Leber's Hereditary Optic Neuropathy
Conditions
Keywords
Gene therapy, Mitochondrial Genes, Leber's, AAV2 Viral vectors
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.
Detailed description
The purpose of this dose-escalation study is to assess the safety and tolerability of scAAV2-P1ND4v2 (abbreviated as AAV-ND4) gene replacement therapy in subjects confirmed with the G11778A mutation in mtDNA responsible for Leber's Hereditary Optic Neuropathy. Ocular and systemic toxicity will be assessed following vector administration to determine if there are adverse changes that may be associated with vector administration. 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.
Interventions
DRUGinjection of scAAV2-P1ND4v2 1.18x10e9 vg (Low),
injection of Total Volume of each intravitreal injection is 200 µL
DRUGinjection of scAAV2-P1ND4v2 5.81 X10e9 vg (Med)
injection of Total Volume of each intravitreal injection is 200 µL
DRUGinjection of scAAV2-P1ND4v2 2.4 X10e10vg (High)
injection of Total Volume of each intravitreal injection is 100 µL
DRUGinjection of scAAV2-P1ND4v2 1.0 X10e11vg (Higher)
injection of Total Volume of each intravitreal injection is 100 µL
Sponsors
National Eye Institute (NEI)
Byron Lam
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
15 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age 15 or older; 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
1. Unwilling or unable to give consent, 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Treatment Related Adverse Events | 3 years | Number of treatment-related adverse events will be assessed as per investigator with respective to relationship to the investigative product. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best-corrected Visual Acuity | up to 36 months after treatment | Best-corrected visual acuity(BCVA) was tested using the ETDRS Chart. The LogMAR visual acuity scale was adapted from the ETDRS chart to facilitate statistical analysis. Longitudinal analyses of BCVA changes at months 12, 24, and 36 versus baseline 2 were performed. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at Bascom Palmer Eye Institute (Single institution study) in Florida, United States(US) from 14 July 2014 to 18 Nov 2020.
Pre-assignment details
A total of 28 participants with G11778A Leber Hereditary Optic Neuropathy (LHON) were enrolled in the study. They were distributed in the following groups: chronic bilateral visual loss \> 12 months (group 1, n=11), acute bilateral visual loss \< 12 months (group 2, n=9), or unilateral visual loss (group 3, n=8). Each participant received a unilateral intravitreal injection. Group 1 was treated with low, medium, high and higher dose, group 2 and 3 were treated with low, medium, or higher dose.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 9 |
| 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 administrated 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. | 9 |
| 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. | 3 |
| 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 administrated 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. | 7 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Low-dose (1.18x10e9 vg) | Medium Dose (5.81x10e9 vg) | High Dose (2.40x10e10 vg) | Higher Dose (1x10e11vg) |
|---|---|---|---|---|---|
| Age, Continuous | 31.1 years | 36.44 years | 25.22 years | 25.66 years | 34.14 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants | 8 Participants | 9 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 27 Participants | 9 Participants | 8 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Female | 5 Participants | 1 Participants | 3 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 23 Participants | 8 Participants | 6 Participants | 3 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 9 | 0 / 3 | 0 / 7 |
| other Total, other adverse events | 3 / 9 | 3 / 9 | 1 / 3 | 7 / 7 |
| serious Total, serious adverse events | 1 / 9 | 1 / 9 | 0 / 3 | 0 / 7 |
Outcome results
Primary
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.
Time frame: 3 years
Population: One subject for medium dose was a loss to follow up after month 06. One subject for low dose missed visits for month 12, month 24 and month 36
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low-dose (1.18x10e9 vg) | Number of Treatment Related Adverse Events | 1 Participants |
| Medium Dose (5.81x10e9 vg) | Number of Treatment Related Adverse Events | 1 Participants |
| High Dose (2.40x10e10 vg) | Number of Treatment Related Adverse Events | 1 Participants |
| Higher Dose (1x10e11vg) | Number of Treatment Related Adverse Events | 5 Participants |
Secondary
Best-corrected Visual Acuity
Best-corrected visual acuity(BCVA) was tested using the ETDRS Chart. The LogMAR visual acuity scale was adapted from the ETDRS chart to facilitate statistical analysis. Longitudinal analyses of BCVA changes at months 12, 24, and 36 versus baseline 2 were performed.
Time frame: up to 36 months after treatment
Population: One subject for low dose missed visits 12, 24, and 36 months but he completed the majority of the other study visits.~One subject for medium dose was a loss to follow up after visit 6 months. One subject for higher dose missed a visit 12 months to the COVID-19 pandemic.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Low-dose (1.18x10e9 vg) | Best-corrected Visual Acuity | 24 Months/Acute Unilateral Severe Vision | 0.95 logMar | Standard Deviation 0.21 |
| Low-dose (1.18x10e9 vg) | Best-corrected Visual Acuity | 24 Months/Chronic Bilateral Severe Vision | -0.19 logMar | Standard Deviation 0.39 |
| Low-dose (1.18x10e9 vg) | Best-corrected Visual Acuity | 12 Months/Acute Bilateral Severe Vision | -0.54 logMar | Standard Deviation 0.43 |
| Low-dose (1.18x10e9 vg) | Best-corrected Visual Acuity | 12 Months/Chronic Bilateral Severe Vision | 0.03 logMar | Standard Deviation 0.06 |
| Low-dose (1.18x10e9 vg) | Best-corrected Visual Acuity | 24 Months/Acute Bilateral Severe Vision | -0.95 logMar | Standard Deviation 0.61 |
| Low-dose (1.18x10e9 vg) | Best-corrected Visual Acuity | 36 Months/Acute Unilateral Severe Vision | 1.03 logMar | Standard Deviation 0.24 |
| Low-dose (1.18x10e9 vg) | Best-corrected Visual Acuity | 36 Months/Chronic Bilateral Severe Vision | -0.19 logMar | Standard Deviation 0.39 |
| Low-dose (1.18x10e9 vg) | Best-corrected Visual Acuity | 12 Months/Acute Unilateral Severe Vision | 1.08 logMar | Standard Deviation 0.17 |
| Low-dose (1.18x10e9 vg) | Best-corrected Visual Acuity | 36 Months/Acute Bilateral Severe Vision | -1.01 logMar | Standard Deviation 0.63 |
| Medium Dose (5.81x10e9 vg) | Best-corrected Visual Acuity | 24 Months/Acute Bilateral Severe Vision | -0.23 logMar | Standard Deviation 0.36 |
| Medium Dose (5.81x10e9 vg) | Best-corrected Visual Acuity | 12 Months/Chronic Bilateral Severe Vision | -0.26 logMar | Standard Deviation 0.42 |
| Medium Dose (5.81x10e9 vg) | Best-corrected Visual Acuity | 12 Months/Acute Bilateral Severe Vision | 0.07 logMar | Standard Deviation 0.18 |
| Medium Dose (5.81x10e9 vg) | Best-corrected Visual Acuity | 12 Months/Acute Unilateral Severe Vision | 1.29 logMar | Standard Deviation 0.53 |
| Medium Dose (5.81x10e9 vg) | Best-corrected Visual Acuity | 24 Months/Chronic Bilateral Severe Vision | -0.23 logMar | Standard Deviation 0.14 |
| Medium Dose (5.81x10e9 vg) | Best-corrected Visual Acuity | 24 Months/Acute Unilateral Severe Vision | 1.47 logMar | Standard Deviation 0.44 |
| Medium Dose (5.81x10e9 vg) | Best-corrected Visual Acuity | 36 Months/Chronic Bilateral Severe Vision | -0.25 logMar | Standard Deviation 0.39 |
| Medium Dose (5.81x10e9 vg) | Best-corrected Visual Acuity | 36 Months/Acute Bilateral Severe Vision | 0.00 logMar | Standard Deviation 0.14 |
| Medium Dose (5.81x10e9 vg) | Best-corrected Visual Acuity | 36 Months/Acute Unilateral Severe Vision | 1.49 logMar | Standard Deviation 0.4 |
| High Dose (2.40x10e10 vg) | Best-corrected Visual Acuity | 24 Months/Chronic Bilateral Severe Vision | -0.41 logMar | Standard Deviation 0.23 |
| High Dose (2.40x10e10 vg) | Best-corrected Visual Acuity | 12 Months/Chronic Bilateral Severe Vision | -0.39 logMar | Standard Deviation 0.25 |
| High Dose (2.40x10e10 vg) | Best-corrected Visual Acuity | 36 Months/Chronic Bilateral Severe Vision | -0.40 logMar | Standard Deviation 0.22 |
| Higher Dose (1x10e11vg) | Best-corrected Visual Acuity | 36 Months/Chronic Bilateral Severe Vision | -0.06 logMar | Standard Deviation 0.11 |
| Higher Dose (1x10e11vg) | Best-corrected Visual Acuity | 12 Months/Chronic Bilateral Severe Vision | -0.007 logMar | Standard Deviation 0.13 |
| Higher Dose (1x10e11vg) | Best-corrected Visual Acuity | 36 Months/Acute Unilateral Severe Vision | 0.49 logMar | Standard Deviation 0.24 |
| Higher Dose (1x10e11vg) | Best-corrected Visual Acuity | 24 Months/Chronic Bilateral Severe Vision | -0.07 logMar | Standard Deviation 0.13 |
| Higher Dose (1x10e11vg) | Best-corrected Visual Acuity | 24 Months/Acute Bilateral Severe Vision | -0.11 logMar | Standard Deviation 0.46 |
| Higher Dose (1x10e11vg) | Best-corrected Visual Acuity | 36 Months/Acute Bilateral Severe Vision | -0.16 logMar | Standard Deviation 0.65 |
| Higher Dose (1x10e11vg) | Best-corrected Visual Acuity | 12 Months/Acute Unilateral Severe Vision | 1.09 logMar | Standard Deviation 0.3 |
| Higher Dose (1x10e11vg) | Best-corrected Visual Acuity | 24 Months/Acute Unilateral Severe Vision | 0.83 logMar | Standard Deviation 0.24 |
| Higher Dose (1x10e11vg) | Best-corrected Visual Acuity | 12 Months/Acute Bilateral Severe Vision | 0.26 logMar | Standard Deviation 0.23 |