Leber Hereditary Optic Neuropathy
Conditions
Keywords
Leber's Hereditary Optic Neuropathy,11778 LHON mutation,, rAAV2-ND4,triamcinolone acetonide
Brief summary
This study is meant to assess the safety and efficacy of rAAV2-ND4 treatment of Leber hereditary optic neuropathy with 11778 LHON mutation.
Detailed description
Leber's Hereditary Optic Neuropathy (LHON) is a maternally inherited ocular disorder associated with a mutation in mtDNA . The common manifestation is visual loss which caused by the respiratory chain enzymes complex dysfunction resulting in increased oxidative stress enzymes production. Material and Method Seven patients with 11778 LHON mutation were randomly treated with a Single IVT Injection of recombinant Adeno-Associated Virus-NADH dehydrogenase, subunit 4 (complex I)（rAAV2-ND4)（0.05ml).The dose was 5 × 10\^9 vg/0.05 mL for patients younger than 12 years old, and 1 × 10\^10 vg/0.05 mL for patients older than 12 years old. The visual acuity, visual evoked potential （VEP）,optical coherence tomography（ OCT）, computerized visual field, electroretinograms(ERG), retinal nerve fiber layer(RNFL)and Liver and kidney function in plasma were compared before and after treatment at 1,3,and 6, months interval.
Interventions
DRUGrAAV2-ND4
injection
Sponsors
Huazhong University of Science and Technology
Bin Li
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
8 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
1. comply with Leber hereditary optic neuropathy diagnostic criteria. 2. in patients with informed consent, voluntary participation. 3. signed informed consent. 4. 8 ≤ Age ≤ 60 years old, good health, the patient can tolerate local anesthesia surgery. 5. to comply with doctor's instructions, can in the time of referral.
Exclusion criteria
1. Cardiopulmonary and renal function in severe weakness, cancer, a variety of bleeding disorders, acute sensing disease, high fever, high fever disease, women during pregnancy, heart disease, such as post-operative recovery period. 2. Are participating in other clinical studies of patients. 3. Patients with mental disorders.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Best Corrected Visual Acuity(BCVA) | Up to 3 years | — |
| Results of CD3/CD4/CD8 Test | up to 6 months | The mean percentage of CD3+/CD4+/CD8+ test before and after treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Computerized Visual Field(MD: Mean Deviation, the Value Close to 0 Regarded Normal) | up to 3 years | MD: mean deviation, the value Close to 0 regarded normal.VFI/MD：The bigger one was more close to the normal value. |
| Intraocular Pressure; | Up to 3 years | — |
| Neutralizing Antibody Assay | up to 3 years | The mean of Neutralizing antibody assay of 8 patients before and after treatment |
| Average RNFL Thickness Througth Optical Coherence Tomography(OCT) Test | Up to 3 years | Average RNFL thickness of 8 patients througth Optical coherence tomography(OCT) test before and after treatment |
| Computerized Visual Field(VFI: Visual Field Index ,the Value Close to 100% Regarded Normal) | up to 3 years | VFI: visual field index ,the value Close to 100% regarded normal. VFI/MD：The bigger one was more close to the normal value. |
Countries
China
Participant flow
Recruitment details
Patients diagnosed with LHON (with a verified point mutation at the 11778 nucleotide site)
Pre-assignment details
All patients were administered rAAV2-ND4 by intravitreal injection to one eye and then followed for 36 months.
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants Age,Gender,Ethnicity,Race,Region of Enrollment | 9 |
| Total | 9 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Continuous | 15 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 9 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Region of Enrollment China | 9 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 9 | 0 / 9 |
| serious Total, serious adverse events | 0 / 9 | 0 / 9 |
Outcome results
Primary
Results of CD3/CD4/CD8 Test
The mean percentage of CD3+/CD4+/CD8+ test before and after treatment
Time frame: up to 6 months
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| BCVA of Un-treated Eyes | Results of CD3/CD4/CD8 Test | Values of CD3+ | 51 Percentage of total cells |
| BCVA of Un-treated Eyes | Results of CD3/CD4/CD8 Test | Values of CD4+ | 26 Percentage of total cells |
| BCVA of Un-treated Eyes | Results of CD3/CD4/CD8 Test | Values of CD8+ | 20 Percentage of total cells |
| BCVA of Treated Eyes | Results of CD3/CD4/CD8 Test | Values of CD3+ | 53 Percentage of total cells |
| BCVA of Treated Eyes | Results of CD3/CD4/CD8 Test | Values of CD4+ | 20 Percentage of total cells |
| BCVA of Treated Eyes | Results of CD3/CD4/CD8 Test | Values of CD8+ | 13 Percentage of total cells |
Primary
The Best Corrected Visual Acuity(BCVA)
Time frame: Up to 3 years
Population: The data are expressed as mean±standard error. Comparisons before and after treatment of the BCVA were analyzed using the paired t-test.A probability (P) value of less than 0.05 was considered statistically significant.Lower logMAR represents a better outcome.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BCVA of Un-treated Eyes | The Best Corrected Visual Acuity(BCVA) | 1 months after treament | 1.36 logMAR | Standard Error 0.58 |
| BCVA of Un-treated Eyes | The Best Corrected Visual Acuity(BCVA) | 6 months after treament | 1.20 logMAR | Standard Error 0.68 |
| BCVA of Un-treated Eyes | The Best Corrected Visual Acuity(BCVA) | 3 months after treament | 1.31 logMAR | Standard Error 0.58 |
| BCVA of Un-treated Eyes | The Best Corrected Visual Acuity(BCVA) | 9 months after treament | 1.23 logMAR | Standard Error 0.62 |
| BCVA of Un-treated Eyes | The Best Corrected Visual Acuity(BCVA) | before treament | 1.40 logMAR | Standard Error 0.55 |
| BCVA of Treated Eyes | The Best Corrected Visual Acuity(BCVA) | 9 months after treament | 1.27 logMAR | Standard Error 0.58 |
| BCVA of Treated Eyes | The Best Corrected Visual Acuity(BCVA) | before treament | 1.69 logMAR | Standard Error 0.43 |
| BCVA of Treated Eyes | The Best Corrected Visual Acuity(BCVA) | 1 months after treament | 1.58 logMAR | Standard Error 0.44 |
| BCVA of Treated Eyes | The Best Corrected Visual Acuity(BCVA) | 3 months after treament | 1.38 logMAR | Standard Error 0.46 |
| BCVA of Treated Eyes | The Best Corrected Visual Acuity(BCVA) | 6 months after treament | 1.23 logMAR | Standard Error 0.6 |
Secondary
Average RNFL Thickness Througth Optical Coherence Tomography(OCT) Test
Average RNFL thickness of 8 patients througth Optical coherence tomography(OCT) test before and after treatment
Time frame: Up to 3 years
Population: RNFL thickness of 8 patients except Patient 1 because he once accepted the other eye's treatment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BCVA of Un-treated Eyes | Average RNFL Thickness Througth Optical Coherence Tomography(OCT) Test | injected eye | 47.3125 Micrometer | Standard Deviation 7.87259 |
| BCVA of Un-treated Eyes | Average RNFL Thickness Througth Optical Coherence Tomography(OCT) Test | uninjected eye | 50.1875 Micrometer | Standard Deviation 13.402 |
| BCVA of Treated Eyes | Average RNFL Thickness Througth Optical Coherence Tomography(OCT) Test | injected eye | 46.7813 Micrometer | Standard Deviation 7.5397 |
| BCVA of Treated Eyes | Average RNFL Thickness Througth Optical Coherence Tomography(OCT) Test | uninjected eye | 47.9688 Micrometer | Standard Deviation 9.7031 |
Secondary
Computerized Visual Field(MD: Mean Deviation, the Value Close to 0 Regarded Normal)
MD: mean deviation, the value Close to 0 regarded normal.VFI/MD：The bigger one was more close to the normal value.
Time frame: up to 3 years
Population: Patient 2 refused the vision field test,there are MD outcome measure of 8 patients.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BCVA of Un-treated Eyes | Computerized Visual Field(MD: Mean Deviation, the Value Close to 0 Regarded Normal) | injected eye | -29.377 dB | Standard Deviation 5.16805 |
| BCVA of Un-treated Eyes | Computerized Visual Field(MD: Mean Deviation, the Value Close to 0 Regarded Normal) | uninjected eye | -28.701 dB | Standard Deviation 3.65595 |
| BCVA of Treated Eyes | Computerized Visual Field(MD: Mean Deviation, the Value Close to 0 Regarded Normal) | injected eye | -23.813 dB | Standard Deviation 7.27537 |
| BCVA of Treated Eyes | Computerized Visual Field(MD: Mean Deviation, the Value Close to 0 Regarded Normal) | uninjected eye | -23.427 dB | Standard Deviation 8.15747 |
Secondary
Computerized Visual Field(VFI: Visual Field Index ,the Value Close to 100% Regarded Normal)
VFI: visual field index ,the value Close to 100% regarded normal. VFI/MD：The bigger one was more close to the normal value.
Time frame: up to 3 years
Population: Patient 2 refused the vision field test,there are VFI outcome measure of 8 patients.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BCVA of Un-treated Eyes | Computerized Visual Field(VFI: Visual Field Index ,the Value Close to 100% Regarded Normal) | injected eye | 11 Percentage of normal | Standard Deviation 0.14513 |
| BCVA of Un-treated Eyes | Computerized Visual Field(VFI: Visual Field Index ,the Value Close to 100% Regarded Normal) | uninjected eye | 10.5 Percentage of normal | Standard Deviation 0.28714 |
| BCVA of Treated Eyes | Computerized Visual Field(VFI: Visual Field Index ,the Value Close to 100% Regarded Normal) | injected eye | 28 Percentage of normal | Standard Deviation 0.23305 |
| BCVA of Treated Eyes | Computerized Visual Field(VFI: Visual Field Index ,the Value Close to 100% Regarded Normal) | uninjected eye | 25 Percentage of normal | Standard Deviation 0.24804 |
Secondary
Intraocular Pressure;
Time frame: Up to 3 years
| Arm | Measure | Value (MEAN) |
|---|---|---|
| BCVA of Un-treated Eyes | Intraocular Pressure; | 14 mmHg |
| BCVA of Treated Eyes | Intraocular Pressure; | 16 mmHg |
Secondary
Neutralizing Antibody Assay
The mean of Neutralizing antibody assay of 8 patients before and after treatment
Time frame: up to 3 years
Population: Neutralizing antibody assay of 8 patients except Patient 1 because he once accepted the other eye's treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BCVA of Un-treated Eyes | Neutralizing Antibody Assay | 0.9221 titer | Standard Deviation 0.142437 |
| BCVA of Treated Eyes | Neutralizing Antibody Assay | 0.8723 titer | Standard Deviation 0.201054 |