Promising New Treatment for a Common Hereditary Nerve Disease Revealed by Scientists

Scientists from Tokyo Medical and Dental University (TMDU) have introduced a revolutionary genome-editing technique to help suffering from Charcot–Marie–Tooth disease by suppressing the levels of PMP22 protein, paving the way for a new clinical treatment in a field that currently has limited available cures. The AAV gene therapy-based genome editing was able to restore the myelination in the nerve of a human CMT1A patient, differentiated from iPS cells. The credit goes to the Department of Neuropathology, TMDU.

The researchers from Tokyo Medical and Dental University have developed a novel genome-editing technique which reduces the problematic protein levels in the cells of patients diagnosed with Charcot–Marie–Tooth disease type 1A.

Genetic research has come a long way over the past century, offering numerous promising possibilities such as improved human capabilities, disease cures, and even potential alterations in the evolution course.

A recent publication in Communications Medicine has highlighted a breakthrough genome-editing method by Tokyo Medical and Dental University (TMDU). This innovative technique shows a great potential to treat Charcot–Marie–Tooth (CMT), a relatively prevalent genetic nerve disorder with no existing clinical therapies.

CMT impacts the function of nerves, affecting 10 to 80 individuals per 100,000 individuals. CMT1A is the most prevalent subtype, caused by a duplication of the gene that produces peripheral myelin protein 22 (PMP22). This leads to an overproduction of PMP22 in affected people. PMP22 plays a critical role in forming the myelin structural unit, which is responsible for allowing rapid signaling between the limbs and the brain.

Previous attempts to reduce PMP22 levels in CMT1A animal models have proven unsuccessful in humans as current animal models do not duplicate the human PMP22 gene. The researchers aim to address this issue.

Dr. Hitoshi Okazawa, the senior author of the study, explains that they managed to create a cell model, growing Schwann cells from a CMT1A patient. The team then leveraged a precise genome-editing approach, AAV vectors, to lessen the output of PMP22 protein by the cells.

Given the potential harmful impact of PMP22 level fluctuations on nerve diseases, or neuropathies, the researchers had to precisely control the decrease in PMP22. After creating and testing various AAV vectors, the team settled on one that eradicated 20% to 40% of PMP22 gene copies from the genome. This managed to reverse many CMT-related modifications in Schwann cell cultures and improved these cells' myelination capabilities, indicating this treatment's potential as a clinical therapy.

There are several hurdles to overcome before shifting this therapy to the clinic setting, acknowledges Dr. Okazawa. The most optimum injection site for reaching Schwann cells remains a mystery, and the timing of injections also requires further investigation.

The researchers maintain a cautious optimism as the FDA is beginning to approve similar AAV-based gene therapies for hematological diseases. Their therapeutic technique supposedly carries minimal risks for human applications and could be relatively easily transitioned into clinical therapy options. As there are no current CMT treatments aside from physiotherapy, occupational therapy, and pain management, development of this PMP22-centered genome-editing approach represents a significant advance and may alleviate symptoms and improve CMT patients' life quality.

For reference, the study, "AAV-mediated editing of PMP22 rescues Charcot-Marie-Tooth disease type 1A features in patient-derived iPS Schwann cells" was authored by various individuals including Yuki Yoshioka, Juliana Bosso Taniguchi, Hidenori Homma, Takuya Tamura, Kyota Fujita, Maiko Inotsume, Kazuhiko Tagawa, Kazuharu Misawa, Naomichi Matsumoto, Masanori Nakagawa, Haruhisa Inoue, Hikari Tanaka and Hitoshi Okazawa, and was published on 28 November 2023 in Communications Medicine.

The Ministry of Education, Culture, Sports, Science and Technology in Japan supported the study.