AAVRh.10 Administered to Children With Late Infantile Neuronal Ceroid Lipofuscinosis

NCT01414985 | Completed Phase 1 DMC FDA Drug

• 2 other identifiers: 1005011054IND 13951
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Late Infantile Neuronal Ceroid Lipofuscinosis; Batten Disease

Keywords

Batten Disease

Outcome Measures

Primary Outcomes (2)

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

  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.

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

• Safety, as measured by MRI

  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.

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

Secondary Outcomes (2)

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

  Screening, Pre-transfer (optional) and Month 18

• Change in psychological development, as measured by the Mullen Scale

  Screening, Pre-transfer (optional) and Month 18

Study Arms (2)

Group A

EXPERIMENTAL

Group A consists of 2 subjects who received 9x10\^11 molecules of AAVrh.10CUCLN2, the gene transfer vector carrying the CLN2 gene. This is equal to 900,000,000,000 molecules of the study drug. The drug will be administered only once in the study.

Biological: AAVrh.10CUCLN2

Group B

EXPERIMENTAL

Group B will consist of 6 subjects who will receive 2.85x10\^11 molecules of AAVrh.10CUCLN2, the gene transfer vector carrying the CLN2 gene. This is equal to 285,000,000,000 molecules of the drug. The drug will be administered only once in the study.

Biological: AAVrh.10CUCLN2

Interventions

AAVrh.10CUCLN2 BIOLOGICAL

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.

Also known as: AAVrh.10

Group A; Group B

Eligibility Criteria

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

You may qualify if:

• Definitive diagnosis of LINCL, based on clinical phenotype and genotype. The study does not limit to one specific genotype (genetic constitution).
• The subject must be between the age of 3 and 18 years.
• 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. The total LINCL 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.
• Sexually active subjects will have to use contraception during the treatment and for 2 months after completion of the treatment.

You may not qualify if:

• 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.
• 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.
• Renal disease or altered renal function as defined by serum creatinine \> 1.5 mg/dl at admission.
• Abnormal serum sodium, potassium calcium, magnesium, phosphate at grade III or IV by Division of AIDS Toxicity Scale
• Hepatic disease or altered liver function as defined by SGPT \> 150 U/L, and or T.Bilirubin\> 1.3 mg/dL
• Immunosuppression as defined by WBC \< 3,000 at admission
• Uncorrected coagulopathy during the baseline period defined as INR \> 1.4; PTT \> 35 sec; PLT \< 150,000/mm3
• Anemia (hemoglobin \< 11.0 mg/dl at \> 2 years of age, with normal serum iron studies)

Sponsors & Collaborators

• Weill Medical College of Cornell University: lead

Study Sites (1)

Weill Cornell Medical College

New York, New York, 10065, United States

Location

Related Publications (1)

• De BP, Cram S, Lee H, Rosenberg JB, Sondhi D, Crystal RG, Kaminsky SM. Assessment of Residual Full-Length SV40 Large T Antigen in Clinical-Grade Adeno-Associated Virus Vectors Produced in 293T Cells. Hum Gene Ther. 2023 Aug;34(15-16):697-704. doi: 10.1089/hum.2023.032.

  PMID: 37171121 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 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

Study Record Dates

• First Submitted: December 13, 2010
• First Posted: August 11, 2011
• Study Start: April 15, 2010
• Primary Completion: November 30, 2015
• Study Completion: February 8, 2017
• Last Updated: August 31, 2020

Record last verified: 2020-08

Locations

US (1)