Gene Therapy: The Comeback Kid of Hematology Treatments?

Despite slow progress and unexpected setbacks, the future of gene therapy remains bright.

Ashanthi de Silva was the first human to be treated successfully with gene therapy. At the time, in 1990, she was a 4-year-old living with severe combined immunodeficiency (SCID), which is caused by insufficient levels of the enzyme adenosine deaminase (ADA). Without treatment, patients rarely survive toddlerhood. In addition to hematopoietic cell transplantation, standard treatment at that time consisted of lifelong replacement with synthetic ADA given via intramuscular injections once or twice weekly. However, few patients achieve full immune reconstitution and improvements in immune function can wane in just a few years with enzyme replacement therapy. Turning to a cutting-edge treatment, scientists were able to deliver to Ashanthi a healthy version of the gene that produces ADA using a viral vector. She is still alive today.1

Some early trial participants who came after her did not fare as well. Patients with a similar disease (SCID-X1) received a comparable gene therapy in the late 1990s. The trial seemed successful, until five of the 20 patients developed leukemia. It turned out that the viral vector that delivered the gene to their T cells also had activated an oncogene. Around the same time, Jesse Gelsinger, an 18-year-old with the rare metabolic disorder ornithine transcarbamylase deficiency syndrome, volunteered to be the 18th patient injected with an adenovirus that carried a normal ornithine transcarbamylase gene to treat his disease. He developed a blood clotting disorder almost immediately and inflammation shut down several of his organs. Within four days, he was declared brain dead.1

“We were all very much aware of what happened there and what a tragedy that was,” commented Jennifer Doudna, PhD, who won the Nobel Prize in Chemistry in 2020 for her discovery of the CRISPR gene-editing tool.2 “That made the whole field of gene therapy go away, mostly, for at least a decade. Even the term gene therapy became kind of a black label. You didn’t want that in your grants. You didn’t want to say, ‘I’m a gene therapist’ or ‘I’m working on gene therapy.’ It sounded terrible.”

The progress being made by gene therapy researchers came to a screeching halt.

It took years, but researchers have now developed a variety of new gene therapy techniques, several of which have been brought to clinical trial.

“The progress that we’re seeing in the field is a testament to the investment in basic science research that preceded the clinical applications by many years,” said David Williams, MD, 2015 American Society of Hematology (ASH) President and a pediatric hematologist at Boston Children’s Hospital and Harvard Medical School whose research focuses on gene transfer methods.

However, there have been some recent setbacks for scientists testing gene therapies to treat hematologic malignancies and other blood disorders. In February 2021, trials of bluebird bio’s LentiGlobin gene therapy product for patients with sickle cell disease were paused after two patients developed serious illnesses, acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). The pharmaceutical company’s investigation has so far shown no link between cancer and the vector, but, as of mid-April, the trials have not resumed.3

While these data suggest that the vector was not causative, “it is very important that this be investigated thoroughly, to better understand the cause of those complications that have happened years after therapy,” said Haydar Frangoul, MD, a pediatric hematologist at Tristar Medical Group in Nashville, Tennessee.

ASH Clinical News spoke with Drs. Williams, Frangoul, and other experts in the field who expressed optimism about the future of gene therapy, despite relatively slow progress and new obstacles.

Types of Gene Therapies

All gene therapies are categorized as either in vivo or ex vivo. When gene therapy is in vivo, scientists use an inactivated virus or other vector to deliver a healthy gene to replace an abnormal gene on targeted cells that remain in a person’s body. With ex vivo gene therapies, scientists remove cells from the body, genetically alter them in the lab, then infuse them back into the patient. The four U.S. Food and Drug Administration (FDA)–approved chimeric antigen receptor (CAR) T-cell therapies used to treat myeloma and certain types of lymphoma and leukemia are examples of ex vivo gene therapy: A patient’s own T cells are extracted, altered so that they are better able to recognize and attack cancer cells, then infused back into his or her body.

There are a variety of techniques within those two overarching categories. To deliver a healthy gene or inactivate an unhealthy one in vivo, researchers can use adenoviruses, adeno-associated viruses (AAV), or lentiviruses. Each of these viruses is engineered so that it will not harm the person receiving it, while delivering genes to certain cells in organs of interest. The biggest challenge of in vivo gene therapy is ensuring that enough cells receive the gene and that very few nontargeted cells are affected.

Scientists can use these same viruses and several other techniques to alter cells genetically in the lab before infusing them into patients. CRISPR-Cas 9, a gene-editing technique that repurposes a natural phenomenon that bacteria use to cut viral RNA out of their genomes, took off in the early 2010s. Another genome-editing tool uses zinc finger nucleases similarly to CRISPR-Cas 9. The enzymes can be designed to target specific DNA sequences, which they cut, forcing the DNA to repair itself.

Researchers also can design tiny pieces of RNA that bind to specific DNA sequences and interfere with the function genes, silencing or otherwise modulating them in a technique called RNA interference. Lastly, they can use electroporation or even a “gene gun” that uses physical force to insert DNA into a cell.

While most ex vivo techniques alter and return a patient’s own cells, some researchers are working on off-the-shelf therapies. Using cells from a donor would eliminate the delays and expense associated with removing a patient’s T cells, altering them in a centralized lab, and then reintroducing them to the patient. If cells could be engineered to deliver a healthy gene without triggering an immune response, they could be thawed and given to the patient, significantly shortening the lengthy manufacturing process.

Successes and Setbacks

Despite years of research devoted to ex vivo strategies field, only a handful of gene therapies have received FDA approval, though many more have entered clinical trials. The first two gene therapies to gain FDA approval in 2017 were tisagenlecleucel, a CAR T-cell therapy for patients with B-cell precursor acute lymphocytic leukemia whose disease had not responded well to other treatments, followed by voretigene neparvovec for certain inherited retinal diseases. The latter therapy is an in vivo treatment which uses a viral vector to edit genes within a patient’s eye.5

One of the biggest gains in the field came in the spring of 2019, when the FDA approved onasemnogene abeparvovec, a drug to treat children under age two with spinal muscular atrophy. The progressive and debilitative disease starts in childhood and results from a single genetic mutation. The treatment uses an AAV to deliver a healthy gene through the bloodstream.6

In the world of hematology, several therapies have made it to late-stage trials for genetic diseases including hemophilia, beta thalassemia, and sickle cell disease (SCD).

“From the standpoint of developing an ex vivo gene therapy, the hemoglobinopathies are now front and center, followed by beta thalassemia,” said Dr. Williams. Next are the in vivo therapies for hemophilia. Given the strides made in the past few years, he considers hemophilia a success story. “Patients who have been on lifelong factor IX replacement therapy have received gene therapy that corrects their factor deficiency,” he said. “They are now living their lives without bleeds.”

At the 2020 ASH Annual Meeting, Dr. Frangoul and his team reported preliminary data on the CRISPR/Cas9-based gene editing platform CTX001 for the treatment of patients with SCD and beta thalassemia.7 “Although the numbers are small, the effects are more uniform and lasting,” he commented. The trial enrolled 10 patients with SCD and two with beta thalassemia. One participant with SCD had received treatment for 18 months before the presentation and her average number of vaso-occlusive crises or hospitalizations had been drastically reduced (from 7 in the year prior to 0 since treatment).

However, even gene therapies that were expected to gain regulatory approval stumbled on their way to the finish line. BioMarin submitted a biologics license application for valoctocogene roxaparvovec in December 2019, supported by three years of data from phase I/II trials and interim data from a phase III trial. The company expected the AAV gene therapy for hemophilia A to be approved in late 2020. Instead, the FDA sent BioMarin a Complete Response Letter (CRL) requesting two additional years of safety and efficacy data from the ongoing phase III trial.8

The agency cited differences between the phase I/II and phase III study in its decision, concluding that it could not rely on the earlier-phase data to support durability of effect. In early trials, the therapy appeared to decrease patients’ need for infusions, but the effects seemed to taper off after about a year. The FDA was concerned that the therapy might not be long lasting.

“The Agency first informed the Company of this recommendation in the CRL having not raised this at any time during development or review,” BioMarin noted in a press release announcing the decision.

To meet the FDA’s demands, BioMarin will need to complete the phase III study, which was fully enrolled with 134 patients in November 2019. The last patient will complete two years of follow-up in November 2021, pushing the earliest FDA approval date to 2022.

Researchers are still learning how gene editing techniques can affect patients in the long term. While the approaches can be extremely precise, they are not perfect. Both ex vivo and in vivo techniques can have “off-target” effects, where they influence cells they were not intended to edit. For example, if DNA is inserted close to genes that regulate cell growth, the new DNA may interfere with the regulation, causing the patient to develop tumors.

News of the temporary suspension of trials of bluebird bio’s LentiGlobin products in February 2021 reverberated through the gene therapy field. In addition to halting research, the company also paused sales of the ex vivo gene therapy in the European Union, where the treatment is already approved for beta thalassemia.

At the time of the announcement, patient dosing had just begun in the phase III HGB-210 trial, which enrolled patients with SCD between the ages of 2 and 50. The participant who was diagnosed with AML was enrolled in the phase I/II HGB-206 trial and had received the one-time treatment in 2015. The FDA classified the diagnosis as a Suspected Unexpected Serious Adverse Reaction, meaning there is a “reasonable possibility” that LentiGlobin caused the patient to develop AML.9

The patient who developed MDS was enrolled in a separate group of HGB-206 and received a LentiGlobin therapy manufactured using a process designed to increase vector copy number and derived from stem cells collected from peripheral blood after mobilization with plerixafor.

Following these developments, the FDA also halted a separate trial that was testing a similar treatment using disabled lentivirus to deliver a gene in patients with SCD.10 Researchers, including Dr. Williams as the principal investigator, had recently reported positive results from the study’s first six pediatric patients in the New England Journal of Medicine.10 The treatment, which uses lentiviral vectors to deliver RNA that can silence the BCL11A gene to treat patients with SCD, demonstrated safety and efficacy lasting an average of at least 18 months.

Bluebird bio launched an investigation into the possible link between LentiGlobin therapy and the malignancies. The patient who was reported to have developed MDS after treatment with LentiGlobin may have been prematurely diagnosed, said Philip Gregory, DPhil, chief scientific officer at bluebird bio. The company was unable to find any cancer cells in the patient’s bone marrow. In addition, the patient diagnosed with AML was found to carry genetic mutations associated with the disease.11

“[Bluebird bio] reported that they identified the gene where the vector was sitting in these leukemic cells and it did not seem to be in a gene that anybody could figure out had any connection to cancer,” explained Cynthia Dunbar, MD, ASH Secretary and chief of the Translational Stem Cell Biology Branch within the Intramural Research Program of the National Heart, Lung, and Blood Institute at the National Institutes of Health (NIH). “It is not a gene that has ever been identified as an oncogene in naturally-occurring tumors.” Nevertheless, the company is continuing to study whether the treatment could be otherwise connected to the disease process.

Teams from both bluebird bio and Boston Children’s Hospital have requested permission from the FDA and NIH to restart their trials.

Despite these setbacks, the researchers who spoke with ASH Clinical News remained optimistic about the direction gene therapy is headed, but they did share one concern about the LentiGlobin news: It could discourage patient participation in future studies.

“The sickle cell community and the beta thalassemia community, especially in the era of social media, are very well connected,” said Dr. Frangoul. “So, a complication like this in a gene therapy trial definitely can affect how current and potential participants in those clinical trials will perceive gene therapy research in the future.”

Dr. Dunbar echoed these concerns, and noted that initiatives such as the ASH Research Collaborative Sickle Cell Disease Clinical Trials Network will play a critical role in educating community and patient organizations about what gene therapies are and what happened in the trial. (See the SIDEBAR for more information about this initiative.) “They are complicated to understand and to explain, even to people who are hematologists,” she said.

Rules and Regulations

Our ability to edit the human genome has raised ethical concerns, ranging from moral objections to scientists “playing God” to anxieties about the field moving too quickly to avoid unintended side effects, such as malignancies.

In 2018, much to the consternation of the global scientific community, Chinese researcher He Jiankui, PhD, used CRISPR to genetically alter the embryos of twin girls to reduce their risk of contracting HIV.12 Researchers later found that the gene did more than modulate this risk. The version of the gene that he delivered is associated with a likelihood of dying two years younger than average. The scientist was fired, and the World Health Organization and other organizations called for a global halt to gene editing.13 Michael Deem, PhD, a professor of biochemical and genetic engineering at Rice University in Texas, also came under fire for his role in the controversial project.

In 1974, decades before gene editing became a reality, the NIH had the foresight to create the Recombinant DNA Advisory Committee (RAC), which was tasked with providing recommendations regarding safety and ethical issues in basic and clinical research involving recombinant or synthetic nucleic acid molecules.14

Former RAC member Mildred Cho, PhD, associate director at the Stanford Center for Biomedical Ethics, said the group “provided a layer of additional expertise that could take an in-depth look at the data being generated, data from previous trials, and trial protocols looking at adverse effects, then apply that knowledge to new trials.”

The RAC included basic scientists, physicians, ethicists, theologians, and patient advocates. The first RAC-approved gene therapy trial began in September 1990 – the trial in which Ashanthi de Silva was treated. To assure transparency and adherence to safety guidelines, the group opened public comment periods on trials under review.

In 2019, following concerns over redundancies with the FDA’s role in regulating drug development, the group was refocused into a role closer to its original mandate and renamed the Novel and Exceptional Technology and Research Advisory Committee (NExTRAC).

“Although this motion comes at a time when ample oversight from institutional review boards and the FDA is in place, we cannot discount the timely action of the pioneering scientists who proactively tackled the inevitable controversies in the field,” commented James Wilson, MD, PhD, director of the Gene Therapy Program and a professor of medicine and pediatrics at the University of Pennsylvania’s Perelman School of Medicine.15 “While not everyone agreed with recombinant DNA research, their actions meant no one could accuse the community of conducting clandestine experiments.”

The approval process for gene therapies is now essentially the same as that for other drugs and devices. However, the FDA’s decision to reject valoctocogene roxaparvovec’s application points to a possible shift in the approval process for one-and-done gene therapies. The rejection could signal that the FDA is taking a more conservative stance on gene therapy at large. Given that gene therapies have irreversible effects, the agency might request more data over a longer period before considering approval.

The regulatory future for these treatments may be uncertain, but gene therapy researchers are ready to meet the requirements.

“These trials are very heavily regulated by the FDA. The FDA may require 15 years of follow-up to assess long-term efficacy, as well as toxicity,” said Dr. Frangoul.

“We don’t take conducting these trials lightly.” —By Emma Yasinski


  1. Boston Children’s Hospital. After decades of evolution, gene therapy arrives. December 22, 2020. Accessed April 6, 2021.
  2. Science History Institute. The Death of Jesse Gelsinger, 20 Years Later. June 4, 2019. Accessed April 6, 2021.
  3. Bluebird bio. bluebird bio Announces Temporary Suspension on Phase 1/2 and Phase 3 Studies of LentiGlobin Gene Therapy for Sickle Cell Disease (bb1111). February 16, 2021. Accessed April 6, 2021.
  4. U.S. Food and Drug Administration. FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine release syndrome. Updated September 7, 2017. Accessed April 6, 2021.
  5. U.S. Food and Drug Administration. LUXTURNA. Updated July 26, 2018. Accessed April 6, 2021.
  6. U.S. Food and Drug Administration. FDA approves innovative gene therapy to treat pediatric patients with spinal muscular atrophy, a rare disease and leading genetic cause of infant mortality. May 24, 2019. Accessed April 5, 2021.
  7. Frangoul H, Bobruff Y, Cappellini MD, et al. Safety and Efficacy of CTX001 in Patients with Transfusion-Dependent β-Thalassemia and Sickle Cell Disease: Early Results from the Climb THAL-111 and Climb SCD-121 Studies of Autologous CRISPR-CAS9–Modified CD34+ Hematopoietic Stem and Progenitor Cells. Abstract 4. Presented at the 2020 American Society of Hematology Annual Meeting; December 6, 2020.
  8. BioMarin press release. BioMarin receives Complete Response Letter (CRL) from FDA for valoctocogene roxaparvovec gene therapy for severe hemophilia A. August 19, 2020. Accessed April 6, 2021.
  9. STAT. Bluebird suspends sickle cell gene therapy studies after cancer diagnoses. February 16, 2021. Accessed April 8, 2021.
  10. Esrick EB, Lehmann LE, Biffi A, et al. Post-transcriptional Genetic Silencing of BCL11A to Treat Sickle Cell Disease. New Engl J Med. 2021;384(3):205-215.
  11. The New York Times. Sickle Cell Treatment Not Linked to Cancer, Researchers Say. March 10, 2021. Accessed April 8, 2021.
  12. Associated Press. 1 year later, mystery surrounds China’s gene-edited babies. November 26, 2019. Accessed April 11, 2021.
  13. Scientific American. Genetic Mutation in “CRISPR Babies” May Shorten Life Span. June 3, 2019. Accessed April 11, 2021.
  14. National Institutes of Health. Recombinant DNA Advisory Committee Archives. Accessed April 11, 2021.
  15. Wilson JM. The RAC Retires after a Job Well Done. Genetic Engineering & Biotechnology News. 2019;39(1).

The ASH Research Collaborative Sickle Cell Disease (SCD) Clinical Trials Network was launched with a mission of improving outcomes for individuals with SCD by expediting the development of treatments and facilitating innovation in clinical trial research.

With more than 110 participating sites, the Network is an unprecedented national effort to streamline operations and facilitate data sharing to expedite the development of new treatments for this rare disease.

The Network aims to promote quality, participant safety, and efficiency in SCD clinical trials by centralizing contracting and institutional review board oversight, sharing best practices, and ensuring a network of research-ready institutions.

For more information about this initiative, visit