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Gene Therapy for APOE4 Homozygote of Alzheimer's Disease

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ClinicalTrials.gov Identifier: NCT03634007
Recruitment Status : Recruiting
First Posted : August 16, 2018
Last Update Posted : June 25, 2021
Sponsor:
Collaborators:
Alzheimer's Drug Discovery Foundation
Weill Medical College of Cornell University
Information provided by (Responsible Party):
Lexeo Therapeutics

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 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.10hAPOE2 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: LX1001 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 : November 6, 2019
Estimated Primary Completion Date : January 31, 2023
Estimated Study Completion Date : January 31, 2023

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Arms and Interventions
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Arm Intervention/treatment
Experimental: Cohort I: 5.0 x 10^10 gc/mL CSF
Subjects will receive 5.0 x 10^10 gc/mL CSF of LX1001
 Biological: LX1001
LX1001 (AAVrh.10hAPOE2) is a serotype rh.10 adeno-associated virus (AAV) gene transfer vector expressing the cDNA coding for human apolipoprotein E2 (APOE2).
Other Name: AAVrh.10hAPOE2
Experimental: Cohort II: 1.6 x 10^11 gc/mL CSF
Subjects will receive 1.6 x 10^11 gc/mL CSF of LX1001
 Biological: LX1001
LX1001 (AAVrh.10hAPOE2) is a serotype rh.10 adeno-associated virus (AAV) gene transfer vector expressing the cDNA coding for human apolipoprotein E2 (APOE2).
Other Name: AAVrh.10hAPOE2
Experimental: Cohort III: 5.0 x 10^11 gc/mL CSF
Subjects will receive 5.0 x 10^11 gc/mL CSF of LX1001
 Biological: LX1001
LX1001 (AAVrh.10hAPOE2) is a serotype rh.10 adeno-associated virus (AAV) gene transfer vector expressing the cDNA coding for human apolipoprotein E2 (APOE2).
Other Name: AAVrh.10hAPOE2


Outcome Measures
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Primary Outcome Measures :
  1. Safety of LX1001 gene therapy, based on adverse events and serious adverse events [ Time Frame: 1 year ]
  2. Maximum tolerated dose of LX1001 gene therapy to APOE4 homozygotes with Alzheimer's disease [ Time Frame: 1 year ]

Secondary Outcome Measures :
  1. Shift from baseline in APOE2-APOE4 isoforms [ Time Frame: 1 year ]
  2. Evaluate brain amyloid plaques as assessed by PET scan [ Time Frame: 1 year ]
  3. Assess the levels of CSF biomarkers [ Time Frame: 1 year ]
  4. Hippocampal and entorhinal cortex volumes as assessed by brain magnetic resonance imaging (MRI) [ Time Frame: 1 year ]
  5. Clinical status as assessed using the Clinical Dementia Rating Global and Sum of Boxes (CDR-SB) [ Time Frame: 1 year ]
  6. Cognitive status as assessed using the Mini Mental State Examination (MMSE) [ Time Frame: 1 year ]
  7. Cognitive status as assessed using the Alzheimer's Disease Assessment Scale - Cognition 13 (ADAS-Cog 13) [ Time Frame: 1 year ]

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 mild to moderate 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 >38.5̊ C, 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: Lexeo Clinical Trials +1 212-547-9879 clinicaltrials@lexeotx.com
Contact: Lexeo Clinical Trials

Locations
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United States, Florida
PPD Development Recruiting
Orlando, Florida, United States, 32806
Contact: Jessica Garaycoa       jessica.garaycoa@ppd.com   
United States, New York
Weill Cornell Medicine Recruiting
New York, New York, United States, 10065-4870
Contact: Anisette Ruda       amr2034@med.cornell.edu   
Sponsors and Collaborators
Lexeo Therapeutics
Alzheimer's Drug Discovery Foundation
Weill Medical College of Cornell University
Investigators
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Study Director: Lexeo Clinical Trials Lexeo Therapeutics
More Information
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Responsible Party: Lexeo Therapeutics
ClinicalTrials.gov Identifier: NCT03634007    
Other Study ID Numbers: 1806019315
First Posted: August 16, 2018    Key Record Dates
Last Update Posted: June 25, 2021
Last Verified: June 2021
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