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New Gene Therapy With Potential For SMARD

08 March 2017

New pre-clinical research has shown the exciting potential of using viruses to treat Spinal Muscular Atrophy with Respiratory Distress (SMARD), a recessive motor neuron disease similar to SMA.

SMARD is caused by mutations in the IGHMBP2 gene, which produces a protein involved in numerous cellular processes throughout all cells of the body. It is not currently known why disruption of IGHMBP2 causes motor neuron death leading to wasting of the diaphragm and limb muscles.

Viruses that have been genetically engineered to produce the SMN protein have shown great promise for the treatment of SMA. The AveXis gene therapy, AVXS-101, is currently being tested in a Phase I trial (click here for more information) with additional
clinical studies planned for the near future (click here for more information).

Two independent research groups have adapted this therapeutic strategy for SMARD and tested IGHMBP2-producing viruses, known as AAV9 viruses, on SMARD model mice.

The laboratory of Christian Lorson (University of Missouri) showed that injection of the IGHMBP2 viruses into the brains of mice boosted the amount of IGHMBP2 protein in the brain, spinal cord, and, importantly, in the motor neurons.

Low and high doses of the virus were tested and, as expected, the increase in IGHMBP2 was shown to be dependent on the amount of virus injected.

The low dose increased survival of the SMARD mice from a median of 151 days to approximately a year. The increase in IGHMBP2 also improved motor neuron and muscle health, causing advances in weight gain and overall muscle strength in the mice.

Less expected was the finding that the higher viral dose did not have a greater impact on disease progression. In fact, the opposite was observed; the high viral dose reduced SMARD mouse survival, and this was also shown when viruses were injected into the blood instead of the brain. It remains unclear why exactly this happened.

This highlights a very important feature of gene therapies – a larger increase in a protein does not always equate to greater improvements in symptoms. The concentration of a gene therapy dose must therefore be carefully considered and tested in pre-clinical experiments before migrating to a clinical setting.

A second study from researchers at the University of Milan showed that injection of IGHMBP2-producing viruses into the blood stream rather than the brain had a similar positive effect on SMARD mice. Furthermore, this work also showed that the virus was capable of improving the health of patient-derived motor neurons in culture.

Together, these pre-clinical studies demonstrate the feasibility of using viral gene therapy to treat SMARD, providing an exciting proof-of-principle that such a therapy could be a viable strategy for SMARD patients.

Given that the high dose of virus caused adverse effects in SMARD mice, it appears as though there may unfortunately only be a small concentration range over which the drug can be safely administered. Determining the optimal dose and delivery route of the IGHMBP2 virus will be critical before early phase clinical trials can be conducted.

Further Information