A promising breakthrough in the development of a new treatment for Charcot-Marie-Tooth disease

GENEVA, Switzerland, August 25, 2023

Charcot-Marie-Tooth disease (CMT) is a progressive, hereditary motor neuroprathy causing degeneration of the peripheral nervous system. Many variations of the disease exist owing to various genetic mutations.

In CMT type 1A (CMT1A), the most prevalent subtype of the disease, a duplication of the pmp22 gene prevents Schwann cells from producing a protective myelin sheath around axons. As the disease progresses, these unprotected peripheral nerves begin to degenerate, triggering the weakening and breakdown of distal muscles. As a result, CMT1A patients suffer from symptoms such as high arch in the feet and difficulty with normal use of the limbs.

As with many rare diseases, CMT is currently without a cure and lacks any FDA approved treatments, leaving its three million global patients with only pain management and physiotherapy as options for relief.

In a promising new advancement, the United States Food and Drug Administration (FDA) has granted Orphan Drug Designation (ODD) to Alpha 1 Anti-trypsin (AAT), a plasma-derived therapeutic, for the treatment of CMT. AAT is a serine protease inhibitor produced abundantly in humans that plays a role in protecting the lungs from progressive destruction by neutrophil elastase. As well as this, AAT is recognised to have much broader anti-inflammatory and immunomodulatory functions, leading researchers to probe its efficacy in inflammatory diseases such as CMT.

Research into the therapeutic potential of AAT on CMT has been pioneered by Ageronix, a privately held pharmaceutical company based in Geneva, Switzerland. AAT has a well-established safety profile for the treatment of AAT deficiency, but its efficacy in other inflammatory conditions is only now being uncovered. Nikolay Zhukovsky, Ph.D., CEO of Ageronix, said, “AAT holds the potential to relieve the inflammatory component of CMT, alleviating symptoms as well as reversing disease progression."

In another exciting development, Ageronix has secured the Rare Pediatric Disease (RPD) designation from the FDA for its recombinant AAT, which further signifies a vote of confidence from the regulatory agency in AAT’s therapeutic potential, specifically for helping children affected by CMT.

In research published in the journal IJMS, Nikolay Zhukovsky’s team focused on testing the effect of human AAT in a transgenic mouse model of CMT1A. The study found that treatment with AAT both reduces progression of the disease and dampens inflammation. A key finding was that AAT largely recovers the characteristic degeneration of peripheral nerves associated with the disease. It is believed that part of this action occurs through a reduction of IL-6 and TNF-α levels, both inflammatory cytokines playing a significant role in propagating pathological inflammation. A further mechanism of AAT is suggested to involve the inhibition of ADAM-17, a disintegrin and metalloprotease which blocks axon myelination. While AAT’s full mechanism of action is still being elucidated, the present findings provide encouraging evidence for its therapeutic poten in CMT.

The designation of human AAT for ODD and recombinant AAT for RPD signifies the FDA’s recognition of AAT as a promising new therapeutic in the field. “These are particularly significant milestones for both us and the CMT community, as there are currently no approved therapeutics for the treatment of this disease”, said Nikolay Zhukovsky.

Orphan drug designation marks the initial stride on the path toward obtaining complete approval for the use in patients. The FDA Office of Orphan Products Development (OOPD) provides orphan status to drugs and biologics which are intended to treat, diagnose, or prevent rare diseases that affect fewer than 200,000 people in the U.S. Encouraged by AAT's promising pre-clinical results in recovering a mouse model of CMT1A, there is optimism that delving into clinical trials for this drug could pave the way for its eventual approval by the FDA.

This significant step forward underscores the potential impact of targeted treatments in the realm of rare diseases. With no approved therapeutics for the treatment of CMT, both the orphan drug designation and the rare pediatric disease designation for AAT offers new hope for the future of improving the quality of life of both patients and their families struggling with CMT.

Related Information

Original research: open access “Alpha-1 Antitrypsin Reduces Disease Progression in a Mouse Model of Charcot-Marie-Tooth Type 1A: A Role for Decreased Inflammation and ADAM-17 Inhibition” by Zhukovsky et al. (2022). International Journal of Molecular Sciences

FDA's Orphan Drug Designation for AAT