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CMT Research Foundation: Perspective from a funder, Riann Egusquiza, Director of Research

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CMT Research Foundation Riann Egusquiza

Preface: Rare diseases, including Charcot-Marie-Tooth (CMT), collectively affect more than 300 million people around the world. We know that research funding is necessary to advance our understanding and develop treatments for people with the disease. However, we also know that funding must be used effectively. In this Funder Perspective interview series, we are excited to speak with Riann Egusquiza, Director of Research at CMT Research Foundation, who shares with us her passion to help those with CMT through supporting researchers. Read on to find out how CMT Research Foundation supports CMT researchers and its grantees.

Please tell us more about Charcot-Marie-Tooth disease, specifically, how rare is it, and is there a cure for it?

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 as well as abnormal functioning of hands and feet. CMT affects one in 2,500 people (about the same prevalence as cystic fibrosis), including 150,000 Americans and nearly 3 million people worldwide. At the moment, there is no treatment or cure for CMT. 

What is the approach of the Charcot-Marie-Tooth Research Foundation when it comes to supporting research on CMT?

The CMT Research Foundation is unlike any other CMT organization. Our impact goes beyond simply making investments. We identify key problems or gaps in progress to a cure, then aggressively find partners to attack the problems. We introduce CMT to the greater drug development community, something that has rapidly increased the number of experts working to solve the disease. We fund projects with the highest likelihood of leading to clinical trials and approved treatments in the near term. All investments are gated, meaning projects need to achieve milestones defined for each phase of work before receiving funding for the next. Every contract includes a potential return on the CMT Research Foundation’s initial investment, which is then reinvested in new projects.

What is the application process like for CMTRF funding support? Could you please share more details here?

Applicants first submit a 1-2 page Letter of Intent (LOI) that highlights key points of the project summary, scientific rationale supported by preliminary data (if available), specific aims, and how the results will benefit CMT drug development. We will evaluate the LOI on its alignment with our funding priorities. This step typically takes around 3 weeks. If alignment is confirmed, we ask the applicant to submit a full proposal that will contain all the details of the experimental plan and project rationale, as well as a detailed budget and timeline for study completion. The full proposal will be evaluated by our Scientific Advisory Board (SAB). The timing of this step often depends on if the SAB has additional questions that need to be addressed before an evaluation can be made, but typically it takes 3-8 weeks and we will remain in close contact with the applicants along the way. If a project is recommended for funding by the SAB, it is then presented to the Board of Directors for final approval of the funds. Please see our website for more details on the application process: https://cmtrf.org/apply/ 

Could you please provide information on the allocated budget for eligible projects and is co-funding an option in cases of elevated research costs?

We don’t predicate a budget range for a project: since the research is funded by donors, most of whom have a personal connection with CMT, we aim to optimize every dollar. That often means co-funding projects with institutions and other foundations so that we can support as many research projects as possible. Each project is unique and requires its own evaluation, but if we believe the project will lead to treatments for CMT, then we will find ways to support it! One thing to note, we do look for less than 10% in indirect expenses. 

A common frustration for researchers is that many grant applications provide minimal feedback. CMT Research Foundation’s application process stands out as it provides researchers with expert guidance for improvement. Please tell us more!

Supporting our research partners with our expertise accelerates the development of treatments for CMT, which is our ultimate goal. If we are presented with a good idea, we want to leverage all the expertise we can to set it up for success. This also encourages investigators new to CMT to begin working in the space because we will serve as their thought partner and CMT expert throughout the project. For example, if a proposal comes to us suggesting the use of a certain model and our scientific team believes that there is a better model to use, we work with the applicant to consider modifying the proposal to include the better model AND provide them with resources to obtain that model.  Bottom line, we aim to serve as partners to applicants to optimize the project proposals to be better setup for success and/or aligned with our funding priorities, and once funded, we aim to continue to be partners to interpret results, troubleshoot, pivot, etc. We want good ideas to be supported and developed into a successful project and will do everything we can to guarantee that!

Often, researchers we speak with ask about success rates of particular grant applications. We understand that this is not always a useful indicator of whether an applicant should apply. When applicants inquire about the success rate, how do you typically respond to this question?

The answer to this question is complex as it may vary on the status of available funds and the current research priorities. We encourage prospective applicants to reach out to us with their idea to discuss how it fits with our current funding priorities. If the idea is a good fit, we partner with our applicants to develop a successful proposal. 

What advice do you have for researchers interested in applying for CMT Research Foundation funding?

Bring us your best ideas!  Don’t worry about coming to us with deep knowledge about CMT – that’s our job.  We can help you determine if there is a viable pathway to CMT. Don’t wait until you’ve researched the best CMT models to use – we know those answers.  Call us when you think you have an idea, technology or drug that is suitable to CMT.  We will partner with you through the application process, and if your project is funded, we will be there as your partner through its development. 

Which recent funding recipients that you are particularly proud to have funded?

Here are three of our 1A projects that are headed toward the clinic: 

  1. One of the early programs CMTRF funded was DTx Pharma, a young company that had developed a platform for RNA therapeutics called Fatty Acid Ligand Conjugated Oligonucleotide. CMTRF executives suggested DTx’s platform, developed for another indication, could be relevant to the delivery challenge of drugs to Schwann cells.  CMTRF then funded an initial project to validate that in January 2020. DTx Pharma, Inc. (DTx) designed and tested a variety of novel RNA-based compounds that target PMP22, the gene that when over-expressed causes CMT1A. The success of that work earned DTx a grant from the NIH and supported them raising more than $115 million based on the development of DTx-1252, a first-in-class FALCON siRNA therapeutic for the treatment of CMT1A. DTx was recently acquired by Novartis for $1 billion. Novartis is now working towards taking the CMT1A compound to human clinical trials. And before CMTRF met with them in 2019 DTx hadn’t heard of CMT.
  2. A novel gene therapy for CMT1A continues to make progress in early development, driven by the collaborative research efforts of Dr. Kleopas Kleopa of the Cyprus Institute for Neurology and Genetics in Greece and Dr. Scott Harper of Nationwide Children’s Hospital in Columbus Ohio, and supported by funding from the CMTRF. This program has been licensed to Armatus Bio as ARM-101 and is delivering compelling results in preclinical studies. The company is now taking the necessary steps to be able to take this compound to clinical trials. The potential therapy is based on research that CMTRF funded by renowned neuromuscular disease expert, Dr. Kleopas Kleopa in collaboration with RNAi-based treatments for neuromuscular disorders expert, Dr. Scott Q. Harper and his team at Nationwide Children’s Hospital. Backstory: CMTRF approached Dr. Kleopa (who had already studied viral gene therapy in two other forms of demyelinating CMT) about the relevance of his approach to CMT1A. After subsequent discussions with our Scientific Advisory Board the CMT Research Foundation funded the project. In collaboration with Dr. Harper, Dr. Kleopa’s team developed a vectorized RNAi for CMT1A that is aimed at reducing or eliminating disease symptoms by lowering levels of PMP22, the culprit behind CMT1A. 
  3. Oryzon Genomics has presented positive preclinical efficacy data of ORY-4001, a selective histone deacetylase 6 (HDAC6) inhibitor demonstrating that ORY-4001 treatment was able to reverse disease progression symptoms in a Charcot-Marie-Tooth (CMT) animal model. The presented results are the fruit of a collaboration agreement between Oryzon and the CMT Research Foundation in 2022 to explore the therapeutic potential of Oryzon’s HDAC6 inhibitors. Oryzon is now conducting the necessary studies to understand the safety, efficacy, and drug properties of ORY-4001 to support bringing this compound to human clinical trials.

What motivates you the most in your work?

People who are afflicted by CMT suffer through a lifetime of ongoing physical pain, emotional distress, humiliation, and ongoing discomfort. It can be very difficult to walk, pick up small objects, get dressed, and engage in any form of robust physical activity. Depending on the form and type of the disease, confinement to a wheelchair is possible. The disease is progressive and as such advances over time so you have no idea just how bad you will be affected in the coming years.  Emotionally, CMT takes a toll because of the physical limitations associated with the disease. Imagine losing your ability to operate your cell phone, cook, play your favorite sport or unlock the door.  Or being laughed at as a child because of being “different.” This is the life of someone with CMT.

Acknowledgments

We extend our sincere gratitude to Riann Egusquiza, Director of Research at CMT Research Foundation, for this invaluable contribution and George Simpson, Director of Communications for supporting this initiative. This interview emphasized the pivotal role of the CMT Research Foundation and its commitment to supporting dedicated researchers striving to enhance the quality of life for individuals affected by Charcot-Marie-Tooth (CMT) disorder.

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