In their offices in Maryland, just northwest of Washington, DC, miRecule Inc. and its founder Anthony Saleh, PhD, are hard at work developing a novel treatment for FSHD.
In the early 2000s, Saleh was a graduate student at Johns Hopkins School of Public Health in Baltimore, Maryland, working on a new class of drugs known as RNA therapeutics. He had lost two grandparents to cancer, and he wanted to focus on developing new treatments. “RNA therapeutics were incredibly intriguing,” he recalled. “They can be designed to target nearly any gene to tackle the underlying causes of diseases.”
All of our genetic information is encoded in our DNA, but DNA’s lesser known cousin RNA is an important intermediary messenger that shepherds information encoded in our DNA, so that the cell can create the necessary proteins that perform most of our bodies’ functions. When we inherit mutations in our DNA that cause diseases like FSHD, there is also that RNA messenger that orders the cells to create toxic proteins like DUX4, which causes the breakdown of muscles in FSHD. RNA therapeutics can stop those RNA messengers in their tracks, eliminating those specific RNAs and preventing the toxic proteins from ever being made.
After graduating from Johns Hopkins, Saleh went on to a fellowship at the National Institutes of Health (NIH) in Bethesda, Maryland. It was there, working for about a decade with a large team of experts in cancer biology and treatment, that he helped to develop the underlying technology for miRecule.
“When I started my career, RNA therapeutics were relatively new, and the field ran into some major challenges developing therapeutics that could be safe and effective,” Saleh said. “At NIH, our team spent a great deal of time to create a technology platform that could overcome these challenges focusing on RNA therapeutics for cancer. But we also knew what we were learning about RNA therapeutics could be applied to a range of other diseases.”
In 2016, Saleh left NIH and recruited Robert Place, PhD, and Ashwin Kulkarni, MS, to co-found miRecule with the goal of translating the NIH work into treatments. “We started the company with money from the founders and an investment from my father,” he said. “It took us a couple of years to get the company up and running, and to license our technology from NIH.” Once they were organized, they designed a new therapeutic for head and neck cancer, and gained some additional early investment and a grant from the government.
About the time the company was launched, one of Saleh’s uncles was diagnosed with FSHD. “It was the first I had ever heard of the disorder, so I started to read the scientific and medical literature on it,” he said. Then, in 2017, his father, now in his mid-60s, started to experience symptoms and went to see Dr. Rabi Tawil, an FSHD specialist. Saleh’s father was also diagnosed with FSHD.
“As I learned more about FSHD, I realized that an RNA therapeutic that could directly prevent expression of DUX4, the protein which causes the underlying muscle toxicity in the disorder, could potentially be a more effective treatment than traditional therapeutics currently being explored,” Saleh said.
By 2018, miRecule was doing well. The company was growing, had found additional funding, and its first therapeutic for cancer was progressing through preclinical development.
Shortly after his father’s diagnosis, Saleh read a paper by Kathryn Wagner, MD PhD, at the Kennedy Krieger Institute in Baltimore, Maryland, about testing an RNA therapeutic targeting DUX4. He met with Wagner to discuss her research and get himself tested for FSHD. He indeed tested positive. Saleh also came across the research of Yi-Wen Chen, PhD, at Children’s National Hospital in Washington, DC, who is also working on RNA therapeutics targeting DUX4. (Both Wagner and Chen have been supported by FSHD Society grants.)
In discussing FSHD within the company, Saleh learned that his co-founder Rob Place had previously worked on RNA therapeutics for other muscle disorders, and Saleh thought miRecule’s technology might also work for FSHD. “I have never experienced such a serendipitous situation,” Saleh marveled. “Here I was, diagnosed with FSHD along with multiple members of my family, and the best therapeutic strategy to treat FSHD was a technology I had spent my career working on. Additionally, I had two leading experts in the field working on RNA therapeutics for FSHD less than an hour’s drive from my company. How could we not work on this therapy?”
In late 2018, miRecule officially started its FSHD program. By this time several more members of Saleh’s family had been diagnosed with FSHD. “My father has 11 siblings, and many of them are positive for FSHD. In retrospect, it is obvious that my grandmother’s many physical symptoms as she aged were those of FSHD,” Saleh said. “I want to see a therapeutic developed not just for my father and myself, but also for the next generation. As we test our kids, I know some of them will have it as well.”
With a strong resolve to take on FSHD, miRecule raised some initial funding from family members, hired a full-time scientist dedicated to FSHD, and began work designing an RNA therapeutic targeting DUX4. Saleh reports that they already have a dozen compounds that can eliminate DUX4 expression in FSHD patient muscle cells in culture, and he hopes to get proof-of-concept data from mouse models of FSHD in the coming months in his collaborations with Wagner’s and Chen’s groups.
“With luck in our science, in our fundraising, and through our partnerships with organizations like the FSHD Society,” said Saleh, “we hope to have a therapeutic in human clinical trials in a few years.”