Charcot Marie Tooth Disease - CMT Disease - Hereditary Neuropathy

Discovering the gene that is causing a genetic disease is the most important step in curing any disease.  Without that knowledge, it is impossible to move forward.  Fourteen years ago, Dr. Pragna Patel was on the research team that found the gene for CMT1A.  It was significant discovery, one that was lauded in many notable scientific journals.  Since then, many other genes for other forms of CMT have been discovered, laying the foundation for a cure-driven research strategy. At HNF, we are extremely encouraged that this knowledge is available to us, because it guides our approach to finding a cure.
 
In our quest to find a cure, HNF has developed a targeted and comprehensive research plan designed to identify new areas of potential research, as well as areas of translational research not yet applied to CMT.  Additionally, HNF will continuously scan the domestic and international horizon for important and relevant research that might otherwise not be continued, as well as thematically relevant proposals that are currently unfunded.  By providing a goal-oriented focus to the research process, HNF will be able to constantly refine and rearticulate its research strategy.   HNF will also reduce the research timetable by funding a collaborative research effort that establishes defined deliverables at inception and calls for the sharing of discovery at each stage.   This will promote a truly synergistic and dynamic process, one that we believe will lead to the discovery of drug targets that can be further studied by pharmaceutical companies.
 
THERAPEUTIC STRATEGIES FOR CMT1A
The remarkable and unprecedented discovery that the majority of patients with CMT1A carry three copies of the PMP22 gene, instead of the usual two immediately suggested that treatment of this disease would require turning down production of PMP22 protein.   Exciting advances in the ability to therapeutically regulate gene expression has set the stage for developing new approaches to treat this disorder. Modulation of PMP22 expression as a therapeutic strategy may be approached in a variety of ways including modulation of messenger RNA transcription or stability, modulation of messenger RNA translation, or stability or localization of the resulting polypeptide. Knowledge about the molecular switches that regulate PMP22 gene expression is limited. Because development of strategies to affect these switches may well emerge as a viable therapeutic approach, we will follow this line of investigation namely, the identification of DNA switches that normally regulate PMP22 levels and to leverage these discoveries to design therapeutic strategies for patients with CMT1A.
 
THERAPEUTIC STRATEGIES FOR CMT2
The most common cause of Charcot-Marie-Tooth Syndrome Type 2A (CMT2A) is a genetic error, or mutation, in the sequence of the mitofusion 2 gene.  Mitofusion 2 is a protein that plays an essential role in the function of mitochondria which generate energy in cells.  In those individuals with a mitofusion 2 mutation, the energy produced by neuronal mitochondria is insufficient to sustain axons.  As a consequence, axonal degeneration gradually occurs, causing slowly progressive weakness.
 
A faithful animal model of mutant mitofusion CMT2A is urgently needed to permit testing of therapies to restore sufficient neuronal energy production and thus to prevent axonal degeneration.  The one animal model that now exists is characterized by axonal degeneration during fetal life which does not worsen after birth.  Hence, this model is not optimal for therapeutic testing.  The HNF now plans to support the development of new mouse mutant mitofusion CMT2A models that faithfully mirror the gradually progressive weakness and axonal loss seen in humans.  These mice will then be distributed to many laboratories to speed the development of effective therapies.
 

Please click on the logo to learn more about the research we fund.