a total of 83% of the mutations in the study by Sleat et al and 82% of the mutations in our studies15. The study does not limit to one specific genotype (genetic constitution) since our data regarding the natural history of the disease (Appendix II) and the studies of Steinfeld2, show that, for these 5 genotypes (genetic constitution), LINCL subjects have similar clinical course.
  • The subject must be between the age of 2 and 18 years.
  • Subjects will have an average total score of 6-10 on the Weill-Cornell LINCL scale, and the total score should not be outside the 95th percentile confidence limits for age based on our historic data.
  • The subject will not previously have participated in a gene transfer or stem cell study.
  • 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, and both parents or legal guardians must give consent for their child's participation.
  • The subject must be within NYPH pediatric laboratory value ranges for the following tests: Complete Blood Count (CBC) - hematocrit, hemoglobin, white blood count, differential, platelets; ESR (erythrocyte sedimentation rate); Clotting - prothrombin time, partial thromboplastin time; Chemistry - sodium, potassium, chloride, total CO2, blood urea nitrogen (BUN), glucose, magnesium, uric acid, (SGOT), calcium, serum total protein, albumin, alkaline phosphatase, bilirubin (total).
  • Sexually active subjects will have to use contraception during the treatment and for 2 months after completion of the treatment.

Exclusion Criteria:

  • Presence of other significant medical or neurological conditions may disqualify the subject from participation in this study, particularly those which would create an unacceptable operative risk or risk to receiving the AAVrh.10CUhCLN2 vector, e.g., malignancy, congenital heart disease, liver or renal failure, or HIV positive.
  • Subjects without adequate control of seizures.
  • Subjects with heart disease that would be a risk for anesthesia or a history of major risk factors for hemorrhage.
  • Subjects who cannot participate in MRI studies.
  • Concurrent participation in any other FDA approved Investigational New Drug.
  • Subjects with history of prolonged bleeding or abnormal platelet function or taking aspirin.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01161576

Contacts
Contact: Charleen Hollmann, PhD 646.962.2672 chollman@med.cornell.edu
Contact: Denesy Mancenido, BA 646.962.4537 dem2026@med.cornell.edu

Locations
United States, New York
Weill Cornell Medical College Recruiting
New York, New York, United States, 10021
Contact: Charleen Hollmann, RN,MPA,PhD    646-962-2672    chollman@med.cornell.edu   
Contact: Denesy Mancenido, BA    646-962-4537    dem2026@med.cornell.edu   
Principal Investigator: Ronald G Crystal, MD         
Sponsors and Collaborators
Weill Medical College of Cornell University
Investigators
Principal Investigator: Ronald G Crystal, MD Weill Medical College of Cornell University
  More Information

No publications provided

Responsible Party: Weill Medical College of Cornell University
ClinicalTrials.gov Identifier: NCT01161576     History of Changes
Other Study ID Numbers: 0810010013, 5 U01 NS047458-04
Study First Received: March 22, 2010
Last Updated: November 5, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Weill Medical College of Cornell University:
Batten Disease
Late Infantile Neuronal Lipofuscinosis
gene transfer

Additional relevant MeSH terms:
Neuronal Ceroid-Lipofuscinoses
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Nervous System Diseases
Genetic Diseases, Inborn
Lipidoses
Lipid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Lipid Metabolism Disorders
Metabolic Diseases

ClinicalTrials.gov processed this record on August 26, 2014