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Gene Therapy for APOE4 Homozygote of Alzheimer's Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03634007
Recruitment Status : Recruiting
First Posted : August 16, 2018
Last Update Posted : November 20, 2019
Sponsor:
Information provided by (Responsible Party):
Weill Medical College of Cornell University

Study Description
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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
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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

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Arms and Interventions
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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
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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
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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
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03634007


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

Locations
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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
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Principal Investigator: Ronald G Crystal, MD Weill Cornell Medicine
More Information
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Responsible Party: Weill Medical College of Cornell University
ClinicalTrials.gov Identifier: NCT03634007    
Other Study ID Numbers: 1806019315
First Posted: August 16, 2018    Key Record Dates
Last Update Posted: November 20, 2019
Last Verified: November 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Alzheimer Disease
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
 Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders