Gene Therapy for APOE4 Homozygote of Alzheimer's Disease

• ClinicalTrials.gov Identifier: NCT03634007
• Recruitment Status: Recruiting
• First Posted: August 16, 2018
• Last Update Posted: November 20, 2019
• Sponsor: Weill Medical College of Cornell University
• Information provided by (Responsible Party): Weill Medical College of Cornell University

Study Description

Brief Summary:

This clinical trial is an open label, dose-ranging study designed to evaluate gene therapy to treat patients who are APOE4 homozygotes with clinical diagnosis varying from subjective or mild cognitive impairment to very mild to severe dementia due to Alzheimer's disease. All subjects will have evidence of amyloid plaque by nuclear PET scan and/or cerebrospinal fluid (CSF) biomarkers consistent with Alzheimer's disease. The study will assess the safety and toxicity of intracisternal administration of AAVrh.10hAPOE2, serotype rh.10 adeno-associated virus (AAV) gene transfer vector expressing the cDNA coding for human apolipoprotein E2 (APOE2), directly to the CNS/ CSF of APOE4 homozygotes with Alzheimer's disease. The study will establish a maximum tolerable dose and generate preliminary evidence regarding whether direct administration of AAVrh.10hPOE2 to the CNS of those Alzheimer's patients will lead to conversion of the APOE protein isoforms in the CSF of APOE4 homozygotes from APOE4 to APOE2-APOE4.

Condition or disease	Intervention/treatment	Phase
Alzheimer Disease; Early Onset Alzheimer Disease	Biological: AAVrh.10hPOE2 vector	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 15 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Gene Therapy for APOE4 Homozygote of Alzheimer's Disease
• Actual Study Start Date: October 6, 2019
• Estimated Primary Completion Date: December 2020
• Estimated Study Completion Date: December 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort I: 8.0 x 10^10 gc/kg; Subjects will receive 8.0 x 10^10 gc/kg of AAVrh.10hAPOE2.	Biological: AAVrh.10hPOE2 vector; AAVrh.10hAPOE2 is a serotype rh.10 adeno-associated virus (AAV) gene transfer vector expressing the cDNA coding for human apolipoprotein E2 (APOE2).
Experimental: Cohort II: 2.5 x 10^11 gc/kg; Subjects will receive 2.5 x 10^11 gc/kg of AAVrh.10hAPOE2.	Biological: AAVrh.10hPOE2 vector; AAVrh.10hAPOE2 is a serotype rh.10 adeno-associated virus (AAV) gene transfer vector expressing the cDNA coding for human apolipoprotein E2 (APOE2).
Experimental: Cohort III: 8.0 x 10^11 gc/kg; Subjects will receive 8.0 x 10^11 gc/kg of AAVrh.10hAPOE2.	Biological: AAVrh.10hPOE2 vector; AAVrh.10hAPOE2 is a serotype rh.10 adeno-associated virus (AAV) gene transfer vector expressing the cDNA coding for human apolipoprotein E2 (APOE2).

Outcome Measures

Primary Outcome Measures :

1. Safety of AAVrh.10hAPOE2 gene therapy, as measured by number of adverse events or serious adverse events [ Time Frame: 2 years ]

Secondary Outcome Measures :

1. Maximum tolerated dose of intracisternal delivery of AAVrh.10hAPOE2 gene therapy to APOE4 homozygotes with Alzheimer's disease [ Time Frame: 2 years ]

Eligibility Criteria

• Ages Eligible for Study: 50 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• APOE4 homozygotes
• Males and females, age 50 or older
• Willing and able to provide informed consent (or consent provided by legally authorized representative)
• Mild cognitive impairment due to Alzheimer's disease, or clinical diagnosis of very mild to severe dementia due to Alzheimer's disease
• Evidence of amyloid plaques by nuclear PET scan and/or cerebrospinal fluid (CSF) biomarkers consistent with Alzheimer's disease
• Serum neutralizing anti-AAVrh10 titer <10-2
• No evidence of active infection of any type, including hepatitis virus (A, B or C) or human immunodeficiency virus (HIV-1 and HIV-2)
• Fertile or infertile individuals; it will be recommended that fertile individuals utilize barrier birth control measures to prevent pregnancy for the duration of the study
• Individuals not receiving experimental medications or participating in another experimental protocol for at least 4 weeks prior to entry to the study

Exclusion Criteria:

• Individuals receiving corticosteroids, other immunosuppressive medications, or anti-coagulant medications (other than aspirin)
• Individuals who do not fit the American Journal of Neuroradiology recommendations for image guided spinal procedures9
• Presence of other significant medical or neurological conditions may disqualify the subject from participation in this study, particularly those which would create an unacceptable risk to receiving the AAVrh.10APOE2 vector, for example, malignancy, heart failure, liver or renal failure, or HIV positive.
• Evidence of ongoing infection
• Elevated white blood cell count, temperature >38.5̊C, infiltrate on chest x-ray
• Prior or concurrent participation in any gene and/or cell therapy
• Any condition, disorder, or abnormal laboratory test findings at screening which, in the judgment of the investigator, would interfere with the individual's ability to comply with all study requirements, or would require the administration of treatment during the study that could potentially affect the interpretation of the study data, or would place the individual at an unacceptable risk by his/her participation in the study
• Individuals who cannot participate in MRI, PET and CSF studies
• Individuals who cannot undergo study-related procedures without general anesthesia
• More than 4 cerebral microhemorrhages (regardless of their anatomical location or diagnostic characterization as "possible" or "definite"), a single area of superficial siderosis, or evidence of a prior macrohemorrhage

Contacts and Locations

Contacts

Contact: Grace W Mammen, BA, CCRP; 646-962-2672; gwm2004@med.cornell.edu

Locations

United States, New York

Weill Cornell Medical College and Weill Cornell Medical Center, Department of Genetic Medicine; Recruiting

New York, New York, United States, 10065-4870

Contact: Denesy Mancenido, BA 646-962-5583 dem2026@med.cornell.edu

Contact: Grace Mammen, BA gwm2004@med.cornell.edu

Sponsors and Collaborators

Weill Medical College of Cornell University

Investigators

• Principal Investigator: Ronald G Crystal, MD; Weill Cornell Medicine

More Information

• Responsible Party: Weill Medical College of Cornell University
• ClinicalTrials.gov Identifier: NCT03634007 History of Changes
• Other Study ID Numbers: 1806019315
• First Posted: August 16, 2018
• Last Update Posted: November 20, 2019
• Last Verified: November 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Alzheimer Disease; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders