Terry Horgan, the 27-year-old patient who died eight days after receiving a CRISPR therapy custom-built for him, likely suffered a fatal innate immune response to the virus used to deliver the treatment, investigators concluded.
The findings, posted late Thursday to the preprint server Medrxiv, confirmed that CRISPR, the Nobel-Prize winning genome editing tool now being used to develop treatments for a wide range of diseases, played no role in Terry’s death.
The investigation offered the first detailed analysis of a case that had spurred excitement and trepidation in the rare disease world before ending in tragedy. CRISPR and other new genetic technologies had raised hopes that researchers might be able to design custom therapies for patients’ particular mutations, even if those mutations were too rare to convince industry to invest in development.
Terry, whose family requested reporters refer to him by his first name, had been the first patient to receive a custom CRISPR drug, albeit an altered form of CRISPR that doesn’t cut DNA. It was developed by a nonprofit his brother founded, to target the particular rare form of Duchenne muscular dystrophy that ran in his family.
The investigation, led by two researchers at Yale University and two researchers at the UMass Chan School of Medicine, affirmed STAT’s reporting on the case last month. It offers a rare detailed look at one of several gene therapy deaths that have occurred in the last few years — companies sponsoring trials in which deaths occurred have rarely published full investigations — although experts will caution that it is difficult to generalize the case beyond this individual patient.
Investigators, indeed, spotlighted multiple key differences between Terry’s case and the cases of other patients who suffered severe side effects from high doses of the gene therapy virus, known as AAV.
They confirmed his death was not related to CRISPR, because he died too soon for the virus to begin even producing the gene-editing machinery. Other analyses confirmed the genome-editing tool was not active and had not triggered an immune response.
That left the virus. Although researchers use AAV to deliver genes because it is relatively benign, delivering enough to reach most of a patient’s muscle requires using high doses that can sometimes trigger serious side effects.
Unlike in a couple of earlier cases of severe gene therapy side effects, Terry did not show signs of TMA, a type of immune-mediated vascular damage, or heart inflammation. He also suffered acute respiratory distress syndrome, which investigators said had not been seen in prior gene therapy trials for Duchenne.
They found he suffered what’s known as cytokine-mediated capillary leak syndrome, in which fluid leaks out of blood vessels, damaging the heart and other organs. This syndrome, investigators said, has been seen in trials for cell therapy and gene therapy with a different, more immune-stimulating virus.
These differences, they argued, were likely specific to the patient, Terry, rather than the therapy. He appeared to suffer a more severe innate immune response than other patients who received similar or higher doses of AAV gene therapy. And he might have been less able to weather the damage to his heart and lungs because his disease was already advanced. Most Duchenne patients pass away around the age of 30 and Terry already had, the investigators wrote, “severe muscle weakness” and “low lean muscle mass of 45%.” (A healthy adult has between 70% and 90%.)
They called for more research into how patient characteristics can affect their response to AAV. And they offered a cautionary note for other groups developing custom gene therapies, where “by definition” it’s difficult to establish a safe and efficacious dose of the virus ahead of time, by first testing lower doses or by testing it first on the healthiest patients, as companies often do.
“As more applications of high-dose [AAV] gene therapy are developed the potential for such toxicities should be considered and carefully monitored among patients whose underlying disease may lessen their ability to tolerate these adverse effects,” they wrote, “especially for custom-designed gene therapy products without prior dosing in humans.”