PHILADELPHIA—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.
“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).
About Penn Medicine:
Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, excellence in patient care, and community service. The organization consists of the University of Pennsylvania Health System and Penn’s Raymond and Ruth Perelman School of Medicine, founded in 1765 as the nation’s first medical school.
The Perelman School of Medicine is consistently among the nation's top recipients of funding from the National Institutes of Health, with $550 million awarded in the 2022 fiscal year. Home to a proud history of “firsts” in medicine, Penn Medicine teams have pioneered discoveries and innovations that have shaped modern medicine, including recent breakthroughs such as CAR T cell therapy for cancer and the mRNA technology used in COVID-19 vaccines.
The University of Pennsylvania Health System’s patient care facilities stretch from the Susquehanna River in Pennsylvania to the New Jersey shore. These include the Hospital of the University of Pennsylvania, Penn Presbyterian Medical Center, Chester County Hospital, Lancaster General Health, Penn Medicine Princeton Health, and Pennsylvania Hospital—the nation’s first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Medicine at Home, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.
Penn Medicine is an $11.1 billion enterprise powered by more than 49,000 talented faculty and staff.
About Children’s Hospital of Philadelphia:
A non-profit, charitable organization, Children’s Hospital of Philadelphia was founded in 1855 as the nation’s first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, the 595-bed hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. The institution has a well-established history of providing advanced pediatric care close to home through its CHOP Care Network, which includes more than 50 primary care practices, specialty care and surgical centers, urgent care centers, and community hospital alliances throughout Pennsylvania and New Jersey, as well as an inpatient hospital with a dedicated pediatric emergency department in King of Prussia. In addition, its unique family-centered care and public service programs have brought Children’s Hospital of Philadelphia recognition as a leading advocate for children and adolescents. For more information, visit https://www.chop.edu.