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

NCT01161576 | Completed Phase 1 DMC FDA Drug

• 2 other identifiers: 0810010013UL1TR000457-06
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

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 central nervous system (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.

Conditions

Batten Disease; Late-Infantile Neuronal Ceroid Lipofuscinosis

Keywords

Batten Disease; Late Infantile Neuronal Lipofuscinosis; gene transfer

Outcome Measures

Primary Outcomes (4)

• Change in Weill-Cornell LINCL scale from Baseline to 18 months

  A clinical rating, 12 point scale which combines assessment of feeding, gait, motor and language to give an overall assessment of various CNS functions.

  18 Months

• Disease progression based on change in MRI imaging parameter (% grey matter volume) from Baseline to 18 Months

  Based on previous analyses, we have determined that 3 imaging parameters (% grey matter volume, MRI Assessment, % ventricular volume and cortical apparent diffusion coefficient) correlate best with age and with the Weill Cornell LINCL scale and will be used to assess disease progression and the effect of the gene transfer.

  18 Months

• Disease progression based on change in MRI imaging parameter (% ventricular volume) from Baseline to 18 Months

  Based on previous analyses, we have determined that 3 imaging parameters (% grey matter volume, MRI Assessment, % ventricular volume and cortical apparent diffusion coefficient) correlate best with age and with the Weill Cornell LINCL scale and will be used to assess disease progression and the effect of the gene transfer.

  18 Months

• Disease progression based on change in MRI imaging parameter cortical apparent diffusion coefficient) from Baseline to 18 Months

  Based on previous analyses, we have determined that 3 imaging parameters (% grey matter volume, MRI Assessment, % ventricular volume and cortical apparent diffusion coefficient) correlate best with age and with the Weill Cornell LINCL scale and will be used to assess disease progression and the effect of the gene transfer.

  18 Months

Secondary Outcomes (2)

• Change in Quality of Life Survey from Baseline to 18 Months

  18 months

• Mullen Scale (developmental assessment) from Baseline to 18 Months

  18 months

Study Arms (2)

Group A

EXPERIMENTAL

The first dose cohort consists of 6 subjects who received AAVrh.10CUhCLN2 vector 9.0x10\^11 genome copies (gc) total dose. This is equal to 900,000,000,000 molecules of the drug.

Biological: AAVrh.10CUhCLN2 vector 9.0x10^11 genome copies

Group B

EXPERIMENTAL

The second dose cohort consists of 10 subjects, who will receive AAVrh.10CUhCLN2 vector 2.85x10\^11 genome copies (gc) total dose. This is equal to 285,000,000,000 molecules of the drug.

Biological: AAVrh.10CUhCLN2 vector 2.85x10^11 genome copies

Interventions

AAVrh.10CUhCLN2 vector 9.0x10^11 genome copies BIOLOGICAL

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.

Group A

AAVrh.10CUhCLN2 vector 2.85x10^11 genome copies BIOLOGICAL

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.

Group B

Eligibility Criteria

• Age: 2 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• All individuals who meet the following criteria will be included without bias as to a gender or race/ethnicity. Each case will be individually reviewed with the Eligibility Committee comprised of 3 physicians other than the PI, including a pediatric neurosurgeon, pediatric neurologist and general pediatrician.
• Definitive diagnosis of LINCL, based on clinical phenotype and genotype. The genotype must include at least one 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). If either parental allele is R447H, the patient will not be included in the study. These account for a total of 83% of the mutations in the study by Sleat et al and 82% of the mutations in our studies. The study does not limit to one specific genotype (genetic constitution) since our data regarding the natural history of the disease and the studies of Steinfeld, 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 4 - 12 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.
• Sexually active subjects will have to use contraception during the treatment and for 2 months after completion of the treatment.
• If asymptomatic (i.e - An LINCL score of 12), has one older sibling who has a positive genotype and has clinical manifestations of the disease.

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 Total Bilirubin \> 1.3 mg/dL
• Immunosuppression as defined by WBC \< 3,000/µL at admission
• Uncorrected coagulopathy during the baseline period defined as INR \> 1.4; PTT \> 35 sec; PLT \< 100,000/mm3.
• Anemia (hemoglobin \< 11.0 g/dl at \> 2 years of age, with normal serum iron studies).

Sponsors & Collaborators

• Weill Medical College of Cornell University: lead
• National Institutes of Health (NIH): collaborator

Study Sites (1)

Weill Cornell Medical College

New York, New York, 10021, 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 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: We chose an initial dose two fold lower of 9.0x10\^11 genome copies/subject (Group A). Initially, the study plan was to proceed to Group B, which would receive a higher dose of 1.8x10\^12 genome copies if the initial dose was well tolerated. However, after assessing the MRI images of the first 6 children who received the dose of 9.0x10\^11 gc, we discovered that 4 of the 6 subjects at 6 months and 1 of the 6 subjects at 12 months exhibited varying degrees of T2 hyperintensities related to diffusion restriction at the sites of vector deposition. Although there are no clinical correlates to these MRI findings, we have decided to lower the dose by ½ log to 2.85x10\^11 gc for the remaining subjects to be enrolled in protocol #0810010013. The volume of the drug solution will be the same as in Group A, but the concentration of the vector will be ½ log less.

Study Record Dates

• First Submitted: March 22, 2010
• First Posted: July 13, 2010
• Study Start: August 19, 2010
• Primary Completion: January 5, 2016
• Study Completion: December 31, 2020
• Last Updated: February 2, 2021

Record last verified: 2021-01

Locations

US (1)