The blood-nerve barrier limits systemic delivery of therapies to peripheral nerve tissue. CMTA-STAR is funding four parallel delivery science projects to address this.
Charcot-Marie-Tooth Association (CMTA) is funding four research projects targeting a fundamental challenge in the development of CMT treatments: delivering therapies to the nerve cells where they can work. Recognizing delivery as essential to turning research into treatments, CMTA is leading the effort to solve this challenge, with these four projects representing the latest phase in this work.
While scientists have made progress in understanding the genetic causes of CMT and identifying potential treatments, getting those treatments past the body’s natural defenses and to the affected cells remains unsolved. Peripheral nerves can stretch over three feet from the spine to fingers and toes and are protected by biological barriers designed to keep foreign substances out, including medications. Without solving the delivery issue, promising CMT therapies remain stuck in the lab, unavailable to people who desperately need them.
Through its Strategy To Accelerate Research (CMTA-STAR), CMTA is supporting four complementary approaches to overcome treatment delivery barriers with an investment of $523,000 and related support. Each project targets a different aspect of the challenge, increasing the likelihood of success across all types of CMT.
What is delivery science?
Delivery science is the field concerned with how therapeutic agents reach their intended biological targets reliably, safely, and with sufficient specificity to produce the desired effect. In the context of CMT, delivery science addresses a specific, well-defined problem: the peripheral nervous system is structurally protected from systemic exposure. The blood-nerve barrier limits access to peripheral nerve tissue, and Schwann cells and peripheral neurons are not readily targeted by conventional delivery methods. A therapy that cannot reach its target cell cannot work.
Overcoming the delivery hurdles in CMT is a key focus of CMTA-STAR. Treatments with validated targets and strong preclinical efficacy stall without a viable delivery method. By investigating a range of delivery modalities in parallel with target identification and the creation of genetic therapy cargoes, CMTA-STAR is constructing the infrastructure that future CMT treatments require to advance.
What are CMTA-STAR’s delivery science projects?
Project 1: STEP Platform for Genome-Editing Delivery Jiangbing Zhou, PhD | Yale University | $66,000 | 1 year
Zhou’s lab is characterizing the STEP platform, a non-viral, chemical-based delivery system for genome-editing cargo, including CRISPR-based constructs. Non-viral delivery has historically struggled with PNS penetration, making this a meaningful feasibility question for the field. The project will evaluate delivery to Schwann cells and neurons in CMT models across multiple routes of administration, with genome-editing activity in target cells as the primary readout. If STEP demonstrates adequate PNS biodistribution and on-target editing, it will represent a broadly applicable delivery vehicle across CMT subtypes.
Project 2: Blood-Nerve Barrier-Crossing Conjugates for RNA Medicine Delivery Yizhou Dong, PhD | Icahn School of Medicine at Mount Sinai | $54,051 | 1 year
Dong’s group is engineering blood-nerve barrier-crossing conjugates (BCC): bespoke molecules formed by chemical conjugation, designed to ferry RNA-based payloads across the BNB and into Schwann cells and neurons. The project will screen multiple conjugate designs in CMT models for PNS delivery efficiency and Schwann cell and neuron targeting. This work directly addresses the challenge of BNB permeability for RNA therapeutics, which otherwise exhibit limited PNS bioavailability.
Project 3: Peptide-LNP Delivery of siRNA Against PMP22 in CMT1A Umar Iqbal, PhD (National Research Council Canada), | $102,968 total | CMTA, SharkTooth Bio, and NRC Canada | 1 year
Iqbal’s team is developing Schwann cell-targeted peptide-lipid nanoparticles (peptide-LNPs) for delivery of siRNA targeting PMP22 in CMT1A. CMT1A, caused by PMP22 duplication, is the most common CMT subtype, and reducing PMP22 overexpression in Schwann cells is a validated therapeutic approach. The peptide-LNP format is designed to combine cell-type specificity with the established safety and manufacturing profile of LNP platforms. A successful result would have direct translational implications for CMT1A and could be applicable to other demyelinating subtypes, including CMT1B and CMT1X (aka CMTX1, CMTX).
Project 4: Nanoparticle-Based GJB1 Gene Delivery in CMTX1 Alexia Kagiava, PhD | Cyprus Institute of Neurology and Genetics, co-funded with MDA | $299,992 | 3 years
Kagiava’s project is the longest-running and most advanced of the four. Prior work from her group demonstrated functional improvement following AAV9-mediated GJB1 delivery in a CMTX1 model. CMTX1 is caused by GJB1 mutations disrupting Connexin32, and Schwann cell-targeted gene replacement remains the primary therapeutic strategy. The current project tests nanoparticle systems as a non-viral alternative to AAV9. Recent data confirmed that nanoparticles successfully delivered genetic cargo to peripheral nerve cells. Results from this project have potential applicability to other Schwann cell-dependent forms of CMT, including CMT1A and CMT1B.
Portfolio context
Advances in any of these four delivery platforms could be leveraged across multiple therapeutic programs. CMTA will use results from this cohort to determine which modalities warrant continued investment and where preclinical gaps remain.
Clinicians and researchers working on peripheral nerve biology, gene therapy delivery, or CMT subtypes addressed in this portfolio are encouraged to connect with CMTA’s research team. CMTA-STAR funds investigator-initiated projects and maintains a growing portfolio of institutional partnerships. To explore potential collaboration or learn more about CMTA-STAR, visit the hub or contact us directly at research@cmtausa.org.
