Safety Study of an Adeno-associated Virus Vector for Gene Therapy of Leber's Hereditary Optic Neuropathy
NCT ID: NCT02161380
Last Updated: 2025-06-05
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE1
28 participants
INTERVENTIONAL
2014-07-14
2025-03-31
Brief Summary
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Detailed Description
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This first-in-man (FIM) clinical trial will assess the safety, tolerability, and potential efficacy of a single intravitreal injection in patient groups reflecting the acute, pre-symptomatic, and chronic stages and manifestation of the LHON disease.
Conditions
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Study Design
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NON_RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Low-dose (1.18x10e9 vg)
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
injection of scAAV2-P1ND4v2 1.18x10e9 vg (Low),
injection of Total Volume of each intravitreal injection is 200 µL
Medium dose (5.81x10e9 vg)
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.
injection of scAAV2-P1ND4v2 5.81 X10e9 vg (Med)
injection of Total Volume of each intravitreal injection is 200 µL
High dose (2.40x10e10 vg)
Participants with Chronic Bilateral Severe Vision Loss were administered 100 µL of scAAV2-P1ND4v2 containing a dose of 2.40x10e10 vg.
injection of scAAV2-P1ND4v2 2.4 X10e10vg (High)
injection of Total Volume of each intravitreal injection is 100 µL
Higher dose (1x10e11vg)
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.
injection of scAAV2-P1ND4v2 1.0 X10e11vg (Higher)
injection of Total Volume of each intravitreal injection is 100 µL
Interventions
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injection of scAAV2-P1ND4v2 1.18x10e9 vg (Low),
injection of Total Volume of each intravitreal injection is 200 µL
injection of scAAV2-P1ND4v2 5.81 X10e9 vg (Med)
injection of Total Volume of each intravitreal injection is 200 µL
injection of scAAV2-P1ND4v2 2.4 X10e10vg (High)
injection of Total Volume of each intravitreal injection is 100 µL
injection of scAAV2-P1ND4v2 1.0 X10e11vg (Higher)
injection of Total Volume of each intravitreal injection is 100 µL
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
2. Patients with LHON and the G11778A mitochondrial DNA mutation. A previous CLIA-certified genetic lab result showing the LHON G11778A mutation will be accepted for inclusion;
3. Ability to perform tests of visual and retinal function;
4. Ability to comply with research procedures;
5. Able and willing to provide informed consent before undergoing any study-related procedures.
6. Good general health as based on the investigator's assessment of the history, physical examination, and laboratory testing performed at the baseline examination.
Exclusion Criteria
2. Unable or unlikely to return for scheduled protocol visits
3. Pregnant or nursing women or unwillingness for subject with childbearing potential to use contraception during the first year of the study.
4. Optic disc drusen on exam or in previous history.
5. Ocular diseases or visual dysfunction conditions other than refractive error (e.g. amblyopia, glaucoma, etc.) in the eye selected for the injection.
6. Previous eye surgery in the eye selected for injection.
7. 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.
8. Type I diabetes or the presence of diabetic retinopathy
9. History of neurodegenerative conditions (e.g. multiple sclerosis, neuromyelitis optica, Parkinson's disease)
10. History of autoimmune conditions (e.g. systemic lupus erythematosus)
11. 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.
12. Allergy to pupil dilating drops or narrow angles precluding safe dilation.
13. No Light Perception (NLP) vision in either eye.
15 Years
ALL
No
Sponsors
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National Eye Institute (NEI)
NIH
Byron Lam
OTHER
Responsible Party
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Byron Lam
Greene Professor of Ophthalmology
Principal Investigators
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Byron Lam, MD
Role: PRINCIPAL_INVESTIGATOR
Bascom Palmer Eye Institute, Miller School of Medicine, University of Miami, Miami, FL 33136
Locations
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Bascom Palmer Eye Institute, University of Miami
Miami, Florida, United States
Countries
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References
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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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Provided Documents
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Document Type: Study Protocol and Statistical Analysis Plan
Document Type: Informed Consent Form
Related Links
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Bascom Palmer News
Other Identifiers
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20140248
Identifier Type: -
Identifier Source: org_study_id
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