Targeted Myostatin Gene Editing With TALENs

As a sidebar to the recently demonstrated use of transcription activator-like effector nucleases (TALENs) to clear out damaged mitochondrial DNA, something that might be of interest as the basis for therapies to partially treat degenerative aging, I though I'd point out another recent paper on how TALENs can be put to work as tools to create effective gene therapies.

Regular readers will recall that references to work on myostatin-related gene therapies show up here every now and again. Mammalian myostatin loss of function mutants are heavily muscled, have less fat, and seem modestly more resistant to a few of the degenerations of age. It is even the case that a small number of human individuals with this mutation exist. Given the degree to which loss of muscle mass and strength occurs with aging, and the cost of that frailty in terms of mortality and quality of life, some corners of the research community are interested in finding ways to trigger the benefits of myostatin loss. By the time it came anywhere near a clinic, this would probably involve a designed drug to temporarily block myostatin signaling rather than any form of gene therapy, however.

Nonetheless, here we have an example of work taking place on a TALENs based platform for gene therapy to edit the myostatin gene. This is intended to provide the basis for further, more effective research aimed at the production of therapies based on myostatin inhibition:

Targeted Myostatin Gene Editing in Multiple Mammalian Species Directed by a Single Pair of TALE Nucleases

Myostatin (MSTN) is a transforming growth factor-β family member that plays a critical role in negatively regulating skeletal muscle mass. Genetic studies have demonstrated that myostatin gene deficiency leads to muscle hypertrophy due to a combination of increased fiber numbers and increased fiber sizes in multiple species including human, cattle, mouse, sheep, and dog without causing severe adverse consequences. Therefore, extensive efforts have been undertaken to develop effective strategies for blocking the myostatin signaling pathway as therapies for various muscle-wasting diseases such as muscular dystrophy, sarcopenia, and long bedding patients. Indeed, myostatin inhibitors have shown great promise to significantly increase muscle growth in model animals.

Here, we report a new class of reagents based on transcription activator-like effector nucleases (TALENs) to disrupt myostatin expression at the genome level. We designed a pair of MSTN TALENs to target a highly conserved sequence in the coding region of the myostatin gene. We demonstrate that codelivery of these MSTN TALENs induce highly specific and efficient gene disruption in a variety of human, cattle, and mouse cells. Based upon sequence analysis, this pair of TALENs is expected to be functional in many other mammalian species.

In summary, TALEN is an effective genome-editing tool. Application of MSTN TALENs in a variety of cell lines and species would allow further investigation of myostatin functions in mammalian animals that do not have naturally occurring mutant MSTN models yet. Moreover, this TALEN pair would also be a valuable tool for cell engineering in translational research such as myoblast transplantation therapy to replace defective genes in genetic diseases including muscular dystrophy.


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