CMTA funds to boost gene therapies for less common CMT types
Researchers seek to develop treatments for CMT2A, CMT4B1
The Charcot-Marie-Tooth Association (CMTA) is funding two research projects to accelerate the development of genetic therapies for less common forms of Charcot-Marie-Tooth disease (CMT), CMT types 2A and 4B1.
The investment is part of the association’s Strategy to Accelerate Research program, known as CMTA-STAR.
One project, supported by $300,000 in funding, seeks to develop a CRISPR-based gene editing therapy for CMT type 2A (CMT2A) that’s able to provide a single solution for different MFN2 mutations, the cause of this CMT subtype.
The other project, granted $380,000, will see researchers work to develop a gene therapy for CMT type 4B1 (CMT4B1) that restores the missing MTMR2 protein.
The projects underscore “CMTA-STAR’s commitment to accelerate bold and impactful research,” Katherine Forsey, PhD, CMTA’s chief research officer, said in an association press release. “The potential of this work to reshape treatment options underscores the power of innovative science.”
CMT is a group of inherited, neuromuscular conditions marked by progressive damage to the peripheral nerves, the network of neurons outside the brain and spinal cord that are responsible for sensation and movement. CMT symptoms include sensory loss, and muscle weakness and wasting.
Developing gene therapies for CMT2A, CMT4B1
CMT2A is caused by mutations in the MFN2 gene, with more than 200 different variants reported associated with the disease. The mutations disrupt the structure and function of axons, the neuronal projections that conduct signals to the next neuron or muscle cell, resulting in slowed transmission of signals. This CMT type is typically inherited through an autosomal dominant manner, meaning a person only needs to inherit one mutated gene copy to develop it.
The project will be led by Bruce Conklin, MD, a researcher at the Gladstone Institutes in San Francisco and member of CMTA-STAR advisory board. He and his team will use a gene-editing technology, called CRISPR/Cas9, to selectively turn off the mutated MFN2 gene copy while preserving the normal one.
For that, researchers will use human cells engineered to carry different CMT2A-causing MFN2 mutations to screen several CRISPR designs, testing their safety and efficacy in restoring normal nerve cell function. The goal is to develop an optimal CRISPR/Cas9 system that can detect and silence all mutated versions of the MFN2 gene where traditional gene-editing therapies require a separate approach for each unique mutation.
“Gene editing technologies like CRISPR/Cas9 offer encouraging possibilities for treating CMT at its source,” Conklin said. “This project provides a blueprint for therapeutic editing of most dominant forms of CMT, and our goal is to overcome critical technical barriers, including efficiently screening thousands of CRISPR designs and validating their effectiveness in human neurons.”
“By investing in these MFN2 gene-editing strategies, we’re addressing the unmet needs of individuals with CMT2A while laying the foundation for therapies that could benefit many other CMT subtypes,” Forsey said.
The other project is aiming for a gene therapy for CMT4B1, a form caused by mutations in both copies of the MTMR2 gene, which lead to damage to the myelin sheath, the protective layer around nerve fibers, in peripheral nerves.
Alessandra Bolino, PhD, at the San Raffaele Scientific Institute in Milan, will lead this effort. Her team has been testing harmless and modified adeno-associated virus type 9 (AAV9) to deliver a working version of the MTMR2 gene to Schwann cells, which are responsible for producing myelin in the peripheral nervous system.
Early studies in a mouse model showed this approach successfully reached the target cells, reduced myelin outfoldings, a hallmark of CMT4B1 nerve damage, and improved myelin structure. The researchers will now evaluate the long-term effects of an optimized, highly purified version of the AAV9-gene therapy on neuronal function and disease progression in the mice.
“Investing in gene therapy research for CMT4B1 is a critical step toward expanding treatment possibilities for the broader CMT community,” Forsey said in a separate press release. “Through CMTA-STAR, we are not only advancing potential therapies for those with CMT4B1, but we are also paving the way for future genetic therapies that could transform treatment options for other recessive forms of CMT, including CMT4B2 and CMT4B3.”
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