Safety and Efficacy Study of rAAV2-ND4 Treatment of Leber Hereditary Optic Neuropathy (LHON)
Study Details
Study Description
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.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
N/A |
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 × 109 vg/0.05 mL for patients younger than 12 years old, and 1 × 1010 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.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: rAAV2-ND4 injection |
Drug: rAAV2-ND4
injection
Other Names:
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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(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.
- 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.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
comply with Leber hereditary optic neuropathy diagnostic criteria.
-
in patients with informed consent, voluntary participation.
-
signed informed consent.
-
8 ≤ Age ≤ 60 years old, good health, the patient can tolerate local anesthesia surgery.
-
to comply with doctor's instructions, can in the time of referral.
Exclusion Criteria:
-
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.
-
Are participating in other clinical studies of patients.
-
Patients with mental disorders.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Department of Ophthalmology ,Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology | Wuhan | Hubei | China | 430030 |
Sponsors and Collaborators
- Bin Li
- Huazhong University of Science and Technology
Investigators
- Study Chair: bin Li, PhD,MD, Deputy Director of Ophthalmology
Study Documents (Full-Text)
None provided.More Information
Publications
- Angebault C, Gueguen N, Desquiret-Dumas V, Chevrollier A, Guillet V, Verny C, Cassereau J, Ferre M, Milea D, Amati-Bonneau P, Bonneau D, Procaccio V, Reynier P, Loiseau D. Idebenone increases mitochondrial complex I activity in fibroblasts from LHON patients while producing contradictory effects on respiration. BMC Res Notes. 2011 Dec 22;4:557. doi: 10.1186/1756-0500-4-557.
- Bainbridge JW, Smith AJ, Barker SS, Robbie S, Henderson R, Balaggan K, Viswanathan A, Holder GE, Stockman A, Tyler N, Petersen-Jones S, Bhattacharya SS, Thrasher AJ, Fitzke FW, Carter BJ, Rubin GS, Moore AT, Ali RR. Effect of gene therapy on visual function in Leber's congenital amaurosis. N Engl J Med. 2008 May 22;358(21):2231-9. doi: 10.1056/NEJMoa0802268. Epub 2008 Apr 27.
- Barnils N, Mesa E, Muñoz S, Ferrer-Artola A, Arruga J. [Response to idebenone and multivitamin therapy in Leber's hereditary optic neuropathy]. Arch Soc Esp Oftalmol. 2007 Jun;82(6):377-80. Spanish.
- Bonnet C, Kaltimbacher V, Ellouze S, Augustin S, Bénit P, Forster V, Rustin P, Sahel JA, Corral-Debrinski M. Allotopic mRNA localization to the mitochondrial surface rescues respiratory chain defects in fibroblasts harboring mitochondrial DNA mutations affecting complex I or v subunits. Rejuvenation Res. 2007 Jun;10(2):127-44.
- Carelli V, Barboni P, Zacchini A, Mancini R, Monari L, Cevoli S, Liguori R, Sensi M, Lugaresi E, Montagna P. Leber's Hereditary Optic Neuropathy (LHON) with 14484/ND6 mutation in a North African patient. J Neurol Sci. 1998 Oct 8;160(2):183-8.
- Carelli V, La Morgia C, Valentino ML, Rizzo G, Carbonelli M, De Negri AM, Sadun F, Carta A, Guerriero S, Simonelli F, Sadun AA, Aggarwal D, Liguori R, Avoni P, Baruzzi A, Zeviani M, Montagna P, Barboni P. Idebenone treatment in Leber's hereditary optic neuropathy. Brain. 2011 Sep;134(Pt 9):e188. doi: 10.1093/brain/awr180. Epub 2011 Aug 2.
- Carelli V, Ross-Cisneros FN, Sadun AA. Mitochondrial dysfunction as a cause of optic neuropathies. Prog Retin Eye Res. 2004 Jan;23(1):53-89. Review.
- Cui G, Ding H, Xu Y, Li B, Wang DW. Applications of the method of high resolution melting analysis for diagnosis of Leber's disease and the three primary mutation spectrum of LHON in the Han Chinese population. Gene. 2013 Jan 1;512(1):108-12. doi: 10.1016/j.gene.2012.09.110. Epub 2012 Oct 9.
- Ellouze S, Augustin S, Bouaita A, Bonnet C, Simonutti M, Forster V, Picaud S, Sahel JA, Corral-Debrinski M. Optimized allotopic expression of the human mitochondrial ND4 prevents blindness in a rat model of mitochondrial dysfunction. Am J Hum Genet. 2008 Sep;83(3):373-87. doi: 10.1016/j.ajhg.2008.08.013. Epub 2008 Sep 4.
- Ghelli A, Porcelli AM, Zanna C, Martinuzzi A, Carelli V, Rugolo M. Protection against oxidant-induced apoptosis by exogenous glutathione in Leber hereditary optic neuropathy cybrids. Invest Ophthalmol Vis Sci. 2008 Feb;49(2):671-6. doi: 10.1167/iovs.07-0880.
- Giordano C, Montopoli M, Perli E, Orlandi M, Fantin M, Ross-Cisneros FN, Caparrotta L, Martinuzzi A, Ragazzi E, Ghelli A, Sadun AA, d'Amati G, Carelli V. Oestrogens ameliorate mitochondrial dysfunction in Leber's hereditary optic neuropathy. Brain. 2011 Jan;134(Pt 1):220-34. doi: 10.1093/brain/awq276. Epub 2010 Oct 13.
- Hsu TK, Wang AG, Yen MY, Liu JH. Leber's hereditary optic neuropathy masquerading as optic neuritis with spontaneous visual recovery. Clin Exp Optom. 2014 Jan;97(1):84-6. doi: 10.1111/cxo.12100. Epub 2013 Aug 1.
- Klopstock T, Yu-Wai-Man P, Dimitriadis K, Rouleau J, Heck S, Bailie M, Atawan A, Chattopadhyay S, Schubert M, Garip A, Kernt M, Petraki D, Rummey C, Leinonen M, Metz G, Griffiths PG, Meier T, Chinnery PF. A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy. Brain. 2011 Sep;134(Pt 9):2677-86. doi: 10.1093/brain/awr170. Epub 2011 Jul 25.
- 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.
- Koilkonda RD, Guy J. Leber's Hereditary Optic Neuropathy-Gene Therapy: From Benchtop to Bedside. J Ophthalmol. 2011;2011:179412. doi: 10.1155/2011/179412. Epub 2010 Dec 26.
- 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.
- Leo-Kottler B, Christ-Adler M. [Leber optic neuropathy in women and children]. Ophthalmologe. 1999 Nov;96(11):698-701. German.
- Li H, Tuyishime S, Wu TL, Giles-Davis W, Zhou D, Xiao W, High KA, Ertl HC. Adeno-associated virus vectors serotype 2 induce prolonged proliferation of capsid-specific CD8+ T cells in mice. Mol Ther. 2011 Mar;19(3):536-46. doi: 10.1038/mt.2010.267. Epub 2010 Dec 14.
- Mackey DA, Oostra RJ, Rosenberg T, Nikoskelainen E, Bronte-Stewart J, Poulton J, Harding AE, Govan G, Bolhuis PA, Norby S. Primary pathogenic mtDNA mutations in multigeneration pedigrees with Leber hereditary optic neuropathy. Am J Hum Genet. 1996 Aug;59(2):481-5.
- Maguire AM, Simonelli F, Pierce EA, Pugh EN Jr, Mingozzi F, Bennicelli J, Banfi S, Marshall KA, Testa F, Surace EM, Rossi S, Lyubarsky A, Arruda VR, Konkle B, Stone E, Sun J, Jacobs J, Dell'Osso L, Hertle R, Ma JX, Redmond TM, Zhu X, Hauck B, Zelenaia O, Shindler KS, Maguire MG, Wright JF, Volpe NJ, McDonnell JW, Auricchio A, High KA, Bennett J. Safety and efficacy of gene transfer for Leber's congenital amaurosis. N Engl J Med. 2008 May 22;358(21):2240-8. doi: 10.1056/NEJMoa0802315. Epub 2008 Apr 27.
- Mashima Y, Kigasawa K, Wakakura M, Oguchi Y. Do idebenone and vitamin therapy shorten the time to achieve visual recovery in Leber hereditary optic neuropathy? J Neuroophthalmol. 2000 Sep;20(3):166-70.
- Mays LE, Vandenberghe LH, Xiao R, Bell P, Nam HJ, Agbandje-McKenna M, Wilson JM. Adeno-associated virus capsid structure drives CD4-dependent CD8+ T cell response to vector encoded proteins. J Immunol. 2009 May 15;182(10):6051-60. doi: 10.4049/jimmunol.0803965.
- Newman NJ. Treatment of Leber hereditary optic neuropathy. Brain. 2011 Sep;134(Pt 9):2447-50. doi: 10.1093/brain/awr192. Epub 2011 Aug 22.
- Oguchi Y. [Past, present, and future in Leber's hereditary optic neuropathy]. Nippon Ganka Gakkai Zasshi. 2001 Dec;105(12):809-27. Review. Japanese.
- Sadun AA, Chicani CF, Ross-Cisneros FN, Barboni P, Thoolen M, Shrader WD, Kubis K, Carelli V, Miller G. Effect of EPI-743 on the clinical course of the mitochondrial disease Leber hereditary optic neuropathy. Arch Neurol. 2012 Mar;69(3):331-8. doi: 10.1001/archneurol.2011.2972.
- Shi H, Gao J, Pei H, Liu R, Hu WK, Wan X, Li T, Li B. Adeno-associated virus-mediated gene delivery of the human ND4 complex I subunit in rabbit eyes. Clin Exp Ophthalmol. 2012 Dec;40(9):888-94. doi: 10.1111/j.1442-9071.2012.02815.x. Epub 2012 Jul 2.
- Testa F, Maguire AM, Rossi S, Pierce EA, Melillo P, Marshall K, Banfi S, Surace EM, Sun J, Acerra C, Wright JF, Wellman J, High KA, Auricchio A, Bennett J, Simonelli F. Three-year follow-up after unilateral subretinal delivery of adeno-associated virus in patients with Leber congenital Amaurosis type 2. Ophthalmology. 2013 Jun;120(6):1283-91. doi: 10.1016/j.ophtha.2012.11.048. Epub 2013 Mar 6.
- Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, Elsas LJ 2nd, Nikoskelainen EK. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science. 1988 Dec 9;242(4884):1427-30.
- Yang S, He H, Zhu Y, Wan X, Zhou LF, Wang J, Wang WF, Liu L, Li B. Chemical and material communication between the optic nerves in rats. Clin Exp Ophthalmol. 2015 Nov;43(8):742-8. doi: 10.1111/ceo.12547. Epub 2015 Jun 25.
- Yu-Wai-Man P, Griffiths PG, Chinnery PF. Mitochondrial optic neuropathies - disease mechanisms and therapeutic strategies. Prog Retin Eye Res. 2011 Mar;30(2):81-114. doi: 10.1016/j.preteyeres.2010.11.002. Epub 2010 Nov 26. Review.
- RAVCT-2
Study Results
Participant Flow
Recruitment Details | Patients diagnosed with LHON (with a verified point mutation at the 11778 nucleotide site) |
---|---|
Pre-assignment Detail | All patients were administered rAAV2-ND4 by intravitreal injection to one eye and then followed for 36 months. |
Arm/Group Title | Participants Receiving Treatment in Left Eye | Participants Receiving Treatment in Right Eye |
---|---|---|
Arm/Group Description | 5 participants receiving treatment in left eye | 4 participants receiving treatment in right eye |
Period Title: Intravitreal rAAV2-ND4 Injection | ||
STARTED | 5 | 4 |
COMPLETED | 5 | 4 |
NOT COMPLETED | 0 | 0 |
Period Title: Intravitreal rAAV2-ND4 Injection | ||
STARTED | 5 | 4 |
COMPLETED | 5 | 4 |
NOT COMPLETED | 0 | 0 |
Baseline Characteristics
Arm/Group Title | All Study Participants |
---|---|
Arm/Group Description | Age,Gender,Ethnicity,Race,Region of Enrollment |
Overall Participants | 9 |
Age (years) [Median (Inter-Quartile Range) ] | |
Median (Inter-Quartile Range) [years] |
15
|
Sex: Female, Male (Count of Participants) | |
Female |
2
22.2%
|
Male |
7
77.8%
|
Ethnicity (NIH/OMB) (Count of Participants) | |
Hispanic or Latino |
0
0%
|
Not Hispanic or Latino |
9
100%
|
Unknown or Not Reported |
0
0%
|
Race (NIH/OMB) (Count of Participants) | |
American Indian or Alaska Native |
0
0%
|
Asian |
9
100%
|
Native Hawaiian or Other Pacific Islander |
0
0%
|
Black or African American |
0
0%
|
White |
0
0%
|
More than one race |
0
0%
|
Unknown or Not Reported |
0
0%
|
Region of Enrollment (participants) [Number] | |
China |
9
100%
|
Outcome Measures
Title | The Best Corrected Visual Acuity(BCVA) |
---|---|
Description | |
Time Frame | Up to 3 years |
Outcome Measure Data
Analysis Population Description |
---|
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/Group Title | BCVA of Un-treated Eyes | BCVA of Treated Eyes |
---|---|---|
Arm/Group Description | BCVA of un-treated eyes in 9 patients | BCVA of trearted eyes in 9 patients |
Measure Participants | 9 | 9 |
Measure logMAR | 9 | 9 |
before treament |
1.40
(0.55)
|
1.69
(0.43)
|
1 months after treament |
1.36
(0.58)
|
1.58
(0.44)
|
3 months after treament |
1.31
(0.58)
|
1.38
(0.46)
|
6 months after treament |
1.20
(0.68)
|
1.23
(0.60)
|
9 months after treament |
1.23
(0.62)
|
1.27
(0.58)
|
Title | Results of CD3/CD4/CD8 Test |
---|---|
Description | The mean percentage of CD3+/CD4+/CD8+ test before and after treatment |
Time Frame | up to 6 months |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | The Mean Percentage of CD3+/CD4+/CD8+ Before Treatment | The Mean Percentage of CD3+/CD4+/CD8+ After Treatment |
---|---|---|
Arm/Group Description | The mean percentage of CD3+ before treatment;The mean percentage of CD4+ before treatment;The mean percentage of CD8+ before treatment | The mean percentage of CD3+ after treatment;The mean percentage of CD4+ after treatment;The mean percentage of CD8+ after treatment |
Measure Participants | 9 | 9 |
Values of CD3+ |
51
|
53
|
Values of CD4+ |
26
|
20
|
Values of CD8+ |
20
|
13
|
Title | Intraocular Pressure; |
---|---|
Description | |
Time Frame | Up to 3 years |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | IOP Before Treatment | IOP After Treatment |
---|---|---|
Arm/Group Description | Ophthalmologic examinations includes IOP of 9 paticipants before treatment | Ophthalmologic examinations includes IOP of 9 participants after treatment |
Measure Participants | 9 | 9 |
Mean (Full Range) [mmHg] |
14
|
16
|
Title | Neutralizing Antibody Assay |
---|---|
Description | The mean of Neutralizing antibody assay of 8 patients before and after treatment |
Time Frame | up to 3 years |
Outcome Measure Data
Analysis Population Description |
---|
Neutralizing antibody assay of 8 patients except Patient 1 because he once accepted the other eye's treatment |
Arm/Group Title | The Mean of Neutralizing Antibody Assay Before Treatment | The Mean of Neutralizing Antibody Assay After Treatment |
---|---|---|
Arm/Group Description | The mean of Neutralizing antibody assay before treatment of 8 patients | The mean of Neutralizing antibody assay after treatment of 8 patients |
Measure Participants | 8 | 8 |
Mean (Standard Deviation) [titer] |
0.9221
(0.142437)
|
0.8723
(0.201054)
|
Title | Average RNFL Thickness Througth Optical Coherence Tomography(OCT) Test |
---|---|
Description | Average RNFL thickness of 8 patients througth Optical coherence tomography(OCT) test before and after treatment |
Time Frame | Up to 3 years |
Outcome Measure Data
Analysis Population Description |
---|
RNFL thickness of 8 patients except Patient 1 because he once accepted the other eye's treatment |
Arm/Group Title | Average RNFL Thickness Before Treatment | Average RNFL Thickness After Treatment |
---|---|---|
Arm/Group Description | Average RNFL thickness before treatment of injected eyes;Average RNFL thickness before treatment of uninjected eyes | Average RNFL thickness after treatment of injected eyes;Average RNFL thickness after treatment of uninjected eyes |
Measure Participants | 8 | 8 |
injected eye |
47.3125
(7.87259)
|
46.7813
(7.5397)
|
uninjected eye |
50.1875
(13.402)
|
47.9688
(9.7031)
|
Title | Computerized Visual Field(MD: Mean Deviation, the Value Close to 0 Regarded Normal) |
---|---|
Description | 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 |
Outcome Measure Data
Analysis Population Description |
---|
Patient 2 refused the vision field test,there are MD outcome measure of 8 patients. |
Arm/Group Title | Mean MD Before Treatment | Mean MD After Treatment |
---|---|---|
Arm/Group Description | Mean MD before treatment of injected eyes;Mean MD before treatment of uninjected eyes | Mean MD after treatment of injected eyes;Mean MD after treatment of uninjected eyes |
Measure Participants | 8 | 8 |
injected eye |
-29.377
(5.16805)
|
-23.813
(7.27537)
|
uninjected eye |
-28.701
(3.65595)
|
-23.427
(8.15747)
|
Title | Computerized Visual Field(VFI: Visual Field Index ,the Value Close to 100% Regarded Normal) |
---|---|
Description | 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 |
Outcome Measure Data
Analysis Population Description |
---|
Patient 2 refused the vision field test,there are VFI outcome measure of 8 patients. |
Arm/Group Title | Mean VFI Before Treatment | Mean VFI After Treatment |
---|---|---|
Arm/Group Description | Mean VFI before treatment of injected eyes;Mean VFI before treatment of uninjected eyes | Mean VFI after treatment of injected eyes;Mean VFI after treatment of uninjected eyes |
Measure Participants | 8 | 8 |
injected eye |
11
(0.14513)
|
28
(0.23305)
|
uninjected eye |
10.5
(0.28714)
|
25
(0.24804)
|
Adverse Events
Time Frame | ||||
---|---|---|---|---|
Adverse Event Reporting Description | ||||
Arm/Group Title | Short-term Affects | Long-term Affects | ||
Arm/Group Description | Lens may be injured during intravitreal injection, and cataract is probably complicated. Retinal detachment or endophthalmitis may be complicated due to retina injury.IOP raised.Endophthalmitis after treament. Hyper-susceptibility or immune response during surgery or after surgery. | Lens may be injured after intravitreal injection, and cataract is probably complicated. Retinal detachment or endophthalmitis may be complicated due to retina injury.IOP raised.Blood and urine routine is affected.Liver and kidney function is affected.Immune response after surgery. | ||
All Cause Mortality |
||||
Short-term Affects | Long-term Affects | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | / (NaN) | / (NaN) | ||
Serious Adverse Events |
||||
Short-term Affects | Long-term Affects | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 0/9 (0%) | 0/9 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
Short-term Affects | Long-term Affects | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 0/9 (0%) | 0/9 (0%) |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title | Bin Li |
---|---|
Organization | Department of Ophthalmology, Tongji Hospital Tongji Medical College, Huazhong University of Science and Technology |
Phone | +86-13638673626 |
libin-12@163.com |
- RAVCT-2