NIH Awards Penn Medicine and Children’s Hospital of Philadelphia $26 Million Grant to Develop Therapies for Rare Newborn Genetic Diseases

A Penn Medicine and Children’s Hospital of Philadelphia (CHOP) team will seek to develop treatments for three rare, incurable genetic diseases with the help of a $26 million grant from the National Institutes of Health (NIH).

The research will focus on three genetic diseases that impact newborns in the first weeks and months after birth: Phenylketonuria (PKU), hereditary tyrosinemia type 1 (HT1), and mucopolysaccharidosis type 1 (MPSI), commonly known as Hurler’s Syndrome. PKU causes an amino acid—called phenylalanine—to build up in the body, and as long as treatment begins at birth, PKU is not life threatening. A late diagnosis, however, can lead to severe intellectual disability, seizures, and psychiatric issues. HT1 is a genetic disorder that leads to disruptions in the breakdown of the amino acid tyrosine—a component in the production of brain chemicals such as dopamine, thyroid hormones, and melanin. If untreated, HT1 can lead to serious health problems or even death. Finally, MPSI, or Hurler’s Syndrome, is a rare disease in which the body is missing or does not have enough of an enzyme to break down sugar molecules. As a result, the molecules build up in the body and cause numerous health problems that can lead to hearing and vision loss, impaired growth, and early death.

Previous studies have demonstrated that it may be possible to treat these diseases by correcting the disease-causing genetic mutations in patients’ liver cells. Although these diseases impact cells all throughout the body, researchers believe correcting the genetic mutation in the liver, specifically, will be enough to greatly improve the disease, if not cure it. With this new five-year grant from the NIH, Penn and CHOP researchers will seek to develop and study new therapies using CRISPR gene editing tools.

“CRISPR technology allows researchers to change just one component in an existing drug to target different diseases—the component that acts as a ‘GPS’ to tell CRISPR where to go in the genome and in which location to make the correction,” said co-PI Kiran Musunuru, MD, PhD, MPH, a professor of Cardiovascular Medicine and Genetics in Penn’s Perelman School of Medicine, scientific director of the Penn Center for Inherited Cardiovascular Disease, and director of the Genetic and Epigenetic Origins of Disease Program at the Cardiovascular Institute at Penn. “Our team is hopeful that this gene editing approach could crack the code around treating these diseases, while showing what’s possible when it comes to developing gene-editing therapies.”

Each of the three diseases is currently incurable, and the most advanced therapies available for each disorder have limitations. For example, HT1 patients typically must take medication twice a day, but about 50% of patients struggle to keep up with the regimen, leading to life-threatening liver issues. With PKU, patients must adhere to a strict low-protein diet. Some take medication—an injectable drug taken daily—which historically has caused a strong allergic reaction in 10% of patients.

William Peranteau, MD, is co-leading the study for CHOP “CRISPR offers the potential to develop highly effective treatments for incurable genetic diseases and improve the quality of life for patients with these conditions,” said co-PI William Peranteau, MD, an attending surgeon in the Center for Fetal Diagnosis and Treatment at CHOP, where he holds the Adzick-McCausland Distinguished Chair in Fetal and Pediatric Surgery. “This NIH funding will help us develop and validate the safety of new gene therapies that can be given to patients in vivo—directly in the body—so that we will have the data we need to be able to move into clinical trials.”

The researchers aim to use lipid nanoparticle base-editing to develop therapies for both PKU and HT1. Lipid nanoparticles are used to deliver nucleic acids, like RNA and DNA, to target cells. Additionally, researchers will utilize adeno associated virus (AAV) base-editing in developing a therapy for MPSI. AAV is a non-enveloped virus that can be engineered to deliver DNA to target cells.

This research is supported by the NIH (U19NS132301).