Safety Study of an Adeno-associated Virus Vector for Gene Therapy of Leber's Hereditary Optic Neuropathy

NCT02161380 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: 201402481U10EY023558-01A1
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 1

Brief Summary

The study is a dose-escalation study, phase 1. The objective of this proposed clinical trial is to evaluate the safety of mitochondrially targeted ND4 gene therapy with the adeno-associated viral vector in appropriate LHON patients.

Conditions

Leber's Hereditary Optic Neuropathy

Keywords

Gene therapy; Mitochondrial Genes; Leber's; AAV2 Viral vectors

Outcome Measures

Primary Outcomes (1)

• Number of Treatment Related Adverse Events

  Number of treatment-related adverse events will be assessed as per investigator with respective to relationship to the investigative product.

  3 years

Secondary Outcomes (1)

• Best-corrected Visual Acuity

  up to 36 months after treatment

Study Arms (4)

Low-dose (1.18x10e9 vg)

EXPERIMENTAL

Participants with Chronic Bilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 1.18x10e9 vg. Participants with Acute Bilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 1.18x10e9 vg. Participants with Acute Unilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 1.18x10e9 vg

Drug: injection of scAAV2-P1ND4v2 1.18x10e9 vg (Low),

Medium dose (5.81x10e9 vg)

EXPERIMENTAL

Participants with Chronic Bilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 5.81x10e9 vg. Participants with Acute Bilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 5.81x10e9 vg. Participants with Acute Unilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 5.81x10e9 vg.

Drug: injection of scAAV2-P1ND4v2 5.81 X10e9 vg (Med)

High dose (2.40x10e10 vg)

EXPERIMENTAL

Participants with Chronic Bilateral Severe Vision Loss were administered 100 µL of scAAV2-P1ND4v2 containing a dose of 2.40x10e10 vg.

Drug: injection of scAAV2-P1ND4v2 2.4 X10e10vg (High)

Higher dose (1x10e11vg)

EXPERIMENTAL

Participants with Chronic Bilateral Severe Vision Loss were administered 100 µL of scAAV2-P1ND4v2 containing a dose of 1x10e11vg. Participants with Acute Bilateral Severe Vision Loss were administered 100 µL of scAAV2-P1ND4v2 containing a dose of 1x10e11vg. Participants with Acute Unilateral Severe Vision Loss were administered 100 µL of scAAV2-P1ND4v2 containing a dose of 1x10e11vg.

Drug: injection of scAAV2-P1ND4v2 1.0 X10e11vg (Higher)

Interventions

injection of scAAV2-P1ND4v2 1.18x10e9 vg (Low), DRUG

injection of Total Volume of each intravitreal injection is 200 µL

Also known as: AAV-ND4

Low-dose (1.18x10e9 vg)

injection of scAAV2-P1ND4v2 5.81 X10e9 vg (Med) DRUG

injection of Total Volume of each intravitreal injection is 200 µL

Also known as: AAV-ND4

Medium dose (5.81x10e9 vg)

injection of scAAV2-P1ND4v2 2.4 X10e10vg (High) DRUG

injection of Total Volume of each intravitreal injection is 100 µL

Also known as: AAV-ND4

High dose (2.40x10e10 vg)

injection of scAAV2-P1ND4v2 1.0 X10e11vg (Higher) DRUG

injection of Total Volume of each intravitreal injection is 100 µL

Also known as: AAV-ND4

Higher dose (1x10e11vg)

Eligibility Criteria

• Age: 15 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 15 or older;
• Ability to perform tests of visual and retinal function;
• Ability to comply with research procedures;
• Able and willing to provide informed consent before undergoing any study-related procedures.
• Good general health as based on the investigator's assessment of the history, physical examination, and laboratory testing performed at the baseline examination.

You may not qualify if:

• Unwilling or unable to give consent,
• Unable or unlikely to return for scheduled protocol visits
• Pregnant or nursing women or unwillingness for subject with childbearing potential to use contraception during the first year of the study.
• Optic disc drusen on exam or in previous history.
• Ocular diseases or visual dysfunction conditions other than refractive error (e.g. amblyopia, glaucoma, etc.) in the eye selected for the injection.
• Previous eye surgery in the eye selected for injection.
• Aspartate transaminase (AST)/alanine transaminase (ALT) \>5.0 x upper limit of normal (ULN); Total bilirubin \>3 x ULN; Hemoglobin \< 8 g/dL; neutrophil count \<1.0 x 109/L; or platelet count \< 50 x 109/L
• a) Any laboratory screening test that meets the abnormality criteria stated above can be repeated once between Baseline one to Baseline 2.
• Type I diabetes or the presence of diabetic retinopathy
• History of neurodegenerative conditions (e.g. multiple sclerosis, neuromyelitis optica, Parkinson's disease)
• History of autoimmune conditions (e.g. systemic lupus erythematosus)
• Systemic diseases having ocular manifestations likely to confound assessment of study results. History of cancer within five years other than localized basal or squamous cell carcinoma not near the orbital area. Patients with a prior history of cancer will need documentation from their cancer specialist that the cancer was cured at least 5 years before study entry.
• Allergy to pupil dilating drops or narrow angles precluding safe dilation.
• No Light Perception (NLP) vision in either eye.

Sponsors & Collaborators

• Byron Lam: lead
• National Eye Institute (NEI): collaborator

Study Sites (1)

Bascom Palmer Eye Institute, University of Miami

Miami, Florida, 33136, United States

Location

Related Publications (11)

• Feuer WJ, Schiffman JC, Davis JL, Porciatti V, Gonzalez P, Koilkonda RD, Yuan H, Lalwani A, Lam BL, Guy J. Gene Therapy for Leber Hereditary Optic Neuropathy: Initial Results. Ophthalmology. 2016 Mar;123(3):558-70. doi: 10.1016/j.ophtha.2015.10.025. Epub 2015 Nov 19.

  PMID: 26606867 RESULT

• Guy J, Feuer WJ, Davis JL, Porciatti V, Gonzalez PJ, Koilkonda RD, Yuan H, Hauswirth WW, Lam BL. Gene Therapy for Leber Hereditary Optic Neuropathy: Low- and Medium-Dose Visual Results. Ophthalmology. 2017 Nov;124(11):1621-1634. doi: 10.1016/j.ophtha.2017.05.016. Epub 2017 Jun 21.

  PMID: 28647203 RESULT

• Lam BL, Feuer WJ, Davis JL, Porciatti V, Yu H, Levy RB, Vanner E, Guy J. Leber Hereditary Optic Neuropathy Gene Therapy: Adverse Events and Visual Acuity Results of All Patient Groups. Am J Ophthalmol. 2022 Sep;241:262-271. doi: 10.1016/j.ajo.2022.02.023. Epub 2022 Mar 7.

  PMID: 35271811 RESULT

• Lam BL, Feuer WJ, Porciatti V, Davis JL, Zheng DD, Vanner EA, Savatovsky EJ, Alba DE, Guy J. Leber Hereditary Optic Neuropathy Gene Therapy: Longitudinal Relationships Among Visual Function and Anatomical Measures. Am J Ophthalmol. 2024 Jan;257:113-128. doi: 10.1016/j.ajo.2023.09.005. Epub 2023 Sep 15.

  PMID: 37716450 RESULT

• Porciatti V, Alba DE, Feuer WJ, Davis J, Guy J, Lam BL. The Relationship Between Stage of Leber's Hereditary Optic Neuropathy and Pattern Electroretinogram Latency. Transl Vis Sci Technol. 2022 Mar 2;11(3):31. doi: 10.1167/tvst.11.3.31.

  PMID: 35344016 RESULT

• Lam BL. Leber hereditary optic neuropathy gene therapy. Curr Opin Ophthalmol. 2024 May 1;35(3):244-251. doi: 10.1097/ICU.0000000000001028. Epub 2023 Dec 20.

  PMID: 38117686 RESULT

• Lam BL, Burke SP, Wang MX, Nadayil GA, Rosa PR, Gregori G, Feuer WJ, Cuprill-Nilson S, Vandenbroucke R, Zhang X, Guy J. Macular Retinal Sublayer Thicknesses in G11778A Leber Hereditary Optic Neuropathy. Ophthalmic Surg Lasers Imaging Retina. 2016 Sep 1;47(9):802-10. doi: 10.3928/23258160-20160901-02.

  PMID: 27631475 RESULT

• Koilkonda R, Yu H, Talla V, Porciatti V, Feuer WJ, Hauswirth WW, Chiodo V, Erger KE, Boye SL, Lewin AS, Conlon TJ, Renner L, Neuringer M, Detrisac C, Guy J. LHON gene therapy vector prevents visual loss and optic neuropathy induced by G11778A mutant mitochondrial DNA: biodistribution and toxicology profile. Invest Ophthalmol Vis Sci. 2014 Oct 23;55(12):7739-53. doi: 10.1167/iovs.14-15388.

  PMID: 25342621 RESULT

• Guy J, Feuer WJ, Porciatti V, Schiffman J, Abukhalil F, Vandenbroucke R, Rosa PR, Lam BL. Retinal ganglion cell dysfunction in asymptomatic G11778A: Leber hereditary optic neuropathy. Invest Ophthalmol Vis Sci. 2014 Feb 10;55(2):841-8. doi: 10.1167/iovs.13-13365.

  PMID: 24398093 RESULT

• Koilkonda RD, Yu H, Chou TH, Feuer WJ, Ruggeri M, Porciatti V, Tse D, Hauswirth WW, Chiodo V, Boye SL, Lewin AS, Neuringer M, Renner L, Guy J. Safety and effects of the vector for the Leber hereditary optic neuropathy gene therapy clinical trial. JAMA Ophthalmol. 2014 Apr 1;132(4):409-20. doi: 10.1001/jamaophthalmol.2013.7630.

  PMID: 24457989 RESULT

• Davis JL. The Blunt End: Surgical Challenges of Gene Therapy for Inherited Retinal Diseases. Am J Ophthalmol. 2018 Dec;196:xxv-xxix. doi: 10.1016/j.ajo.2018.08.038. Epub 2018 Sep 5.

  PMID: 30194931 DERIVED

Related Links

• Bascom Palmer News

MeSH Terms

Conditions

Optic Atrophy, Hereditary, Leber

Interventions

Matrilin Proteins

Condition Hierarchy (Ancestors)

Optic Atrophies, Hereditary; Optic Atrophy; Optic Nerve Diseases; Cranial Nerve Diseases; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Eye Diseases, Hereditary; Eye Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Mitochondrial Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Extracellular Matrix Proteins; Scleroproteins; Proteins; Amino Acids, Peptides, and Proteins

Results Point of Contact

• Title: Dr. Byron Lam.
• Organization: Bascom Palmer Eye Institute.

blam@med.miami.edu

305 326 6021

Study Officials

• Byron Lam, MD

  Bascom Palmer Eye Institute, Miller School of Medicine, University of Miami, Miami, FL 33136

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Greene Professor of Ophthalmology

Study Record Dates

• First Submitted: June 6, 2014
• First Posted: June 11, 2014
• Study Start: July 14, 2014
• Primary Completion: March 31, 2023
• Study Completion: March 31, 2025
• Last Updated: June 5, 2025
• Results First Posted: August 7, 2024

Record last verified: 2025-05

Locations

US (1)