Mount Sinai researchers are leading innovative clinical trials to discover new treatments for the patients who need them most.
Clinical trials are essential for the development of treatments, devices, and procedures that drive the field of medicine forward. For rare genetic disorders — more than 95 percent of which have no approved treatment available — clinical trials are critical for identifying therapeutic options.
However, studying rare diseases is inherently challenging. Medical conditions are considered rare when they affect less than 1 in 2,000 people, meaning that accumulating a large participant pool is not always feasible. Some proposed treatments, such as gene editing, are relatively new with lesser-known side effects. Other barriers include an incomplete understanding of the disease mechanisms and pathophysiology.
The Department of Genetics and Genomics Sciences at Icahn Mount Sinai has a longstanding history of overcoming these hurdles to conduct clinical trials for rare genetic disorders. To date, the Department has performed more than 50 industry, National Institutes of Health, and investigator-initiated studies. These clinical trials have led to approval of much-needed treatments by the Food and Drug Administration (FDA) and European Medicines Agency (EMA).
In particular, Mount Sinai researchers have been at the forefront of conducting gene therapy trials, including first-in-human phase I trials. These have used novel adeno-associated virus, liver-targeted technology to treat rare diseases such as phenylketonuria, Fabry disease, and ornithine transcarbamylase (OTC) deficiency. Some therapies included preclinical work performed at Mount Sinai, such as a novel gene editing approach developed to treat Fabr disease, illustrating the Department’s success with translational research.
“We see the rarest of the rare, and all of these patients should have the opportunity for treatment,”
says Manisha Balwani, MD, Chief of the Division of Medical Genetics and Genomics at Icahn School Mount Sinai. “We really are a true bench-to-bedside department, with expertise on conducting successful clinical trials and the ability to administer drugs clinically to patients once they’re FDA-approved.”
The Department of Genetics and Genomic Sciences has a dedicated Clinical Trials Office to support investigators in executing all types of clinical research studies. Whether the study is observational, a first-in-human trial, or a phase 3 pivotal trial, the Clinical Trials Office assists with regulatory paperwork, recruitment and retention of study subjects, hiring study personnel such as genetic counselors, and other key components.
The arrangement has allowed investigators to focus on the research itself and caring for patients, rather than getting bogged down with administrative tasks. It has led to an expansion in the number as well as the type of clinical trials done under the Department, including the addition of multiple gene therapy studies for both adult and pediatric patients.
Margo Breilyn, MD, Assistant Professor of Genetics and Genomics Sciences and Pediatrics
“These patients are underrepresented because their diseases are rare, but the impact on their lives is tremendous,”
says Margo Breilyn, MD, Assistant Professor of Genetics and Genomics Sciences and Pediatrics. “If there is a better therapy that is being developed for our patients, we want to be at the forefront to give them early access to the best possible care, and clinical trials is a way to allow that to happen.”
Breilyn is leading a number of clinical trials that focus on inborn errors of metabolism, a diverse group of rare genetic disorders that affect the breakdown or storage of carbohydrates, fatty acids, and proteins. A first-in-human phase 1 trial in collaboration with pharmaceutical giant Moderna is investigating an messenger RNA (mRNA) therapy for propionic acidemia, a devastating childhood disease.
“Propionic acidemia affects about one in 100,000 individuals worldwide and can be quite life-limiting, resulting in developmental delays and overall metabolic instability,” says Breilyn. “That means children with this disease wind up in the hospital with even mild intercurrent illnesses.”
Moderna’s drug, known as mRNA-3927, contains two mRNA sequences that craft parts of an enzyme necessary to breakdown certain parts of proteins and fats. Individuals with propionic acidemia lack this enzyme, leading to a build-up of toxic substances and recurrent episodes of vomiting, weak muscle tone, and lethargy. Symptoms often appear a few days after birth.
Preliminary results of the study suggest that mRNA-3927, given through infusions every two weeks in a hospital setting, has some benefit for patients. Eight of the 16 participants who had experienced life-threatening episodes in the previous year had 70% reduction in the risk of such events after starting treatment. And anecdotally, some parents report a vast improvement in quality of life for their children.
"It’s been going quite well, and the kids seem to be getting much stronger after the therapy, so the families have decided to continue on with it,” she says.
“One of the children, a young toddler, actually traveled inter- nationally for this therapy. She’s going to museums and playing in parks while staying out of the hospital. It’s really making a difference for her.”
Recently, Balwani led a phase 2 study to investigate the efficacy and safety of a drug called dersimelagon for erythropoietic protoporphyria or X-linked protoporphyria, rare genetic conditions that cause abnormal sensitivity to the sun.
“These patients have an unusual situation where, within a few minutes of sun exposure, they start experiencing severe pain. Typically, the median age of onset is about three to four years, so even the daily activities of going to school, playing at recess, can be a challenge.”
The mean daily time to the first prodromal symptom associated with sunlight exposure increased significantly with dersimelagon the least-squares mean difference from placebo in the change from baseline to week 16 was 53.8 minutes in the 100-mg dersimelagon group (P=0.008) and 62.5 minutes in the 300-mg dersimelagon group.
Dersimelagon, which increases pigmentation of the skin and has anti-inflammatory properties, significantly increased the duration of symptom-free sunlight exposure in patients with erythropoietic protoporphyria or X-linked protoporphyria. The results also suggest that quality of life improved in patients receiving dersimelagon as compared with placebo. Balwani and her colleagues are currently conducting a phase 3 study to in the hopes of achieving FDA approval.
Efrat Eliyahu, PhD, Assistant Professor, Department of Genetics and Genomic Sciences
The lab of Efrat Eliyahu is taking a unique path to drug development that began with veterinary clinical trials. Acid ceramidase is an enzyme that can break the cycle of chronic inflammation which causes tissue damage in certain chronic conditions. For example, inflammation is a major contributor to pulmonary arterial hypertension (PAH), a rare chronic and progressive disorder characterized by high blood pressure in the arteries of the lungs.
“Up to date, most of the chronic inflammatory conditions are treated by drugs that aim to treat the symptoms of the disease, but not to modify or cure the disease,”
says Efrat Eliyahu, PhD, Assistant Professor of Genetics and Genomic Sciences. “We are developing a disease-modifying metabolic gene therapy that eliminates the source of chronic inflammation.”
In 2023, Eliyahu and her colleagues demonstrated in a rodent model that gene delivery of acid ceramidase prevents the progression of PAH, confirming the therapeutic role of the enzyme as a novel target in the disease. They are finalizing a pilot veterinary clinical trial in dogs with PAH and plan to submit a request to the FDA for a first-in-human study.
"Dogs with PAH, like humans, will die from heart failure," Eliyahu says, "Mango, a dog in our clinical trial, went from having a few weeks or months to live and being miserable to getting her life back with this therapy. She ended up living for three more years in good condition."
The Eliyahu lab has launched a startup company, SeneX Therapeutics, and are advancing to clinical trials for human and veterinary use in multiple areas of healthcare, including reproduction medicine, cardiovascular diseases, and orthopedics.