By: Kelsie Timbie, CMT Research Foundation
The CMT Research Foundation is pleased to announce that Dr. Maurizio D’Antonio’s research team at San Raffaele Scientific Institute in Milan, Italy has completed their CMT Research Foundation-funded project investigating the role of a protein called Gadd34 in a mouse model of adult CMT1A/CMT1B. Their work indicates that therapies targeting Gadd34 may prevent disease progression in older people with CMT, although more preclinical research is needed before clinical trials can begin.
Previous work has demonstrated that the buildup of misshapen proteins, formed due to genetic mutations, can cause stress in cells. Prolonged stress can impede the cells’ function and may even cause cell death. In CMT1A/CMT1B patients, myelin-producing Schwann cells often accumulate misshapen proteins, triggering cell stress in a process called the unfolded protein response (UPR). Turning off the UPR using either genetic manipulation or drug-based therapy in very young mice with CMT slowed disease progression and improved symptoms, but since the majority of people with CMT are adults with later-stage disease, it is important to test these therapies in older mice before moving to clinical trials.
To address this important question, scientists at San Raffaele Scientific Institute developed a new mouse model that allowed them to delete the Gadd34 gene in adult animals with CMT1B. Since Gadd34 is needed for the unfolded protein response process, deleting this gene may reduce cell stress and prevent damage to myelinating cells and nerves.
The researchers examined the mice’s motor function, nerve conductivity and biology, and measures of cell stress at several timepoints correlating to early to late adulthood. In early to mid-adulthood, treated mice demonstrated significant improvements in nerve conductivity and biology and reduction in cell stress, as well as possible partial recovery in motor function. In elderly mice, treatment produced little effect, indicating that more aggressive therapies may be needed to abrogate the cell stress response in late-stage disease.
The results of this project are promising for people with CMT1A/CMT1B, demonstrating for the first time that therapies targeting Gadd34 may be able to slow or prevent disease progression in adults. Excitingly, a drug targeting Gadd34 is already in clinical trials for people with ALS. Additional preclinical research testing this drug in mouse models of CMT may pave the way for future clinical trials.
The CMT Research Foundation continues to remain focused on delivering treatments and cures for CMT during our lifetimes and looks forward to following the work of this pioneering research group. To learn about projects we’ve funded, please visit cmtrf.org/research-we-fund.