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| Name | Class |
|---|---|
| Huazhong University of Science and Technology | OTHER |
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This study is meant to assess the safety and efficacy of rAAV2-ND4 treatment of Leber hereditary optic neuropathy with 11778 LHON mutation.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| rAAV2-ND4 | Experimental | injection |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| rAAV2-ND4 | Drug | injection |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| The Best Corrected Visual Acuity(BCVA) | Up to 3 years | |
| Results of CD3/CD4/CD8 Test | The mean percentage of CD3+/CD4+/CD8+ test before and after treatment | up to 6 months |
| Measure | Description | Time Frame |
|---|---|---|
| Intraocular Pressure; | Up to 3 years | |
| Neutralizing Antibody Assay | The mean of Neutralizing antibody assay of 8 patients before and after treatment | up to 3 years |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| bin Li, PhD,MD | Deputy Director of Ophthalmology | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Department of Ophthalmology ，Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology | Wuhan | Hubei | 430030 | China |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 14766317 | Background | 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. doi: 10.1016/j.preteyeres.2003.10.003. | |
| 8755941 | Background | 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. No abstract available. |
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All patients were administered rAAV2-ND4 by intravitreal injection to one eye and then followed for 36 months.
Patients diagnosed with LHON (with a verified point mutation at the 11778 nucleotide site)
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| ID | Title | Description |
|---|---|---|
| FG000 | Participants Receiving Treatment in Left Eye | 5 participants receiving treatment in left eye |
| FG001 | Participants Receiving Treatment in Right Eye | 4 participants receiving treatment in right eye |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Intravitreal rAAV2-ND4 Injection |
| |||||||||||||
| Safety and Efficacy Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | All Study Participants | Age,Gender,Ethnicity,Race,Region of Enrollment |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | The Best Corrected Visual Acuity(BCVA) | 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. | Posted | Mean | Standard Error | logMAR | Up to 3 years | logMAR | logMAR |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Short-term Affects | 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. |
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Early termination leading to small numbers of subjects analyzed.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Bin Li | Department of Ophthalmology, Tongji Hospital Tongji Medical College, Huazhong University of Science and Technology | +86-13638673626 | libin-12@163.com |
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| ID | Term |
|---|---|
| D029242 | Optic Atrophy, Hereditary, Leber |
| ID | Term |
|---|---|
| D015418 | Optic Atrophies, Hereditary |
| D009896 | Optic Atrophy |
| D009901 | Optic Nerve Diseases |
| D003389 | Cranial Nerve Diseases |
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| 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 | Up to 3 years |
| 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. | up to 3 years |
| 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. | up to 3 years |
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| 11802455 | Background | Oguchi Y. [Past, present, and future in Leber's hereditary optic neuropathy]. Nippon Ganka Gakkai Zasshi. 2001 Dec;105(12):809-27. Japanese. |
| 23063736 | Background | 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. |
| 11001192 | Background | 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. doi: 10.1097/00041327-200020030-00006. |
| 9849804 | Background | 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. doi: 10.1016/s0022-510x(98)00239-1. |
| 17573650 | Background | Barnils N, Mesa E, Munoz 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. doi: 10.4321/s0365-66912007000600012. Spanish. |
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| 22410442 | Background | 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. |
| 21859767 | Background | 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. No abstract available. |
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| 18441371 | Background | 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. |
| 17518546 | Background | Bonnet C, Kaltimbacher V, Ellouze S, Augustin S, Benit 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. doi: 10.1089/rej.2006.0526. |
| 18771762 | Background | 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. |
| 24457989 | Background | 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. |
| 25342621 | Background | 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. |
| 22612072 | Background | 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. |
| 19414756 | Background | 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. |
| 23905692 | Background | 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. |
| 10631830 | Background | Leo-Kottler B, Christ-Adler M. [Leber optic neuropathy in women and children]. Ophthalmologe. 1999 Nov;96(11):698-701. doi: 10.1007/s003470050479. German. |
| 21157435 | Background | 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. |
| 20943885 | Background | 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. |
| 23474247 | Background | 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. |
| 25950380 | Background | 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. |
| 18235013 | Background | 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. |
| 21112411 | Background | 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. |
| 21253496 | Background | 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. |
| 26892229 | Result | Wan X, Pei H, Zhao MJ, Yang S, Hu WK, He H, Ma SQ, Zhang G, Dong XY, Chen C, Wang DW, Li B. Efficacy and Safety of rAAV2-ND4 Treatment for Leber's Hereditary Optic Neuropathy. Sci Rep. 2016 Feb 19;6:21587. doi: 10.1038/srep21587. |
| 30878986 | Derived | Liu HL, Yuan JJ, Tian Z, Li X, Song L, Li B. What are the characteristics and progression of visual field defects in patients with Leber hereditary optic neuropathy: a prospective single-centre study in China. BMJ Open. 2019 Mar 15;9(3):e025307. doi: 10.1136/bmjopen-2018-025307. |
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| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Units | Counts |
|---|
| Participants |
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| logMAR |
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| Primary | Results of CD3/CD4/CD8 Test | The mean percentage of CD3+/CD4+/CD8+ test before and after treatment | Posted | Mean | Full Range | Percentage of total cells | up to 6 months |
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| Secondary | Intraocular Pressure; | Posted | Mean | Full Range | mmHg | Up to 3 years |
|
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| Secondary | Neutralizing Antibody Assay | The mean of Neutralizing antibody assay of 8 patients before and after treatment | Neutralizing antibody assay of 8 patients except Patient 1 because he once accepted the other eye's treatment | Posted | Mean | Standard Deviation | titer | up to 3 years |
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| 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 | RNFL thickness of 8 patients except Patient 1 because he once accepted the other eye's treatment | Posted | Mean | Standard Deviation | Micrometer | Up to 3 years |
|
|
|
| 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. | Patient 2 refused the vision field test,there are MD outcome measure of 8 patients. | Posted | Mean | Standard Deviation | dB | up to 3 years |
|
|
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| 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. | Patient 2 refused the vision field test,there are VFI outcome measure of 8 patients. | Posted | Mean | Standard Deviation | Percentage of normal | up to 3 years |
|
|
|
| 0 |
| 9 |
| 0 |
| 9 |
| EG001 | Long-term Affects | 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. | 0 | 9 | 0 | 9 |
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| D009422 |
| Nervous System Diseases |
| D020271 | Heredodegenerative Disorders, Nervous System |
| D019636 | Neurodegenerative Diseases |
| D015785 | Eye Diseases, Hereditary |
| D005128 | Eye Diseases |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D028361 | Mitochondrial Diseases |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| Values of CD8+ |
|