CCOS is pleased to continue our series of hub highlights, celebrating innovative contributions to clinical and translational science across the CTSA Program. Today, we spotlight the leading effort from the University of Pennsylvania’s Institute for Translational Medicine and Therapeutics in the world of gene-editing treatment for rare disorders.
For the first time, researchers have treated a baby born with a rare, life-threatening genetic disorder with a custom gene-editing treatment designed for his precise mutation. This advancement comes on the heels of using gene-editing to treat an adult with congenital blindness in 2020. Prior to this, cells had only been edited outside of the human body and reinfused into a patient.
At a week old, the patient KJ was diagnosed with a rare genetic disorder affecting 1 in 1.3 million babies – Carbamoyl Phosphate Synthetase 1 deficiency (CPS1D). When properly functioning, the CPS1 enzyme plays a critical role in the urea cycle by helping break down ammonia. However, with a deficient CPS1 enzyme, ammonia – which is especially toxic to the central nervous system – starts to build up in the blood. Those who survive exhibit severe mental and developmental delays, eventually needing a liver transplant. Half of all babies with CPS1D die in the first week of life.
Gene editing tools are incredibly complex and nuanced, and until now, researchers have built them to target more common diseases that affect tens or hundreds of thousands of patients. Two diseases of this nature, sickle cell disease and beta thalassemia, currently have U.S. Food and Drug Administration-approved gene-editing therapies. However, relatively few diseases benefit from a “one-size-fits-all” gene editing approach, since so many disease-causing variants exist.
The Institute for Translational Medicine and Therapeutics (ITMAT) at the University of Pennsylvania includes investigators from all schools at Penn, the Children's Hospital of Philadelphia, and the Wistar Institute. Fittingly, the CTSA funded hub focuses on clinical and translational research that aids in the development of new and safer medicines. ITMAT researchers Rebecca Ahrens-Nicklas, M.D., Ph.D., at Children’s Hospital of Philadelphia and Kiran Musunuru, M.D., Ph.D., M.P.H, at the University of Pennsylvania have been collaborating with an international team of scientists for two years on a form of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) base-editing gene therapy for rare diseases, expanding upon years of research into rare metabolic diseases. CRISPR is a technology used to selectively modify the DNA of living organisms, and was adapted for laboratory use from a naturally occurring genome editing system found in bacteria. Base editing – the technology used to develop the therapy for KJ – is a form of CRISPR technology that allows for targeted changes to individual DNA bases without introducing double-stranded breaks into DNA.
Thanks to their prior work, the timing was right to design a CRISPR gene therapy tailor-made to fix KJ’s precise gene mutation. Within six months, the team created a base editing therapy, which was delivered to the liver via lipid nanoparticles to correct KJ’s defective enzyme. After three infusions of the experimental therapy, KJ was able to eat more protein, gain weight, and hit milestones never thought possible. The treatment was successful and KJ was discharged home with his parents.
“Years and years of progress in gene editing and collaboration between researchers and clinicians made this moment possible, and while KJ is just one patient, we hope he is the first of many to benefit from a methodology that can be scaled to fit an individual patient’s needs,” Dr. Ahrens-Nicklas said in a press statement.
The case is detailed in a study published by The New England Journal of Medicine. The breakthrough offers a way to develop personalized treatments for the over 30 million people in the US with more than 7,000 rare genetic diseases. Eventually, it may be used for the treatment of more common genetic disorders like cystic fibrosis and muscular dystrophy. “This is the first step towards an entirely new type of personalized medicine,” Dr. Musunuru told NPR. “I think it's going to utterly transform the way we practice medicine, particularly in the area of rare diseases.”
To read more about exciting advancements in the field of genetics, check out our hub spotlights on the Tandem Repeat Genotyping Tool from the University of Utah, and an effort by Frontiers CTSI at the University of Kansas to bring cutting-edge genetic testing to rural communities.
