Gene Therapy Technology Advancing Rapidly

“Early and ongoing support from leading agencies has catalyzed progress for gene therapies,” said Alexis A. Thompson, MD, MPH, president of the American Society of Hematology (ASH) and a faculty member at the Ann and Robert H. Lurie Children’s Hospital of Chicago. But that does not mean the field is unanimous in its direction, as some recent news in the lay press on embryonic gene editing rapidly received high-level critique from most in the scientific community.

The trajectory for the development of genomic engineering has accelerated as new tools for scientific discovery are being rapidly deployed across diverse hematologic conditions. The early and ongoing support from leading research agencies, such as the National Institutes of Health (NIH), has catalyzed progress for gene-based therapies. Yet this discourse has revealed the need for clear articulation of guidelines and standards that consider the social and ethical considerations of genomic modification.

Donald Kohn, MD (UCLA Broad Stem Cell Research Center), provided an overview of the scientific evolution of gene therapy and genome editing as well as the growing clinical applications of these technologies.

Dr. Kohn’s blood stem cell gene therapy method collects some of a patient’s own blood stem cells and either adds a good copy of the defective gene or fixes the broken genes to eliminate disease-causing mutations. The patient then receives a transplant of their own corrected stem cells, which will ideally create an ongoing supply of healthy blood cells. Importantly, this method eliminates the risk of rejection associated with receiving a bone marrow transplant from a different person, meaning the patient doesn’t have to take a lifelong supply of anti-rejection drugs. Dr. Kohn’s trials for adenosine deaminase-deficient severe combined immunodeficiency (ADA-SCID), also known as bubble baby disease, a condition where babies are born without an immune system and often don’t survive past the first 2 years of life, have cured more than 50 babies to date. He is now using a similar blood stem cell gene therapy technique to overcome the genetic mutations seen in sickle cell disease.

Francis Collins, MD, PhD, director of the NIH, described how fundamental advances in our knowledge of hematologic conditions, biology of viral vectors and target cells, and the development of methods to genetically modify cells are contributing to acceleration in the field.

“It’s fair to say we are at a remarkable junction in 2018,” he said. “SCD was the first molecular disease to be described — shouldn’t it be the first molecular disease that has a gene therapy treatment?” He noted four ongoing studies that use (mostly lenticular) viral vectors to treat SCD.

“When we do find a cure, it won’t be cheap. We will need to rationalize our findings to third-party payors,” he said. “The NIH-ASH collaboration [has] the potential to move things along at a remarkable pace.”

He cited gene editing as the newest advance in gene therapies.

But he also strongly disavowed the work of Dr. He Jiankui, describing his efforts using CRISPR-Cas9 on human embryos to disable the CCR5 gene. In a public statement, Dr. Collins said, “It is profoundly unfortunate that the first apparent application of this powerful technique to the human germline has been carried out so irresponsibly.” He further called the experiment an “epic scientific misadventure” that “flout[ed] international ethical norms” and was “largely carried out in secret” with “utterly unconvincing” justifications.

Most of the current research is done ex vivo, which is not amenable to the majority of the 7,000 genetic diseases where a specific genetic cause has been identified. In short, while somatic gene editing is acceptable science, germline editing is not, he said.

George Daley, MD, PhD (Harvard Stem Cell Institute), discussed other ethical and social challenges that some of these new technologies engender, as well as essential considerations for guidance on all aspects of stem cell research and its clinical translation.

While he also discourages germline genome editing at this point, he believes the concept has potential merit if there is proper regulatory oversight and if trials can be conducted in a targeted and effective manner.

“Caution does not mean prohibition,” he said, noting that in its early stages, in vitro fertilization was also viewed skeptically. In the U.K., for example, The Nuffield Council on Bioethics says changing the DNA of a human embryo could be “morally permissible” if it is in the child’s best interest, and urges research into the safety and effectiveness of the approach.