Creating Custom Genetic Treatments for Critically Ill Newborns
University of Miami Miller School of Medicine researchers are building a rapid pipeline to turn genomic diagnoses into lifesaving therapies for infants with ultra‑rare genetic diseases.
Genomic sequencing has been a godsend for sick infants and their families. By sequencing a baby and, often, both parents, clinicians can quickly identify the genetic variations behind that child’s condition. Before genomic sequencing, that diagnostic process might have taken months or even years. Now, these medical mysteries can be solved in days.
But there’s a catch. While doctors and families may get detailed information about the baby’s condition, there are often no therapies available to treat them. There are more than 7,000 rare genetic diseases and fewer than 5% have specific treatments. Genomic sequencing can provide vital diagnostic information, but treatments are elusive.
To help solve this problem, a team at the University of Miami Miller School of Medicine and Boston Children’s Hospital are working to create a fast, replicable pipeline to develop bespoke therapies for conditions in infants. Called Beginning Genetic Interventions in Infants (BEGIN), the project has received a four-year, $3.2 million grant from the National Institutes of Health (NIH).
“In many of these conditions, if we don’t intervene early, we lose the baby or they will have major long-term complications,” said Pankaj Agrawal, M.D., professor of pediatrics at the Miller School, physician-in-chief at Holtz Children’s Hospital, Jackson Health System, and contact principal investigator on the grant. “We need new ways to develop therapies for these sick infants and do it quickly.”
Using Antisense Oligonucleotides to Address Genetic Errors
While rare diseases are not rare — there are around 30 million Americans who have at least one — each genetic anomaly may affect only a handful of patients, sometimes just one. This negates biopharma’s interest in creating novel therapies. In most cases, they could never recoup their investments.
To overcome this challenge, Dr. Agrawal, along with co-principal investigator Timothy Yu, M.D., Ph.D., will be exploring an emerging class of therapeutic molecules: antisense oligonucleotides (ASOs).
ASOs are DNA or RNA sequences that modulate dysfunctional messenger RNA, which helps create disease-causing proteins. Depending on their design, ASOs can either interrupt protein production or overcome genetic errors. Most importantly, ASOs are relatively easy to manufacture.
“We’re testing a system where we use rapid genome sequencing to diagnose these babies early,” said Dr. Agrawal. “If there is no existing treatment, we will have to create one by studying the disease-causing variant and seeing if it is amenable to an antisense therapy.”
Drs. Agrawal, Dr. Yu and others have been working on this approach for several years. In 2019, they published an article in the New England Journal of Medicine that describes their efforts to create an ASO therapy for a single rare disease patient. Now, with the NIH funding, they hope to build on that work.
From Single‑Patient Breakthroughs to a Scalable Pipeline
Once the group has identified the ASO sequence that could help a patient, they will work with outside organizations to create the actual therapy. They already have ties to GeneDx, which conducts genetic testing, and the n-Lorem Foundation, a California nonprofit that has been working on ASO-based therapies against ultra-rare genetic mutations.
The group will also collaborate with clinicians and parents to develop fair and transparent guidelines for patient selection. They will initially focus on neurological and metabolic disorders, which are often the most devastating and also more likely to be amenable to ASO approach.
“There’s nothing worse for a physician than making a diagnosis but still having to tell parents there are no available therapies for their child,” said Dr. Agrawal. “If we can help even a small fraction of these kids, that would be a game-changer.”
More from Miller School of Medicine Pediatrics
Florida’s Sunshine Genetics Act launches a pilot program to expand newborn screening using genomic sequencing.
Dr. Pankaj Agrawal found clinical interpretive reports are feasible and effectively communicate important genomic information to clinicians.
Dr. Pankaj Agrawal was part of an international research group that identified a mutated gene that deters neural development and function.
Researchers have showed that constrained genes do not tolerate mutations, suggesting the critical roles they play in many cellular functions.
Tags: Department of Pediatrics, Dr. Pankaj Agrawal, genetics, genomics, neonatology, pediatrics, rare diseases