By Keith Fargo, Chief Scientific Officer
The CMT Research Foundation is pleased to announce that Shift Pharmaceuticals (Shift) has successfully completed their CMT Research Foundation-funded RNA-based therapy project.
Shift created and tested a library of novel molecules designed to reduce the expression of PMP22, the gene that – when over-expressed – causes CMT1A. The molecules, referred to as PMO ASOs, work by entering the Schwann cells that make up the myelin sheaths in the peripheral nerves and reducing the amount of PMP22 mRNA; this is in turn reduces the amount of PMP22 protein that the Schwann cells produce. This approach is part of a larger scientific strategy called RNA interference, and several other groups are also taking RNA interference-based approaches to reducing PMP22 levels. The key advantages of the PMO ASO approach, in particular, are that it appears to be able to reach the target cells at lower concentrations than other drugs and does not appear to activate an immune response at therapeutic dose levels. Taken together, these advantages suggest that an eventual PMO ASO therapeutic may have greater safety and effectiveness than other RNA interference-approaches.
In carrying out this research, the scientists at Shift first designed a series of PMO ASOs targeting PMP22 and tested them in Petri dish experiments with cells that normally express PMP22. Based on these results, the most effective PMO ASO was then tested in “CMT1A mice,” genetically modified to have multiple extra copies of human PMP22, and the results were striking. As expected, CMT1A mice had serious deficiencies with balance and mobility, and took much longer than healthy mice to traverse a suspended beam.
When the Shift researchers treated CMT1A mice with the PMO ASO, the treated mice did not develop these severe deficiencies, whether treated early in life or near the time that symptoms would otherwise have emerged. Moreover, the mice performed the beam-walking task nearly as quickly as healthy mice. Much work remains to be done before this potential therapy makes it to patients, but this work serves as an important proof of concept in treating CMT1A safely and effectively.
“We are ecstatic to see how well our PMO ASOs work in CMT1A mice, and we appreciate that the CMT Research Foundation saw our potential early and decided to fund the work,” said Shift Pharmaceuticals Founder and CEO, Steve O’Connor, PhD. “We are committed to furthering this science and bringing our potential treatment closer to the patients who need it.”
Shift’s Chief Scientific Officer, Chris Lorson, PhD, added, “There are currently no effective treatments or cures for CMT, even though the disease has been known for over one-hundred years. This work brings us closer to changing that reality.”
The CMT Research Foundation is pleased to have identified this company and approach that may lead to safe and effective treatments for CMT1A and other CMT types. We are committed to finding and funding the most impactful research projects in pursuit of our singular mission to deliver treatments and cures for CMT during our lifetimes. The CMT Research Foundation continues to offer advice and support to Shift as they move forward with their CMT program.