Developing a treatment is only half the challenge. The other half is getting it to the right place in the body. That’s where the science of drug delivery comes in.
In Charcot-Marie-Tooth disease, CMTA-funded researchers are designing therapies that target the root cause of the disease, the underlying gene mutations that contribute to symptoms. These therapies can only work if they are able to get to the nerve cells where the damage occurs. Making that happen consistently and without unwanted effects remains a central challenge in CMT research.
To address that challenge, in early 2026, CMTA increased its investment in delivery science, committing $523,000 across four research projects. These projects are part of CMTA’s Strategy to Accelerate Research (CMTA-STAR) and reflect our ongoing mission to develop treatments for CMT.
Why drug delivery is so difficult
To understand why treatment delivery is such a challenge, it helps to look at the structure of the peripheral nervous system. This network of nerves carries signals between the brain, spinal cord, muscles, and skin, and can stretch more than three feet from the spine to the toes. Along their entire length, these nerves are protected by a network of tightly connected cells called the blood-nerve barrier.
The job of the blood-nerve barrier is to keep foreign substances such as bacteria, viruses, and other potentially harmful materials, from reaching the nerve tissue. This protection is important for overall health, but it also makes it harder to deliver treatments to nerve cells. Many of the therapies in development for CMT, including RNA-based medicines and gene-editing strategies like CRISPR, are blocked by this barrier before they can reach their targets.
Peripheral nerves present an additional challenge: the cells most affected in many forms of CMT, Schwann cells and neurons, are highly specialized and difficult to access. Schwann cells are the cells responsible for producing myelin, the protective sheath that wraps around nerve fibers (much like the coating on an insulated electrical wire), and allows them to transmit signals efficiently. In CMT, malfunctioning neurons, Schwann cells or the myelin sheath leads to progressive nerve damage, loss of sensation, muscle wasting, balance problems and many other symptoms. Delivering therapies directly to these cells is critical, but reaching them in a predictable way has proven difficult.
This is why delivery science is its own field of research, separate from but essential to the development of the genetic therapies. Even the most effective therapy for CMT will not work if it can’t get to the right cells.
What researchers are testing
To tackle this problem, CMTA is funding four research teams working on distinct delivery strategies. By supporting several approaches at the same time, we are increasing the chances that one or more approach will succeed. Additionally, lessons learned from one project will inform the others, further contributing to research progress.
Principal Investigator: Jiangbing Zhou, PhD, Nixdorff-German Professor of Neurosurgery, Yale School of Medicine
Jiangbing Zhou, PhD, and his team at Yale University are evaluating a non-viral delivery system called STEP, designed to transport genome-editing medicines like CRISPR to peripheral nerve cells. The STEP system is unique in that it uses chemicals instead of viruses or nanoparticles to deliver potential therapies to cells.
Genome-editing therapies have the potential to be effective for many subtypes of CMT. They work by making targeted changes to a person’s DNA to correct a faulty gene at its source. The project will test how well the STEP system reaches Schwann cells and neurons in CMT models using different routes of administration, and whether genome-editing activity can be detected in the targeted cells once the therapy is delivered.
Project: Blood–nerve barrier–crossing conjugates for delivery of RNA medicines in CMT
Principal Investigator: Yizhou Dong, PhD, Mount Sinai Endowed Professor in Nanomedicine, Icahn School of Medicine at Mount Sinai.
At Mount Sinai in New York, Yizhou Dong, PhD, and his team are engineering specialized molecules called blood-nerve barrier-crossing conjugates (BCC). Formed by chemically joining one substance to another, these bespoke molecules are designed to carry RNA medicines across the blood-nerve barrier and into Schwann cells.
RNA medicines work by adjusting the instructions that cells act on, rather than changing the underlying DNA. Because the blood-nerve barrier blocks most treatments from reaching peripheral nerves, finding molecules that can successfully make that crossing with the therapy intact is a critical step. Dong’s team will test different conjugate designs in CMT models to identify which are most effective at reaching peripheral nervous system cells.
Project: Schwann Cell-Targeted Peptide-LNPs for Delivery of siRNA Against PMP22 in CMT1A
Principal Investigator: Umar Iqbal, PhD, Team Leader and Research Scientist, National Research Council Canada
Umar Iqbal, PhD, in collaboration with CMTA partner SharkTooth Bio, is developing and testing peptide-lipid-nanoparticles (peptide-LNPs) for CMT1A. Peptide-LNPs are tiny particles built to seek out and deliver RNA medicines to specific cell types — in this case, Schwann cells.
CMT1A is the most common form of CMT and is caused by a duplication of the PMP22 gene, which leads Schwann cells to produce too much of the PMP22 protein, damaging the myelin sheath over time. As a test case for this delivery technology, Iqbal and team will assess how effectively the peptide-LNPs delivery system enters Schwann cells and whether the RNA medicine can reduce the level of PMP22 produced by CMT1A models. If this works, the delivery approach could be used to treat other types of CMT where the Schwann cell is the delivery target, such as CMT1B and CMTX1.
Project: Nanoparticle-Based Gene Delivery to Schwann Cells for Treating CMT Disease
Principal Investigator: Alexia Kagiava PhD, Post-Doctoral Fellow, The Cyprus Institute of Neurology and Genetics
Alexia Kagiava, PhD, and her team are developing nanoparticle-based delivery systems for CMTX1, a form of CMT caused by mutations in the GJB1 gene. CMTX1 disrupts a protein called Connexin32, which Schwann cells need to maintain the myelin sheath.
Earlier research from Kagiava’s colleagues showed that delivering a healthy copy of the GJB1 gene improved movement and nerve function in CMTX1 models. The current project tests nanoparticles as a delivery system for the healthy gene copy. In laboratory testing, Kagiava’s nanoparticles successfully delivered genetic material to peripheral nerve cells with less spread to other organs compared to the previous approach, suggesting a safer delivery profile. If successful, the approach could be applied to other types of CMT that affect Schwann cells and peripheral myelin, including CMT1A and CMT1B.
Looking ahead
These projects represent an important step in a larger process. Each one is designed to answer a specific and essential question: How can we deliver therapies for CMT to the nerve cells reliably and safely? The answers will help determine which approaches are ready for further development and where additional CMTA-supported research is needed. Together, these studies are building the foundation that future CMT treatments will depend on.
As results emerge, CMTA will assess which approaches show the most promise and support their future development, ensuring delivery will not be the obstacle keeping life-changing treatments from reaching patients.
