Perspective on Adeno-Associated Virus Capsid Modification for Duchenne Muscular Dystrophy Gene Therapy

Nance, Michael E.; Duan, Dongsheng

doi:10.1089/hum.2015.107

Cited by 46 publications

(38 citation statements)

References 178 publications

(138 reference statements)

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“…Several strategies have been used to develop novel capsids for improved systemic delivery. These include (1) isolation and reconstruction from existing or ancestral species [110,111], and (2) modification by rational design and directed evolution [112,113]. …”

Section: Re-engineering Aav For Improved Systemic Deliverymentioning

confidence: 99%

Systemic delivery of adeno-associated viral vectors

Duan

2016

Current Opinion in Virology

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For diseases like muscular dystrophy, an effective gene therapy requires bodywide correction. Systemic viral vector delivery has been attempted since early 90s. Yet a true success was not achieved until mid-2000 when adeno-associated virus (AAV) serotype-6, 8 and 9 were found to result in global muscle transduction in rodents following intravenous injection. The simplicity of the technique immediately attracts attention. Marvelous whole body amelioration has been achieved in rodent models of many diseases. Scale-up in large mammals also shows promising results. Importantly, the first systemic AAV-9 therapy was initiated in patients in April 2014. Recent studies have now begun to reveal molecular underpinnings of systemic AAV delivery and to engineer new AAV capsids with superior properties for systemic gene therapy.

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Section: Re-engineering Aav For Improved Systemic Deliverymentioning

confidence: 99%

Systemic delivery of adeno-associated viral vectors

Duan

2016

Current Opinion in Virology

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“…This is highly beneficial for DMD where long‐term expression is required. Furthermore, the atomic structures of many viruses have been solved and structure–function correlation studies have started to reveal critical structural domains involved in targeting, stability, and immune evasion …”

Section: Viral Vectors As Biological Nanoparticlesmentioning

confidence: 99%

Nanotherapy for Duchenne muscular dystrophy

Nance

Hakim

Yang

et al. 2017

WIREs Nanomed Nanobiotechnol

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Duchenne muscular dystrophy (DMD) is a lethal X-linked childhood muscle wasting disease caused by mutations in the dystrophin gene. Nanobiotechnology-based therapies (such as synthetic nanoparticles and naturally existing viral and nonviral nanoparticles) hold great promise to replace and repair the mutated dystrophin gene and significantly change the disease course. While a majority of DMD nanotherapies are still in early preclinical development, several [such as adeno-associated virus (AAV)-mediated systemic micro-dystrophin gene therapy] are advancing for phase I clinical trials. Recent regulatory approval of Ataluren (a nonsense mutation read-through chemical) in Europe and Exondys51 (an exon-skipping antisense oligonucleotide drug) in the United States shall offer critical insight in how to move DMD nanotherapy to human patients. Progress in novel, optimized nano-delivery systems may further improve emerging molecular therapeutic modalities for DMD. Despite these progresses, DMD nanotherapy faces a number of unique challenges. Specifically, the dystrophin gene is one of the largest genes in the genome while nanoparticles have an inherent size limitation per definition. Furthermore, muscle is the largest tissue in the body and accounts for 40% of the body mass. How to achieve efficient bodywide muscle targeting in human patients with nanomedication remains a significant translational hurdle. New creative approaches in the design of the miniature micro-dystrophin gene, engineering of muscle-specific synthetic AAV capsids, and novel nanoparticle-mediated exon-skipping are likely to result in major breakthroughs in DMD therapy.

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“…Early studies were mainly based on AAV-2 using invasive and complicated methods such as direct myocardial injection 23 , intracavity injection 24 , transcoronary perfusion 25 , and ex vivo coronary perfusion 26 . The identification and development of novel AAV capsids has opened the door to transduce dystrophic hearts with peripheral vein injections 27–32 . This simple method not only greatly reduces the risks associated invasive heart gene transfer but also allows simultaneous treatment of both cardiac and skeletal muscle disease in muscular dystrophy.…”

Section: Strategies To Deliver a Therapeutic Gene To A Dystrophic mentioning

confidence: 99%

“…Indeed, AAV-9 results in robust widespread myocardial transduction in mdx mice irrespective of the age and the route of delivery (intravenous or intra-arterial) 34–36 . Directed evolution and cardiotropic peptide insertion have also yielded novel AAV variants with enhanced cardiac transduction in rodent models of limb girdle muscular dystrophy (LGMD) 2F, an extremely rare type of muscular dystrophy caused by δ-sarcoglycan deficiency 32, 37, 38 .…”

Section: Strategies To Deliver a Therapeutic Gene To A Dystrophic mentioning

confidence: 99%

“…For example, it is not clear whether supra-physiological dystrophin expression in the heart is toxic, whether there exists heart-specific domain(s) in the dystrophin gene that should be included in micro-dystrophin, and whether cardiotropic features of some existing AAV serotypes can cross the species boundary and result in efficient heart transduction in humans. For this last point, some recent developments in the generation of the xenograft model using dystrophic human muscle and forced evolution of human tissue tropic AAV capsids may provide some hints 32, 212, 213 . It should be noted that emerging new technologies such as genome editing with CRISPR/Cas9 not only brings in new hopes, they are also accompanied with new questions such as potential toxicity from off-target editing.…”

Section: Expert Opinionmentioning

confidence: 99%

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Prospect of gene therapy for cardiomyopathy in hereditary muscular dystrophy

Yue

Binalsheikh

Leach

et al. 2015

Expert Opinion on Orphan Drugs

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Introduction Cardiac involvement is a common feature in muscular dystrophies. It presents as heart failure and/or arrhythmia. Traditionally, dystrophic cardiomyopathy is treated with symptom-relieving medications. Identification of disease-causing genes and investigation on pathogenic mechanisms have opened new opportunities to treat dystrophic cardiomyopathy with gene therapy. Replacing/repairing the mutated gene and/or targeting the pathogenic process/mechanisms using alternative genes may attenuate heart disease in muscular dystrophies. Areas covered Duchenne muscular dystrophy is the most common muscular dystrophy. Duchenne cardiomyopathy has been the primary focus of ongoing dystrophic cardiomyopathy gene therapy studies. Here, we use Duchenne cardiomyopathy gene therapy to showcase recent developments and to outline the path forward. We also discuss gene therapy status for cardiomyopathy associated with limb-girdle and congenital muscular dystrophies, and myotonic dystrophy. Expert opinion Gene therapy for dystrophic cardiomyopathy has taken a slow but steady path forward. Preclinical studies over the last decades have addressed many fundamental questions. Adeno-associated virus-mediated gene therapy has significantly improved the outcomes in rodent models of Duchenne and limb girdle muscular dystrophies. Validation of these encouraging results in large animal models will pave the way to future human trials.

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Perspective on Adeno-Associated Virus Capsid Modification for Duchenne Muscular Dystrophy Gene Therapy

Cited by 46 publications

References 178 publications

Systemic delivery of adeno-associated viral vectors

Systemic delivery of adeno-associated viral vectors

Nanotherapy for Duchenne muscular dystrophy

Prospect of gene therapy for cardiomyopathy in hereditary muscular dystrophy

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