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

ABSTRACT: The essential product of the Duchenne muscular dystrophy (DMD) gene is dystrophin¹, a rod-like protein² 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 dystrophin⁵. Importantly, normal thymic expression in DMD patients⁶ 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.

SUBMITTER: Song Y

PROVIDER: S-EPMC7274039 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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

Song Yafeng Y Morales Leon L Malik Alock S AS Mead Andrew F AF Greer Christopher D CD Mitchell Marilyn A MA Petrov Mihail T MT Su Leonard T LT Choi Margaret E ME Rosenblum Shira T ST Lu Xiangping X VanBelzen Daniel J DJ Krishnankutty Ranjith K RK Balzer Frederick J FJ Loro Emanuele E French Robert R Propert Kathleen J KJ Zhou Shangzhen S Kozyak Benjamin W BW Nghiem Peter P PP Khurana Tejvir S TS Kornegay Joe N JN Stedman Hansell H HH

Nature medicine 20191007 10

The essential product of the Duchenne muscular dystrophy (DMD) gene is dystrophin1, a rod-like protein2 that protects striated myocytes from contraction-induced injury3,4. Dystrophin-related protein (or utrophin) retains most of the structural and protein binding elements of dystrophin5. Importantly, normal thymic expression in DMD patients6 should protect utrophin by central immunologic tolerance. We designed a codon-optimized, synthetic tr ...[more]

PMID: 31591596

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Project description:Duchenne muscular dystrophy is a devastating disease that leads to progressive muscle loss and premature death. While medical management focuses mostly on symptomatic treatment, decades of research have resulted in first therapeutics able to restore the affected reading frame of dystrophin transcripts or induce synthesis of a truncated dystrophin protein from a vector, with other strategies based on gene therapy and cell signaling in preclinical or clinical development. Nevertheless, recent reports show that potentially therapeutic dystrophins can be immunogenic in patients. This raises the question of whether a dystrophin paralog, utrophin, could be a more suitable therapeutic protein. Here, we compare dystrophin and utrophin amino acid sequences and structures, combining published data with our extended in silico analyses. We then discuss these results in the context of therapeutic approaches for Duchenne muscular dystrophy. Specifically, we focus on strategies based on delivery of micro-dystrophin and micro-utrophin genes with recombinant adeno-associated viral vectors, exon skipping of the mutated dystrophin pre-mRNAs, reading through termination codons with small molecules that mask premature stop codons, dystrophin gene repair by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (CRISPR/Cas9)-mediated genetic engineering, and increasing utrophin levels. Our analyses highlight the importance of various dystrophin and utrophin domains in Duchenne muscular dystrophy treatment, providing insights into designing novel therapeutic compounds with improved efficacy and decreased immunoreactivity. While the necessary actin and β-dystroglycan binding sites are present in both proteins, important functional distinctions can be identified in these domains and some other parts of truncated dystrophins might need redesigning due to their potentially immunogenic qualities. Alternatively, therapies based on utrophins might provide a safer and more effective approach.

Dataset Information

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

Publications

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

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