Long-term maintenance of dystrophin expression and resistance to injury of skeletal muscle in gene edited DMD mice

Karri, Dileep; Zhang, Yu; Chemello, Francesco; Min, Yi-Li; Kim, Jiwoong; Mammen, Pradeep P.A.; Xu, Lin; Liu, Ning; Bassel‐Duby, Rhonda; Olson, Eric N.

doi:10.1016/j.omtn.2022.03.004

Cited by 19 publications

(17 citation statements)

References 46 publications

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“…Incorporation of the cTnT promoter to restrict expression of the ABE components exclusively to the heart also prevents possible adverse consequences of CaMKIId inhibition in other tissues. Moreover, CRISPR-Cas9 gene editing is permanent, representing a "one and done" therapy (30). In patients, administration of CaMKIId editing components after a myocardial infarction could be achieved in conjunction with the standard of care in response to a heart attack.…”

Section: Discussionmentioning

confidence: 99%

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Ablation of CaMKIIδ oxidation by CRISPR-Cas9 base editing as a therapy for cardiac disease

Lebek

Chemello

Caravia

et al. 2023

Science

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CRISPR-Cas9 gene editing is emerging as a prospective therapy for genomic mutations. However, current editing approaches are directed primarily toward relatively small cohorts of patients with specific mutations. Here, we describe a cardioprotective strategy potentially applicable to a broad range of patients with heart disease. We used base editing to ablate the oxidative activation sites of CaMKIIδ, a primary driver of cardiac disease. We show in cardiomyocytes derived from human induced pluripotent stem cells that editing the CaMKIIδ gene to eliminate oxidation-sensitive methionine residues confers protection from ischemia/reperfusion (IR) injury. Moreover, CaMKIIδ editing in mice at the time of IR enables the heart to recover function from otherwise severe damage. CaMKIIδ gene editing may thus represent a permanent and advanced strategy for heart disease therapy.

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Section: Discussionmentioning

confidence: 99%

“…Incorporation of the cTnT promoter to restrict expression of the ABE components exclusively to the heart also prevents possible adverse consequences of CaMKIIδ inhibition in other tissues. Moreover, CRISPR-Cas9 gene editing is permanent, representing a “one and done” therapy ( 30 ).…”

Section: Discussionmentioning

confidence: 99%

Ablation of CaMKIIδ oxidation by CRISPR-Cas9 base editing as a therapy for cardiac disease

Lebek

Chemello

Caravia

et al. 2023

Science

Self Cite

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“…Early gene replacement or editing through AAV vectors has provided functional improvement in DMD gene therapy. 20,38,39 However, the packaging ability and immunogenicity of AAV still restricted their clinical application. In contrast, the characteristics of LVs, such as large packaging capacity and low immunogenicity, raised our interest.…”

Section: Discussionmentioning

confidence: 99%

Duchenne muscular dystrophy treatment with lentiviral vector containing mini‐dystrophin gene in vivo

Wang,

Zhu,

Liu

et al. 2024

MedComm

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Duchenne muscular dystrophy (DMD) is an incurable X‐linked recessive genetic disease caused by mutations in the dystrophin gene. Many researchers aim to restore truncated dystrophin via viral vectors. However, the low packaging capacity and immunogenicity of vectors have hampered their clinical application. Herein, we constructed four lentiviral vectors with truncated and sequence‐optimized dystrophin genes driven by muscle‐specific promoters. The four lentiviral vectors stably expressed mini‐dystrophin in C2C12 muscle cells in vitro. To estimate the treatment effect in vivo, we transferred the lentiviral vectors into neonatal C57BL/10ScSn‐Dmdmdx mice through local injection. The levels of modified dystrophin expression increased, and their distribution was also restored in treated mice. At the same time, they exhibited the restoration of pull force and a decrease in the number of mononuclear cells. The remissions lasted 3–6 months in vivo. Moreover, no integration sites of vectors were distributed into the oncogenes. In summary, this study preliminarily demonstrated the feasibility and safety of lentiviral vectors with mini‐dystrophin for DMD gene therapy and provided a new strategy to restore truncated dystrophin.

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“…Early gene replacement or editing through AAV has provided functional improvement in DMD gene therapy. 20,38,39 However, the package ability, immunogenicity and duration of AAV still restricted their clinical application. In contrast, the characteristics of LV like the long-term effect, large package capacity and low immunogenicity raised our interest.…”

Section: Discussionmentioning

confidence: 99%

Duchenne muscular dystrophy treatment with lentiviral vector containing mini-dystrophin gene in vivo

Wang

Zhu

et al. 2023

Preprint

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Duchenne muscular dystrophy is an incurable X linked recessive genetic disease caused by mutations in the dystrophin gene. Many researchers aimed at restoring truncated dystrophin via viral vectors. But the low package capacity and short duration of vectors hampered their clinical application. For these reasons, we constructed four lentiviral vectors, which contained truncated and sequence-optimized dystrophin genes driven by muscle specific promoter. The four lentiviral vectors stably expressed mini-dystrophin in C2C12 muscle cells in vitro. To estimate the treatment effect in vivo, we transferred the lentiviral vectors into neonatal C57BL/10ScSn- Dmd mice through the local injection. The level of modified dystrophin expression increased, while the distribution of that also restored in treated mice. At the same time they showed the restoration of pull force and the decrease in the number of mononuclear cells. The remissions lasted three to six months in vivo. Moreover, no integration sites of vectors distributed into the oncogenes. In summary, this study has preliminarily demonstrated the feasibility and safety of mini-dystrophin gene carried by lentiviral vector for DMD gene therapy, and provided new strategy to restore truncated dystrophin.

show abstract

Long-term maintenance of dystrophin expression and resistance to injury of skeletal muscle in gene edited DMD mice

Cited by 19 publications

References 46 publications

Ablation of CaMKIIδ oxidation by CRISPR-Cas9 base editing as a therapy for cardiac disease

Ablation of CaMKIIδ oxidation by CRISPR-Cas9 base editing as a therapy for cardiac disease

Duchenne muscular dystrophy treatment with lentiviral vector containing mini‐dystrophin gene in vivo

Duchenne muscular dystrophy treatment with lentiviral vector containing mini-dystrophin gene in vivo

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