Five-year analysis of efficacy and safety of a bidirectional AAV gene therapy in Tay-Sachs sheep.
СтатьяПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
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История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Taghian Toloo, Gallagher Jillian, Bertrand Stephanie, Baker William C, Lopez Mercado Kalajan, Benatti Hector R, Hall Erin, Lopez Yvette, McElroy Abigail, McCarthy John T, Pulaparthi Sanjana, Fernau Deborah, Mather Samuel, Esteves Sophia, Diffie Elise, Gross Amanda, Lahey Hannah G, Jiang Xuntian, Parsley Elizabeth, Gately Rachael, Prestigiacomo Rachel, Johnson Siauna, Taylor Amanda, Bierfeldt Lindsey, Tuominen Susan, Koehler Jennifer, Gao Guangping, Xie Jun, Su Qin, King Robert, Gounis Matthew J, Anagnostakou Vania, Puri Ajit, Batista Ana Rita, Sena-Esteves Miguel, Martin Douglas R, Gray-Edwards Heather
Аннотация
Tay-Sachs disease (TSD) and Sandhoff disease are fatal neurodegenerative diseases without an effective therapy that are caused by mutations in the HEXA and HEXB genes, respectively. Together they encode the heterodimeric isozyme of hexosaminidase, hexosaminidase A (HexA), that degrades GM2 ganglioside. This report describes a 5-year-long study using a bidirectional adeno-associated virus 9 (AAV9) vector (AAV9-Bic_HexA/HexB) encoding both HEXA and HEXB in the TSD sheep model. Bidirectional AAV9 was delivered i.v. or through various cerebrospinal fluid (CSF) delivery routes: intracerebroventricular (ICV), cisterna magna (CM), and lumbar intrathecal space (LIT). The longest survival and best distribution were achieved by multipoint CSF delivery (combined CM, ICV, and LIT) with treated animals that survived up to 5 years of age (untreated animals with TSD die after ~9 months). Extension in survival was accompanied by lasting improvement in neurological examination and maze testing. Improvement in biomarkers of efficacy, including MRI, magnetic resonance spectroscopy, diffusion tensor imaging, and CSF levels of GM2 ganglioside and HexA activity, was evident. Postmortem assessments showed broad HexA distribution, GM2 ganglioside clearance, and vector genome distribution, especially in deep brain structures. Therapeutic efficacy documented in this study supports translation of bidirectional vector and multipoint CSF delivery to a clinical trial in patients with TSD and Sandhoff disease.