Systemic Delivery of Adeno-Associated Viral Vectors in Mice and Dogs

Wasala, Lakmini P.; Hakim, Chady H.; Yue, Yongping; Yang, N. Nora; Duan, Dongsheng

doi:10.1007/978-1-4939-9065-8_18

Cited by 6 publications

(4 citation statements)

References 22 publications

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“…Systemic delivery of functional gene aimed to restore dystrophin expression, most utilizing AAV as a means of mediated delivery, is another interesting chapter broadly studied since it promises high transduction efficiency and stable long-term expression ( Kimura et al, 2019 ; Łoboda and Dulak, 2020 ). Ideally, recombinant AAVs are best suited for DMD therapy as they exhibit strong tropism toward skeletal muscles ( Wasala et al, 2019 ; Muraine et al, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

A Decade of Progress in Gene Targeted Therapeutic Strategies in Duchenne Muscular Dystrophy: A Systematic Review

Liang

Sulaiman

Yazid

2022

Front. Bioeng. Biotechnol.

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As one of the most severe forms of muscle dystrophy, Duchenne muscular dystrophy (DMD) results in progressive muscle wasting, ultimately resulting in premature death due to cardiomyopathy. In the many years of research, the solution to DMD remains palliative. Although numerous studies including clinical trials have provided promising results, approved drugs, even, the therapeutic window is still minimal with many shortcomings to be addressed. Logically, to combat DMD that arose from a single genetic mutation with gene therapy made sense. However, gene-based strategies as a treatment option are no stranger to drawbacks and limitations such as the size of the dystrophin gene and possibilities of vectors to elicit immune responses. In this systematic review, we aim to provide a comprehensive compilation on gene-based therapeutic strategies and critically evaluate the approaches relative to its efficacy and feasibility while addressing their current limitations. With the keywords “DMD AND Gene OR Genetic AND Therapy OR Treatment,” we reviewed papers published in Science Direct, PubMed, and ProQuest over the past decade (2012–2021).

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Section: Resultsmentioning

confidence: 99%

A Decade of Progress in Gene Targeted Therapeutic Strategies in Duchenne Muscular Dystrophy: A Systematic Review

Liang

Sulaiman

Yazid

2022

Front. Bioeng. Biotechnol.

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“…The injected area was marked with a sterile tattoo dye (Tommy's StarBrite colors, Somers, CT, USA) on the skin. Systemic injection was performed according to our published protocol 49,50 . For in vivo gRNA vector screening studies (Supplementary Figs.…”

Section: Nmentioning

confidence: 99%

Cas9-specific immune responses compromise local and systemic AAV CRISPR therapy in multiple dystrophic canine models

et al. 2021

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Adeno-associated virus (AAV)-mediated CRISPR-Cas9 editing holds promise to treat many diseases. The immune response to bacterial-derived Cas9 has been speculated as a hurdle for AAV-CRISPR therapy. However, immunological consequences of AAV-mediated Cas9 expression have thus far not been thoroughly investigated in large mammals. We evaluate Cas9-specific immune responses in canine models of Duchenne muscular dystrophy (DMD) following intramuscular and intravenous AAV-CRISPR therapy. Treatment results initially in robust dystrophin restoration in affected dogs but also induces muscle inflammation, and Cas9-specific humoral and cytotoxic T-lymphocyte (CTL) responses that are not prevented by the muscle-specific promoter and transient prednisolone immune suppression. In normal dogs, AAV-mediated Cas9 expression induces similar, though milder, immune responses. In contrast, other therapeutic (micro-dystrophin and SERCA2a) and reporter (alkaline phosphatase, AP) vectors result in persistent expression without inducing muscle inflammation. Our results suggest Cas9 immunity may represent a critical barrier for AAV-CRISPR therapy in large mammals.

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“…To address this obstacle, the whole dystrophin gene is abbreviated to partially functional micro-dystrophin gene and packaged into AAV ( Banks et al, 2010 ; Ramos et al, 2019 ). Numerous AAV serotypes have been explored in animal models ( Wasala et al, 2019 ). Among several serotypes of AAV, serotypes 1, 6, 8, and 9 are outstanding candidates for DMD therapy as they exhibit a potent tropism for striated muscles ( Inagaki et al, 2006 ; Leborgne et al, 2019 ).…”

Section: Therapeutic Strategies Targeting Dystrophinmentioning

confidence: 99%

Current Pharmacological Strategies for Duchenne Muscular Dystrophy

Yao

Chen

et al. 2021

Front. Cell Dev. Biol.

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Duchenne muscular dystrophy (DMD) is a lethal, X-linked neuromuscular disorder caused by the absence of dystrophin protein, which is essential for muscle fiber integrity. Loss of dystrophin protein leads to recurrent myofiber damage, chronic inflammation, progressive fibrosis, and dysfunction of muscle stem cells. There is still no cure for DMD so far and the standard of care is principally limited to symptom relief through glucocorticoids treatments. Current therapeutic strategies could be divided into two lines. Dystrophin-targeted therapeutic strategies that aim at restoring the expression and/or function of dystrophin, including gene-based, cell-based and protein replacement therapies. The other line of therapeutic strategies aims to improve muscle function and quality by targeting the downstream pathological changes, including inflammation, fibrosis, and muscle atrophy. This review introduces the important developments in these two lines of strategies, especially those that have entered the clinical phase and/or have great potential for clinical translation. The rationale and efficacy of each agent in pre-clinical or clinical studies are presented. Furthermore, a meta-analysis of gene profiling in DMD patients has been performed to understand the molecular mechanisms of DMD.

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Systemic Delivery of Adeno-Associated Viral Vectors in Mice and Dogs

Cited by 6 publications

References 22 publications

A Decade of Progress in Gene Targeted Therapeutic Strategies in Duchenne Muscular Dystrophy: A Systematic Review

A Decade of Progress in Gene Targeted Therapeutic Strategies in Duchenne Muscular Dystrophy: A Systematic Review

Cas9-specific immune responses compromise local and systemic AAV CRISPR therapy in multiple dystrophic canine models

Current Pharmacological Strategies for Duchenne Muscular Dystrophy

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