ATLANTA (July 18, 2022) The CMT Research Foundation (CMTRF), a non-profit focused solely on delivering treatments and cures for Charcot-Marie-Tooth disease*, has awarded a grant of over $500,000 to find a single gene therapy for every form of CMT1B.
The award was made to Afrooz Rashnonejad, PhD, Principal Investigator at the Nationwide Children’s Hospital Center for Gene Therapy, and Assistant Professor at the Ohio State University’s Department of Pediatrics in Columbus, Ohio. Dr. Rashnonejad is currently the Chair of the American Society of Gene & Cell Therapy (ASGCT) New Investigator Committee and has twice received the ASGCT Excellence in Research Award. She developed an AAV-CRISPR-Cas13 gene therapy for FSHD, and has filed several patent applications, including one for CMT1B-targeted gene therapy.
“The idea behind the approach, known as ‘knockdown and replace,’ is to silence the expression of the mutated gene and replace it with a healthy signal, allowing the nerves to create a healthy protein,” says Dr. Rashnonejad. “This approach could work for all or nearly all forms of CMT1B, a highly desirable outcome.”
CMT1B is caused by mutations of the myelin protein zero (MPZ) gene. To silence the mutant MPZ, the research team uses small, non-coding RNA called micro RNA, or just miRNA.
Dr. Rashnonejad has already designed eleven miRNAs targeting MPZ and has shown that they reduce the expression of MPZ in cells-in-a-dish experiments. She has also built an mRNA for normal healthy MPZ using codons that make it resistant to the silencing effects of these miRNAs. These parts were done during her postdoc in Dr. Scott Harper’s lab. Now as an independent investigator in her lab, Dr. Rashnonejad continues to further develop this and investigate the safety and efficacy of the gene therapy in CMT1B mouse models
“This is state of the art science. Dr. Rashnonejad is a rising star in gene therapy,” says Cleary Simpson, CEO of the CMT Research Foundation. “This project may well produce a therapy that works for all or nearly all people with CMT1B, regardless of their specific genetic mutation.”
The CMT Research Foundation (CMTRF) is focused solely on delivering treatments and cures for CMT. Founded by two patients who are driven to expedite drug delivery to people who live with CMT globally, the organization funds research for drug development. The 501(c)(3) federal tax-exempt organization is supported by personal and corporate financial gifts.
Named to the Top 10 Honor Roll on U.S. News & World Report’s 2022-2023 list of “America’s Best Children’s Hospitals,” Nationwide Children’s Hospital is one of America’s largest not-for-profit freestanding pediatric health care systems providing wellness, preventive, diagnostic, treatment and rehabilitative care for infants, children and adolescents, as well as adult patients with congenital disease. As home to the Department of Pediatrics of The Ohio State University College of Medicine, Nationwide Children’s faculty train the next generation of pediatricians, scientists, and pediatric specialists. The Abigail Wexner Research Institute (AWRI) at Nationwide Children’s is one of the Top 10 National Institutes of Health-funded free-standing pediatric research facilities in the U.S., supporting basic, clinical, translational and health services research. AWRI is comprised of more than 525,000 square feet dedicated to research across three buildings on the Nationwide Children’s campus, with a fourth building slated to open in 2023.
The Center for Gene Therapy (at AWRI) is dedicated to investigating the use of gene and cell-based therapeutics for the prevention and treatment of human disease, including neuromuscular and neurodegenerative diseases, lysosomal storage disorders, and others. Demonstrating the transformative power of translational medicine, the pre-eminent researchers and clinician-scientists in the center have made many first-of-their-kind discoveries that have led to life-changing therapeutics.
*Charcot-Marie-Tooth encompasses a group of inherited, chronic peripheral neuropathies that result in nerve degradation. CMT patients suffer from progressive muscle atrophy of legs and arms causing walking, running and balance problems and abnormal hand and foot functioning. CMT affects one in 2,500 people (about the same prevalence as multiple sclerosis), including 150,000 Americans and nearly 3 million people worldwide. At the moment, there is no treatment or cure for CMT.
CMT1B is a form of CMT that is autosomal dominant, meaning that a person can inherit the disease with only one affected parent. Each child of an affected parent, both boys and girls equally, have a 50/50 chance of inheriting the disease.
It is believed that in CMT1B, the part of the nervous system that is dysfunctional is the myelin sheath of the peripheral nerves. Created by cells called Schwann cells, myelin wraps around the parts of the nerves that facilitate rapid electrical signals to other parts of the body. The myelin sheath is critical for the fast-signaling nerves are accustomed to, and the body’s communication system becomes dysfunctional without it. In CMT1B, the myelin sheath is compromised because the Schwann cells have mutations within a gene called myelin protein zero, or MPZ, a necessary component of the myelin sheath.
A Deeper Dive into the Science Behind the Project
The Gene Therapy for CMT1B project takes advantage of a fundamental principle of molecular biology: genes code for messenger RNA (mRNA), and mRNA codes for proteins. Proteins are made up of individual units called amino acids. Each sequence of three “bases” in the mRNA strand is called a codon and matches to a single amino acid. However, since there are more possible codons than amino acids, most amino acids have several different matching codons. This allows researchers to build mRNA sequences with different codons that code for the same protein.
This project also takes advantage of a normal biological process called RNA interference (RNAi). In addition to messenger RNA (mRNA), the body produces several other kinds of RNA. One of these is called microRNA (miRNA – note the “i”), and one essential function of miRNAs is to silence the expression of their matching mRNAs. However, in order for a miRNA to silence an mRNA, it must be a good match for the sequence. It is therefore possible to design a miRNA that silences the expression of a naturally occurring mutant mRNA and simultaneously add an artificial mRNA for the same protein that is not silenced by the miRNA because it uses a different set of codons to build the healthy protein. This is called codon optimization.
The overall goal of this project is to create the gene therapy by a) combining the best performing miRNA and the resistant mRNA into a single construct, b) inserting this construct into an AAV9 delivery vector, and c) testing the therapy in CMT1B model mice.
Nationwide Children’s Hospital
George H. Simpson