The treatment landscape
With a diagnosis in hand, it’s possible to turn to treatment options, and the CMT landscape is promising. Dr. Madigan’s group recently reviewed 286 CMT clinical trials published between 1999 and 2022, 86% of which were interventions. Most were procedures based on carpal or cubital tunnel release, extracorporeal shockwave therapy, or nerve hydrodissection.
The small-molecule drug combination PXT3003 (Pharnext) – comprising baclofen, naltrexone, and sorbitol – downregulated PMP22 mRNA expression and led to improved myelination in animal models. It is currently being studied in a phase 2 clinical trial. Other approaches include supplements, stem cells, anesthetics, and various devices.
Genetic therapy is in the preclinical stage, including gene replacement using adeno-associated virus (AAV) vectors, gene silencing using antisense oligonucleotides or RNA interference, and gene editing using CRISPR-Cas 9 approaches.
Gene replacement strategies include delivering a normal copy of the gene, a supportive gene, or a gene that delays or reduces axon degeneration. Gene silencing targets PMP22, while CRISPR-Cas9 gene editing aims for PMP22 or neurofilament light polypeptide (NEFL) gene knockout.
The most clinically advanced AAV program delivers neurotrophin-3 via the viral vector to the target muscle, which has been demonstrated to improve symptoms in a mouse model using a muscle-specific promoter. A phase 1/2a trial will test the approach in three patients.
In the antisense space, chemical advances have improved the profile of the RNA, including modifications that influence inflammatory properties, stability, and targeting of specific tissues through conjugation to specific lipids, proteins, or antibodies. A 2018 study sponsored by DTxPharma showed that the formulation could improve outcomes and histologic myelination in a mouse model. In the wake of Novartis’s acquisition of the technology, Dr. Madigan anticipates that clinical trials will likely begin in 2024.
Finally, CRISPR-Cas9 targeting of a promoter region that leads to PMP22 transcription improved remyelination and electrophysiological parameters after injection into the sciatic nerve of mice.
A need for genetic counseling
Advances in testing and therapies represent exciting developments, but they also create a need for genetic counselors, according to Dr. Madigan. His clinic has two certified genetic counselors who meet with patients and discuss testing options, including risks and benefits to family members. The counselors also provide psychological support and assist in shared decision-making. They also handle testing paperwork, which eases the burden on physicians.
If the tests are negative, the genetic counselor informs the patient and lets them know of any additional testing required. In case of a positive test, the genetic counselor informs the patient, but the physician also makes contact to discuss clinical implications of the result. “I think it’s working extremely well, and I would encourage all practices to begin to explore those options moving forward,” said Dr. Madigan.
During the Q&A session after the talk, an audience member noted that genetic counselors are not covered by insurance, which places a financial burden on providers to hire them. He noted that his facility has a large clinical genomics department that was able to fund the two counselors, though they are both part-time. “It wasn’t easy. I think there was at least a year of trying to work out how to do it in terms of finding positions and negotiating, but I think once it’s accomplished it’s incredibly cost effective in terms of getting patients what they need from that perspective, and helping with the testing,” said Dr. Madigan.
Dr. Madigan reported no relevant financial disclosures.