In November-December 2024 the European CMT Federation (ECMTF) organized a series of CMT awareness webinars. There were 5 webinars: 4 of which I attended online and watched the recording of the 5th. Each webinar was a unique chance to learn something new about CMT, whether from the perspective of a researcher, a biotech company representative, a person with CMT, or a caregiver. For me, just like other people with CMT, it is vital to know the status of the drug development process, especially for my type of CMT. There was some news on this front, including some fresh scientific publications I will discuss later, so read on!
I was honored to be invited as a speaker to the second webinar alongside a prominent CMT researcher, Dr. Kleopas Kleopa (Cyprus Institute of Neurology and Genetics). Here is my talk and the full recording. Interestingly, Dr. Kleopa confirmed my assumption about why PXT3003 failed as I described at length in this video. The problem is the endpoints researchers use to test the efficacy of the therapy. For a slowly progressing disease like CMT choosing the correct measures to assess the disease progression is crucial. The ONLS scale has been used to measure CMT progression and to determine if the drug is slowing it down. It has been suspected that this scale is not the best tool for these purposes, and other, more sensitive markers are being developed. One example is a calf muscle MRI fat fraction (FF), which measures the ratio of fat to muscle in the calf. CMT leads to muscle waste, so the more the disease progresses the less muscle and the more fat can be found in the calf. In addition, blood biomarkers such as neurofilament light chain (NfL), a compound released from neurons following axonal damage, are going to be used as end-points in future clinical trials. Novel functional assessment tools are also being developed as highlighted by Dr. Kleopa.
Dr. Kleopa also shared exciting news about plans to launch the first clinical trial to evaluate the effectiveness of a gene therapy for CMT1A. Several types of gene therapy are already being developed to target the harmful effects of PMP22 duplication, using both viral and non-viral methods of gene therapy delivery (see picture). Dr. Kleopa hopes it will be possible to launch a clinical trial using FALCON, small RNAs packaged in lipids, in 2025. This is a non-viral delivery method which has already passed all the necessary animal testing.
Clinical trials to evaluate the effectiveness of gene therapy are also planned for CMT4C (mutations in the SH3TC2 gene). However, this involves a different approach, i.e. delivering a functioning gene using a viral vector. The reason is that this type of CMT is inherited in an autosomal recessive manner, meaning that the symptoms only occur if both copies of the gene are "broken" (watch my video for more details). This results in the non functioning gene. So, unlike CMT1A, where the therapy goal is to reduce protein expression (since the gene duplication leads to its overproduction), in the case of CMT4C, the aim is to add a functioning gene to enable protein production. This method is called "gene replacement". Clinical trials for CMT4C are planned to be launched within the next two years.
Dr. Kleopa also mentioned therapeutic approaches for CMT1X and the already launched gene therapy clinical trial for CMT2S (mutations in the IGHMBP2 gene).
The next exciting webinar was dedicated to the drug development process for CMT SORD. Dr. Perfetti, Chief Medical Officer of Applied Therapeutics, was talking about an aldose reductase inhibitor, Govorestat, as a potential treatment of CMT caused by mutations in the SORD gene (sorbitol dehydrogenase) which causes CMT2. For a long time, such molecules had not even been considered in the context of CMT. However, in 2020, researchers from Miami discovered that mutations in the SORD gene lead to high levels of sorbitol in the body and cause CMT. Aldose reductase inhibitors restore normal sorbitol levels by blocking the conversion of glucose into sorbitol (see picture).
Therefore, Applied Therapeutics decided to test the efficacy of one such inhibitor for CMT SORD. They are now conducting a Phase 3 clinical trial called INSPIRE for CMT SORD. Their interim results are very encouraging: Govorestat was safe and well-tolerated, it reduced sorbitol levels in people with CMT SORD and improved such patient-reported outcomes as mobility, balance, fatigue, etc. Additional data and analysis will follow before this drug is approved (or not). If it is, this could turn out to be an incredible success story: only a few years will have passed from the discovery of the disease-causing gene to the approval of the drug. Typically, this process takes decades!
In another webinar, two representatives of NMD Pharma talked about ClC-1 inhibition muscle function improvement in CMT type 1 and type 2. This biotech company is currently recruiting people with different subtypes of CMT for their Phase 2 clinical trial, named SYNAPSE-CMT, of a small molecule NMD670 drug. The researchers plan to analyze the data collected during the study in several ways including splitting it into the subtypes of CMT, i.e. according to the mutation. Perhaps, the drug is more effective for some types of CMT. Participants will take NMD670 orally twice a day for 21 days. The recruitment for the trial is ongoing in Belgium, Denmark, France, Spain, and the USA. If you are based in those countries or can come to the sites even if you live elsewhere, consider using this opportunity to participate in the study.
NMD670 is an inhibitor of chloride ion channels CIC-1, which are present in muscle cells. The drug is intended to improve nerve-muscle communication in CMT by suppressing the activity of these channels. However, it does not address the root cause of the disease, unlike gene therapy. Nevertheless, neuromuscular junction (NMJ - the connection point between a nerve and a muscle) transmission deficits seem to play an important role in muscle dysfunction in CMT. Therefore, the NMD Pharma approach might work.
Earlier this month the NMD Pharma researchers published promising data for treating animal models of CMT1A and CMT2D (mutations in the gene GARS) with NMD670. Moreover, they showed that people with CMT have impaired NMJ transmission as assessed by electromyography, which correlated with poor muscle strength, mobility, balance, and endurance.
There were two more webinars featuring Dr. Vincent Timmerman (The University of Antwerp, Belgium), another prominent researcher in the field of CMT who discovered the cause of CMT1A (PMP22 duplication), and Dr. Maike F. Dohrn (RWTH Aachen University Hospital, Germany), who leads a team of researchers and works with people with various types of neuropathies, including CMT.
Dr. Timmerman talked about his team’s work on stem cells and organoids (organ-like structures made in a lab) to model different types of CMT. The key word is “to model”, i.e. to use such systems to study the pathological mechanisms of CMT and screen therapeutic candidates. Despite several clinics scattered around the world promising miraculous results for people with CMT by using stem cell therapy, such treatments have not been sufficiently tested for safety and efficacy, nor are they yet approved for any type of CMT although there are some ongoing clinical trials.
Dr. Timmerman’s team developed organoids for modeling CMT1A and CMT2A and showed that applying siRNAs (molecules designed to reduce PMP22 expression) rescues the demyelination in the CMT1A model. The researchers are also looking into autophagy, a natural clean-up and recycling process in our cells, as a common therapeutic target for different types of CMT. For now, they are specifically focusing on the CMT2F and CMT2L caused by mutations in HSPB1/HSPB8 genes, aka heat shock proteins. Earlier this month the team also published a paper demonstrating the beneficial effect of boosting autophagy with known small molecules in cell models of these types of CMT. Next, Dr. Timmerman’s team is developing assambloids - structures more complex than organoids as they are composed of different tissues such as neurons+muscles, or +immune system. This is an exciting approach to disease modeling and drug development as it allows to use human cells instead of animals, but with enough complexity to accurately model an organ or several tissues together.
Dr. Dohrn’s presentation was an overview of what CMT is, how it is diagnosed, and the progress made in identifying new mutations in CMT-causing genes. For me the most interesting part in her presentation was about diagnostics. In addition to a standard process of checking reflexes, performing EMG, and conducting nerve ultrasound, Maike F. Dohrn mentioned sensitivity tests as part of the diagnostic examination for people with CMT. Using specific probes, neurologists assess a patient's sensitivity to vibration, temperature, and pricking sensations. We have different skin receptors responsible for detecting these stimuli, which transmit signals via peripheral nerve fibers to the brain. These tests are good for determining sensory impairment in people with CMT. Previously, I hadn't heard neurologists talk about using such tests for diagnosing CMT, nor have I undergone them myself.
Last, but not least, a third speaker of our webinar was Aliteia, an Italian artist and a relative of a person with CMT. She spoke about the importance of one’s disease perception. By embracing CMT as part of your individuality—as a weakness that, at the same time, makes you stronger—it might be easier to cope with it. Aliteia raises awareness about CMT through her art, taking pictures and creating sculptures of the hands and feet of people with CMT. She also organized an exhibition where visitors were invited to hold the hand of someone with CMT, close their eyes, and experience what it feels like to be walked down the street by someone with this condition. I’ve often thought about how to help healthy people understand what it’s like to live with CMT and what it feels like. I think Aliteia’s exhibition was bang on!
I am grateful to ECMTF for organizing this webinar series and inviting me to be a speaker. I hope this short summary will make people with CMT hopeful about the future of CMT research and drug development. Merry Christmas and a Happy New Year ♥
Comments