Partnerships within the medical community play a huge role in advancing research and developing treatments. According to Charcot-Marie-Tooth News, a new partnership has formed between Dr. Alessandra Bolino, PhD, the CMT Research Foundation, and AcuraStem. Through this partnership, the researchers will test and evaluate potential therapies for patients with Charcot-Marie-Tooth disease (CMT) type 4b1 (CMT4B1). As this childhood-onset form is severe, finding new therapies could represent an advancement in treatment, quality of life (QOL), and patient outcomes.
Caused by MTMR2 gene mutations, CMT4B1 is a rare form of CMT. According to the Genetic Testing Registry, CMT4B1 is:
a severe early-onset demyelinating CMT peripheral sensorimotor polyneuropathy [initially] described in an Italian family and around 10 additional families…so far. Onset occurs during [infancy or early childhood] with distal and proximal muscular weakness starting in the lower extremities, sensory loss, and cranial nerve involvement.
CMT4B1 is inherited in an autosomal recessive pattern. In short, patients must acquire one defective gene from each parent. Normally, MTMR2 plays a role in myelin sheath production. The myelin sheath typically works to protect nerve fibers from damage. But in patients with CMT4B1, gene mutations cause an over-accumulation of PI(3,5)P2, which causes abnormal out folding to form on the myelin sheath. As a result, nerve cells are damaged and eventually die.
In prior studies, the PIKfyve enzyme has been shown to modulate PI(3,5)P2 levels. As a result, PIKfyve inhibitors, like apilimod, could stop myelin out folding development. But researchers do not believe apilimod would be an effective therapeutic option, considering its lifespan and rapid elimination from the body.
Within the partnership, researchers will evaluate new, engineered PIKfyve inhibitors designed to be longer lasting and more efficacious. Over the next 2 years, Dr. Bolino and her research team will:
- Determine which therapies work to target the enzyme
- Understand which therapies reduce PI(3,5)P2 levels
- Learn whether or not these inhibitors reduce or prevent out foldings
To begin, these PIKfyve inhibitors will be evaluated use mice models and cells grown in the lab. Once the researchers determine which PIKfyve inhibitors are most effective, they will move onto the next research step: understanding how effective these therapies are in stopping CMT4B1 in animal models with MTMR2 mutations. During this time, researchers will evaluate the impact of PIKfyve inhibitors in animal models from age 3 weeks to 5 months. Additionally, researchers will compare the results to those treated with a placebo.
Charcot-Marie-Tooth Disease (CMT)
A variety of gene mutations cause the various subtypes of Charcot-Marie-Tooth disease, a rare (yet commonly inherited) neurological disorder. For example, patients with CMT1 and CMT4 often have different contributing genetic mutations. However, regardless of the subtype, these mutations cause the degeneration of peripheral nerves. As a result, nerves and muscles are unable to communicate, causing a host of symptoms. CMT is also sometimes known as hereditary motor and sensory neuropathy. Typically, symptom onset occurs in adolescence or early childhood. Some CMT subtypes have neonatal-onset, while others cause symptom onset in adulthood. Symptoms include:
- Lack of balance and coordination
- Foot and lower leg muscle weakness
- Frequent tripping or falling
- Foot drop
- Muscle weakness and wasting, causing lower leg deformities or hand-related issues
- High arches, hammertoes, or other foot deformities
- Difficulty walking
- Hand contractures
- Slow reflexes
- “Pins and needles” sensation