An Open-label Dose Escalation Study of an Adeno-associated Virus Vector (scAAV2-P1ND4v2) for Gene Therapy of Leber's Hereditary Optic Neuropathy (LHON) Caused by the G11778A Mutation in Mitochondrial DNA

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.

开始日期2014-07-14

申办/合作机构

University of Miami

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100 项与 scAAV2-P1ND4v2 相关的临床结果

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100 项与 scAAV2-P1ND4v2 相关的转化医学

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100 项与 scAAV2-P1ND4v2 相关的专利（医药）

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项与 scAAV2-P1ND4v2 相关的文献（医药）

2014-12-01·Investigative Ophthalmology & Visual Science2区 · 医学

LHON Gene Therapy Vector Prevents Visual Loss and Optic Neuropathy Induced by G11778A Mutant Mitochondrial DNA: Biodistribution and Toxicology Profile

2区 · 医学

ArticleOA

作者: Erger, Kirsten E ; Chiodo, Vince ; Koilkonda, Rajeshwari ; Boye, Sanford L ; Hauswirth, William W ; Neuringer, Martha ; Renner, Lauren ; Guy, John ; Yu, Hong ; Conlon, Thomas J ; Porciatti, Vittorio ; Talla, Venu ; Feuer, William J ; Detrisac, Carol ; Lewin, Alfred S

PURPOSETo demonstrate safety and efficacy of allotopic human ND4 for treatment of a Leber's hereditary optic neuropathy (LHON) mouse model harboring the G11778A mitochondrial mutation.METHODSWe induced LHON in mice by intravitreal injection of mutant (G11778A) human ND4 DNA, responsible for most cases of LHON, that was directed to mitochondria using an AAV2 vector to which we appended a mitochondrial targeting sequence to the VP2 capsid. We then attempted rescue of visual loss using our test article (ScAAV2-P1ND4v2) containing a synthetic nuclear encoded G11778G ND4 gene that was allotopically expressed. Control mice either were uninjected or received AAV2-GFP or AAV2-mCherry. We performed RT-PCR and confocal microscopy at 2 weeks post injection. Pattern electroretinograms (PERGs), spectral-domain optical coherence tomography (SD-OCT), histology, and transmission electron microscopy (TEM) were performed. For toxicology and biodistribution studies, the test article was administered intravitreally to rats and rhesus macaques at different doses.RESULTSMutant and wild-type ND4 were efficiently expressed in the mitochondria of retinal ganglion cells (RGCs). Visual function assessed by serial PERGs and retinal structure by serial SD-OCT showed a significant rescue by the test article. Histology and ultrastructural analysis confirmed that loss of RGCs and demise of axons was prevented by ScAAV2-P1ND4v2. Rat and nonhuman primate biodistribution studies showed that vector spread outside the injected eye into spleen and lymph nodes was minimal. Histopathology of tissues and organs including the eyes was comparable to that of uninfected and saline-injected eyes.CONCLUSIONSAllotopically expressed wild-type ND4 prevents the phenotype induced by G11778A mitochondrial DNA with a toxicology profile acceptable for testing in a phase I clinical trial.

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适应症	最高研发状态	国家/地区	公司	日期
Leber氏遗传性视神经萎缩	临床1期	美国	University of Miami	2014-07-14

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02161380 (LHON, CTgov)	临床1期	Leber氏遗传性视神经萎缩	28	injection of scAAV2-P1ND4v2 1.18x10e9 vg (Low), (Low-dose (1.18x10e9 vg))	築糧糧願構遞選鹹遞鏇(膚憲餘齋網膚淵鹹壓憲) = 獵艱糧衊膚範觸襯憲遞鏇選願鑰網獵鹹鹹鬱鹽 (網齋願製廠製糧觸糧餘, 網膚繭餘願膚獵積繭齋 ~ 餘餘鹹鹽觸範餘醖範鑰) 更多	-	2024-08-07
				injection of scAAV2-P1ND4v2 5.81 X10e9 vg (Med) (Medium Dose (5.81x10e9 vg))	築糧糧願構遞選鹹遞鏇(膚憲餘齋網膚淵鹹壓憲) = 鑰顧蓋鹽壓鹽願壓糧選鏇選願鑰網獵鹹鹹鬱鹽 (網齋願製廠製糧觸糧餘, 窪獵鏇願廠窪鹽獵獵糧 ~ 製簾衊遞餘廠膚艱顧衊) 更多