Novel SMA gene therapy shows safety and potential for efficacy in mouse model

A second-generation experimental gene therapy for spinal muscular atrophy (SMA) has shown greater safety and efficacy than an earlier version, and it may be more effective than currently approved gene therapy for SMA, a study has reported. in a mouse model of disease.

The study was conducted by scientists CANbridge Pharmaceuticals and the Horae Gene Therapy Center at UMass Chan School of Medicine as part of an ongoing research agreement between the two organizations, CANbridge said in a statement. Press release.

The conclusions will be in the poster »Endogenous Human SMN1 Promoter-Induced Gene Replacement Improves Efficacy and Safety of AAV9-Mediated Gene Therapy for Spinal Muscular Atrophy in Micepresented at the 25th Annual Meeting of the ASGCT later this month (p. 127).

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SMA is caused by mutations, usually in the SMN1 resulting in impaired production of the survival motor neuron (SMN) protein, which is involved in the health of nerve cells that control voluntary movement.

As a result, symptoms of SMA include muscle weakness, limited mobility, and problems with breathing and swallowing.

Approved treatments for the disease work to restore SMN levels and include the gene therapy Zolgensma, marketed by Novartis. This treatment is packaged in a viral vector, or carrier, which delivers a healthy copy of SMN1 cells, allowing them to produce their own SMN protein.

While Zolgensma is “a significant breakthrough for the treatment of SMA,” it requires a high dose of vector, which can lead to liver damage and hematological (blood-related) complications, the researchers noted.

To maximize the potential benefits of gene therapy while minimizing its side effects, researchers developed a new gene therapy that they then optimized into a second-generation treatment. His vector contained some differences from those of Zolgensma that the team believed would be beneficial.

The researchers compared this second-generation therapy with a therapy designed similarly to Zolgensma – called the benchmark therapy – in a mouse model of SMA and, briefly, in healthy mice.

A side-by-side comparison showed that their experimental gene therapy resulted in lower accumulation in the liver of healthy mice compared to the reference, suggesting that it may be safer and with lower toxicity.

Tests in SMA model mice also suggested the new therapy might be more effective at treating symptoms of the disease, the researchers reported.

Specifically, SMA mice treated at high doses with this gene therapy survived the entire 90-day study, while survival of those given the Zolgensma-like therapy averaged 60 days.

Mice treated at low or high doses with the second-generation therapy also showed a faster righting response, a test of motor skills that measures how quickly and how quickly a mouse can rock from its back to its feet, than mice. mice from the reference group. , indicating better motor function.

Better restoration of neuromuscular junction structures was also evident in mice given the experimental gene therapy than the reference treatment, approaching that of healthy mice. The neuromuscular junction is where nerve cells and muscles meet to communicate, and is notably affected in SMA.

In the SMA mouse model, necrosis – tissue death – can be seen around the ears of some mice. Necrosis developed in 67% of baseline-treated mice, 33% of mice given the novel low-dose gene therapy, and no high-dose treated animals.

Female mice also gained healthier body weight after the new treatment than after the reference treatment, while no weight difference was observed between the groups of male mice.

“In summary, our novel…gene therapy vector…has improved potency and safety profile over the Zolgensma vector, promising clinical applications,” the researchers wrote.

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