While CMT has many similarities to other neuromuscular diseases like ALS, multiple sclerosis (MS) and spinal muscular atrophy (SMA), there is one stark difference that can’t be ignored: ALS, MS and SMA all have treatments approved and available for patients; CMT does not.

Why is that?

This is a question we asked ourselves when forming the CMT Research Foundation, developing our scientific priorities and as we work every day to deliver treatments and cures for CMT during our lifetime.

We know that studying and harnessing the success in other neuromuscular diseases can lead to breakthroughs for CMT. By taking a creative and unconventional approach to CMT research funding under the leadership and guidance of our Scientific Advisory Board, we’re investing in three companies that have contributed to progress in ALS and SMA but weren’t yet working in CMT. Now they are.

One such partner is Shift Pharmaceuticals, a gene-targeting technology company. By targeting an important gene that is found in SMA patients, Shift’s technology has effectively “shifted” the non-functional gene causing SMA to become functional and alter disease progression with little or no side effects. Their approach to SMA has received early Orphan Drug Designation (ODD) from the Food and Drug Administration (FDA) and has been funded by both the National Institutes of Health (NIH) and Congressionally Directed Medical Research Program (CDMRP). This support is a strong indication that their technology has scientific merit and potential application for patients. Simply stated, these agencies give credibility to Shift’s approach to treat patients with SMA.

While Shift Pharmaceutical’s approach has not been tried in CMT before, it may address one of the key barriers to treating CMT1A at the genetic level: targeting the peripheral nervous system.

What Makes Early Success in SMA Relevant for CMT?
In an interview with Shift Pharmaceutical’s CEO Steve O’Connor, our CMT Research Foundation CEO Susan Ruediger asks him about applying the company’s early success in SMA to CMT. Here’s what he had to say.

Susan: What makes Shift’s early success in SMA relevant to CMT?
Steve: Our core approach at Shift Pharmaceuticals is to develop antisense oligonucleotides (ASO) that “shift” the progress of RNA translation in a patient’s own cells to alter an abnormality in protein production or overproduction. Importantly, we develop our molecules in a manner so that they specifically target the diseased cells and have a very small reaction in other parts of the genome. What this means is that we can alter the progression of a particular disease while minimizing potential side effects.

We have validated this approach with SMA, demonstrating that our core molecules are safe to use in general and effectively improve the underlying cause of SMA progression.

Thanks to our partnership with the CMT Research Foundation, we’ll carefully study the effectiveness of this approach for CMT using technology and laboratory models. The CMT project has already identified the appropriate biological target areas, and we are in the process of validating our effectiveness in the laboratory.

Susan: Why are you excited about this technology for CMT?
Steve: From a biology perspective, CMT1A is a strong target for our overall approach. Like SMA, a single genetic mutation controls the overall disease state. Thus, we should be able to identify a single molecule that has the desired effect. Developing a single molecule greatly assists with the overall clinical development, including receiving FDA approval, and can streamline the overall process.

Susan: The CMT project underway at Shift Pharmaceuticals is expected to last 12 to 14 months. What are some key discoveries you hope to make during that period?
Steve: The current platform involves PMO antisense molecules. These are remarkably stable and have safely been used in the clinic. In a systematic approach, this project would confirm that PMO ASOs enter Schwann cells (the cells affected in CMT1A) and can target PMP22 (in CMT1A there is an extra copy of the PMP22 gene which leads to an overproduction of the PMP22 protein). Targeting this important gene could result in disease prevention.

Susan: Why is partnering with patient-led organizations like the CMT Research Foundation important to Shift Pharmaceuticals?
Steve: First, the CMT Research Foundation has developed relationships that bring tremendous scientific expertise in this field and in genetics generally that we have already begun to leverage. Second, when we get a bit further in our development, having access to CMT patients and clinicians who treat CMT will significantly help us understand key questions like:

• How often would patients be willing to undergo treatment?
• What type of drug delivery (oral, injection, IV, etc.) would patients prefer?
• How do treatment options affect the severity of conditions?

At Shift, we prefer to understand these patient needs early on since it helps in our overall product strategy, animal testing, etc. There is no need to perform tons of experiments on one delivery method if patients and clinicians would require something different. As a small company, being nimble and efficient is a huge advantage. The more we understand product needs early, the more successful we can be.

Applying key learnings and technologies that have been effective in other similar diseases increases opportunities for success in CMT. The CMT Research Foundation has a keen focus on finding successful companies and turning their attention to CMT, bringing more expertise to the CMT drug development effort.