Keeping CRISPR’s promise for patients in need
By Seth Kroll
(BOSTON) — In the not-so-distant past, CRISPR, the revolutionary gene-editing technology, was discovered as a defense system protecting bacteria against viruses. Today, with the persistence and ingenuity of many scientists, it is no longer just the subject of fascinating academic research papers and speculative discussions on its future usefulness for medicine. Early gene-editing pioneers, including George Church, Ph.D., have transformed CRISPR into the leading genome engineering technology that has helped expand the boundaries of science and been brought to bear on many medical problems.
Within the past year, three landmark developments, enabled in part by Church’s early CRISPR research, stand as testaments to the realization of CRISPR’s real-world potential to positively impact patient health.
Church is a Core Faculty member at the Wyss Institute where he leads the Synthetic Biology Platform. He is also a Professor of Genetics at Harvard Medical School and Professor of Health Sciences and Technology at Harvard and MIT.
When I started college, I hoped that as a researcher I could help improve the health of people by at least a fraction of what my father did as a physician.
Organ Transplantation: Cutting the Waitlist
In a groundbreaking procedure performed at Massachusetts General Hospital, Richard “Rick” Slayman, 62, became the first patient ever to receive an organ transplant from a pig donor. On March 16, 2024, a team of talented surgeons successfully connected a CRISPR-modified pig kidney to Slayman, who had end-stage renal failure and was no longer a candidate for a transplant from a human donor. The modified kidney was provided by Wyss startup eGenesis, which used the CRISPR-Cas9 system to genetically edit the pig’s genes to ensure the kidney was safe and compatible for human patients. Within a month, Slayman was discharged from the hospital to return home.
Kidney disease affects about 14% of U.S. adults. More than 550,000 are on dialysis and nearly 90,000 patients are currently on the national kidney transplant waitlist with fewer than 30,000 transplant procedures carried out annually. Many patients who do not receive transplants spend the remainder of their lives enduring dialysis treatment, which, although effective in cleaning blood, affects the rest of the body and can be extremely cumbersome for patients.
In 2013, Church and his team at the Wyss and HMS, alongside other researchers, demonstrated that the CRISPR-Cas9 system could be used for precise, targeted gene editing, which they immediately knew would transform genetic research and enable many medical applications.
Then, in 2015, Church and his team at the Wyss and HMS applied CRISPR-Cas9 to make 62 simultaneous edits to the pig genome to inactivate endogenous retroviral sequences. These stretches of DNA had historically prevented pig organs from being suitable for human patients. The team envisioned that their approach could usher in a future where any patient in need of an organ transplant could receive one.
In 2018, eGenesis launched from the Wyss and HMS to build on this feat in genome engineering, and further develop safe and effective pig organs as transplants for human patients. In the subsequent years, doctors from MGH, scientists from eGenesis, and Church continued to collaborate on this groundbreaking research.
Slayman’s procedure was performed under the FDA Expanded Access, or “compassionate use” protocol, which is granted for patients who have a serious or immediately life-threatening disease or condition, enabling them access to not-yet-approved treatment outside of clinical trials when no comparable therapy options are available. While additional research and data are needed before Church’s vision of eliminating organ transplant waitlists can be realized, the scientific and patient communities are charging ahead.
While recovering at home, Slayman passed away due to downstream consequences of a prolonged history of diabetes and cardiovascular disease. However, his successful transplant already is hailed as a milestone in research into xenotransplantation and serves as a beacon of hope to countless transplant patients worldwide.
Rick Slayman is now a part of history. Like Lesley & Louise Brown for IVF, they’ll forever be the pioneers.
In addition to kidneys, eGenesis is also currently developing liver and heart solutions to address the urgent needs of patients with other organ failures. In September 2024, eGenesis announced they raised $191M to advance toward its first clinical trials.
FDA-Approved: New Sickle Cell Disease Therapy
Church’s early CRISPR research ultimately led to another monumental achievement in CRISPR’s journey: the FDA’s approval of the first-ever CRISPR-based therapy, Casgevy, on December 8, 2023. Casgevy was developed by Vertex Pharmaceuticals to treat patients with sickle cell disease.
Sickle cell disease is an inherited genetic disorder that results in the production of abnormally shaped red blood cells due to mutations in the blood oxygen transport protein hemoglobin, which causes pain, anemia, risk for infections, and organ damage. It can become life-threatening, especially to young children and babies. Sickle cell disease affects about 100,000 people in the U.S., most of whom are African American, and millions of people throughout the world. Casgevy’s approval represents a historic moment in medicine and underscores the potential of CRISPR-based therapies for treating human genetic diseases, and potentially increasing health equity around the globe.
A foundational step toward the development of Casgevy was Church’s group’s validation of the CRISPR-Cas9 system for use in human cells, as well as its robustness and versatility as a genetic engineering tool.
This work, as well as additional CRISPR innovations from Church’s trainees Prashant Mali, Luhan Yang, Feng Zhang, Le Cong at the Wyss, HMS, Broad Institute and MIT, led Church and his colleagues in the CRISPR field (Jennifer Doudna, Keith Joung, David Liu, Feng Zhang) to co-found Editas Medicine in 2014 to develop CRISPR-based therapies. Editas enabled Vertex to use their version of the CRISPR-Cas9 system for Casgevy.
Being the first to receive FDA approval for a CRISPR therapeutic is a significant medical milestone, but there are other companies close behind. In addition to Editas, there are dozens of other companies fiercely working to use CRISPR to treat a broad array of genetic diseases, including Verve Therapeutics, which is also harnessing the initial CRISPR discoveries made at the Wyss, HMS, and the Broad Institute.
Looking to the Future: Treating Hereditary blindness
Inherited blindness, a leading cause of blindness worldwide, is one particularly promising application scientists are developing CRISPR-based therapies for. On May 6, results from a small yet highly promising clinical trial were published in the New England Journal of Medicine. While the trial was focused on the safety of the therapy in the first place, it showed that the CRISPR-based therapy brought measurable improvements to half of the 12 adults between the ages of 17 and 63 and two children carrying a mutation that causes retinal degeneration with a severe early onset. This was the first time any gene therapy was used to cure blindness in children, and both children were among the patients whose sight improved. Importantly, no adverse effects due to the therapy were observed in any of the patients.
The study used a CRISPR-Cas9 therapy developed by Editas and was conducted by researchers at HMS and Mass Eye and Ear. The first doses in the clinical trial were administered in 2019, which was the first time that CRISPR was used directly in patients.
The Continued Impact of CRISPR
As the early CRISPR applications are coming to fruition, from providing new solutions to organ transplantation to pioneering gene therapies for previously incurable genetic diseases, CRISPR is redefining the boundaries of medical possibility.
Patient pioneers like Richard Slayman and the brave clinical study participants for CRISPR-based therapies are just the beginning. As these technologies, and other approaches to gene editing continue to mature and expand, their broad impact on improving patient health is on the horizon.
I’ve been driven by the combination of science and engineering that results in positive societal impact. This is also core to the mission of the Wyss Institute.
The journey of CRISPR from its role in bacteria to a novel versatile instrument of modern medicine is a testament to the power of innovation, perseverance, and collaboration. As we stand on the cusp of a new era in healthcare, the incredible potential impact of CRISPR for patient health is undeniable.