MyoAAV: new gene-delivery vehicle improves targeting of muscle tissue in preclinical models
A new family of adeno-associated viruses (AAVs) – termed MyoAAV – has been developed by researchers at the Broad Institute of MIT and Harvard and Harvard University (both MA, USA) that improves targeting of the muscle tissue, which could be safer and more effective for gene therapy in individuals with muscle diseases.
The study, which has been published in the journal Cell, used preclinical models of muscle diseases where the team described how they modified the outer protein shell of AAV (the capsid) to create MyoAAV. To achieve this, they used a method that they developed known as ‘Directed Evolution of AAV capsids Leveraging In Vivo Expression of transgene RNA’ (DELIVER).
According to the research team, MyoAAV is over 10-times more efficient at reaching muscle tissue than those currently used in clinical trials and largely avoids the liver. Due to this increased efficiency, the investigators revealed that MyoAAV could be used to deliver therapeutic genes at around 100- to 250-times lower doses than other viral vectors currently used in other studies.
In thier study, the team used MyoAAV to deliver either therapeutic genes or the CRISPR–Cas9 gene-editing system specifically to muscle cells. In mouse models of Duchenne muscular dystrophy, MyoAAV carrying CRISPR–Cas9 led to more widespread repair of the dysfunctional gene, known as dystrophin, in muscle tissue compared to the conventional AAV9 carrying the CRISPR components. The muscles of MyoAAV-treated animals also showed greater strength and function.
On the other hand, mice with X-linked myotubular myopathy received 100-times lower amount of the virus that is currently used in clinical trials, and all mice (n = 6) treated with MyoAAV in the study lived as long as normal mice, whereas mice treated with AAV9 lived only up to 21 weeks of age.
MyoAAV designed for non-human primates also delivered genes to muscles in these animals far more efficiently than naturally occurring capsids currently used in clinical trials. MyoAAV also successfully introduced genes to human cells in the lab. The various MyoAAV capsids used a similar mechanism to deliver genes to mouse and human muscle cells, suggesting that MyoAAV can be used for potent muscle-directed gene delivery across different species.
“All of these results demonstrate the broad applicability of the MyoAAV vectors for delivery to muscle. These vectors work in different disease models and across different ages, strains and species, which demonstrates the robustness of this family of AAVs,” commented Amy Wagers, co-senior author of the study (Harvard University). “We have an enormous amount of information about this class of vectors from which the field can launch many exciting new studies.”
Ref: https://www.regmednet.com/myoaav-new-gene-delivery-vehicle-improves-targeting-of-muscle-tissue-in-preclinical-models/
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