This revolutionary new field of medicine is returning the dream of health to families impacted by rare genetic conditions. UPenn cardiologist Kiran Musunuru and computational geneticist Rebecca Ahrens-Nicklas have created a revolutionary personalized gene therapy. Their radical approach is tailored uniquely to KJ Muldoon, a baby born last November with a super rare genetic disorder. Pioneering use of state-of-the-art CRISPR technology, the therapy has transformed KJ’s life. Now, he is able to eat more protein and take less medication to help manage his ammonia levels.
KJ Muldoon was born with a urea cycle disorder that prevents his liver from converting ammonia from metabolized proteins into urea. This devastating disease only impacts around 1 in 1.3 million people, with nearly half of those diagnosed not living to see their first birthday. The immediacy of KJ’s case inspired Musunuru and Ahrens-Nicklas to rapidly assemble a coalition of academic and commercial scientists. Together, they created a mission to make the safest and most effective gene therapy.
Development of Personalized Gene Therapy
The path to developing KJ’s treatment started long before he was born. Musunuru and Ahrens-Nicklas had long since perfected copycat gene therapies. It was this experience that allowed them to handle KJ’s unusual condition—Ileal Aganglionic Mega-colon—with assurance. In fact, they collaborated with researchers at the Children’s Hospital of Philadelphia (CHOP) to develop the therapy. They had, in just six months, manufactured it — no small feat given the complexity of these breakthrough treatments.
This innovative therapy uses the full potential of CRISPR technology. It employs a highly specialized CRISPR base editor to correct one misspelled word in KJ’s gene. This meant correcting a wrongly assigned adenine (A) to guanine (G). The base editor itself is a protein, an engineered form of the CRISPR/Cas9 enzyme. It makes a precise cut into one of the two DNA strands directly on top of the mutation location.
For KJ, three infusions of the personalized gene therapy—administered directly to his liver using lipid nanoparticles—have produced extraordinary results. This novel gene editing strategy offered Nolan a highly specific way to go after the root genetic cause behind the health challenges he faced.
“This is a step towards the use of genetic editing therapies to treat a wide variety of rare genetic disorders for which there are currently no definitive medical treatments.” – Kiran Musunuru
Implications for Future Medical Treatments
Mosaic’s Kiran Musunuru articulated the hope shared by many that this technology could be used in newer medical applications. He stated, “I don’t think I’m exaggerating when I say that this is the future of medicine.” The successful treatment of KJ Muldoon represented an important milestone in the field of gene editing. This milestone paves the way for creating analogous treatments for additional rare genetic diseases.
The U.S. National Institutes of Health–funded Somatic Cell Genome Editing Consortium, to which Musunuru belongs, aims to explore gene editing for various genetic diseases. Petros Giannikopoulos, another expert in the field, highlighted the significance of the progress made at CHOP, stating, “What happened at CHOP was basically the birth of a new medical subspecialty.”
Even as scientists work to improve these practices, they struggle to scale treatments to match the size of the challenge. Giannikopoulos made clear that training practitioners around the world will be essential to implementing these therapies safely and effectively. He cautioned that if we need to reliably test safety and efficacy for each one of the tens of thousands, or perhaps hundreds of thousands, of discrete mutations, we’ll never get anywhere.
Future Challenges and Considerations
Even with the promising results like the one experienced with KJ Muldoon, industry experts agree that more progress is needed before this technology can be widely deployed. Giannikopoulos acknowledged that even with gene editing, there are limits in the technology, specifically when it comes to targeting certain organs efficiently. For instance, he said, “we’re not very good at targeting the kidney right now.”
Plus, in some cases, the need for intervention starts even before birth. Giannikopoulos commented, “For some diseases, you might need to intervene, maybe in utero, but we haven’t gotten there yet.” That’s a huge step forward and indicative of the progress we’re making in gene therapy. To design effective interventions, we need to deeply understand the biology of these diseases and how they mutate.
“You’ve also got to understand the disease well enough to be able to intervene. Because [for] some diseases, we know what the mutation is, but we don’t really understand how the mutation is causing trouble.” – Petros Giannikopoulos
Leave a Reply