Details

Autor(en) / Beteiligte

• Song, Yafeng
• Morales, Leon
• Malik, Alock S.
• Mead, Andrew F.
• Greer, Christopher D.
• Mitchell, Marilyn A.
• Petrov, Mihail T.
• Su, Leonard T.
• Choi, Margaret E.
• Rosenblum, Shira T.
• Lu, Xiangping
• VanBelzen, Daniel J.
• Krishnankutty, Ranjith K.
• Balzer, Frederick J.
• Loro, Emanuele
• French, Robert
• Propert, Kathleen J.
• Zhou, Shangzhen
• Kozyak, Benjamin W.
• Nghiem, Peter P.
• Khurana, Tejvir S.
• Kornegay, Joe N.
• Stedman, Hansell H.

Titel

Non-immunogenic utrophin gene therapy for the treatment of muscular dystrophy animal models

Ist Teil von

• Nature medicine, 2019-10, Vol.25 (10), p.1505-1511

Ort / Verlag

New York: Nature Publishing Group US

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• The essential product of the Duchenne muscular dystrophy (DMD) gene is dystrophin 1 , a rod-like protein 2 that protects striated myocytes from contraction-induced injury 3 , 4 . Dystrophin-related protein (or utrophin) retains most of the structural and protein binding elements of dystrophin 5 . Importantly, normal thymic expression in DMD patients 6 should protect utrophin by central immunologic tolerance. We designed a codon-optimized, synthetic transgene encoding a miniaturized utrophin (µUtro), deliverable by adeno-associated virus (AAV) vectors. Here, we show that µUtro is a highly functional, non-immunogenic substitute for dystrophin, preventing the most deleterious histological and physiological aspects of muscular dystrophy in small and large animal models. Following systemic administration of an AAV-µUtro to neonatal dystrophin-deficient mdx mice, histological and biochemical markers of myonecrosis and regeneration are completely suppressed throughout growth to adult weight. In the dystrophin-deficient golden retriever model, µUtro non-toxically prevented myonecrosis, even in the most powerful muscles. In a stringent test of immunogenicity, focal expression of µUtro in the deletional- null German shorthaired pointer model produced no evidence of cell-mediated immunity, in contrast to the robust T cell response against similarly constructed µDystrophin (µDystro). These findings support a model in which utrophin-derived therapies might be used to treat clinical dystrophin deficiency, with a favorable immunologic profile and preserved function in the face of extreme miniaturization. A gene therapy vector expressing micro-utrophin provides functional replacement of lost dystrophin, and lacks the adverse immunogenicity associated with direct dystrophin therapy, in rodent and canine models of Duchenne muscular dystrophy.