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What Does the Future Hold for Gene Therapy in Nonmalignant Hematology?

December 30, 2021

The human genome contains about 25,000 genes that encode myriad proteins that drive the processes necessary for life. But disruptions, deletions, and mutations can happen, manifesting as diseases and conditions that can be life-depleting or devastating. Gene therapies to "fix" these errors are coming to clinics worldwide at steady clip – and with eye-watering price tags.

Excitement over these potentially curative options has grown exponentially in recent years. The list of inherited nonmalignant hematologic diseases for which gene therapy cures are being developed include the hemophilias, sickle cell disease (SCD), beta-thalassemia, and Fanconi anemia, among others.

"Gene therapy is an exciting opportunity that I think is absolutely groundbreaking, but it should be treated as just one option integrated into a comprehensive care program, rather than approaching it as ‘Oh, we really can't deliver proper care for these patients, so let's just give them gene therapy, cautioned Elliott Vichinsky, MD, the director of hematology/oncology at UCSF Benioff Children's Hospital in Oakland, California.

The unmet need in all these conditions is consistent: For most nonmalignant hematologic diseases there are treatments available to relieve symptoms and stanch bleeding, but none cure or prevent the genetic errors, and the attendant side effects, costs, and morbidity are daunting.

ASH Clinical News spoke with Dr. Vichinsky and others about the up-and-coming gene therapies for nonmalignant hematologic diseases, asking for their opinions on the therapies most likely to land in the clinic in the near future.

Inside and Outside Approaches

There are two broad approaches being considered to introduce gene therapy "fixes" for nonmalignant hematologic conditions. The first approach involves directly introducing the nucleic acid sequences into the target tissue in vivo. This requires a delivery vehicle – a vector – to transport the therapeutic gene to the host cell and transcribe or translate the genetic payload.

The second approach sees the gene of interest introduced to ex vivo cells (either allogeneic or autologous) in culture, followed by expansion of desired cells, and introduction into the host.

For the hemophilias, hereditary lack of coagulation factors is targeted with engineered recombinant adeno-associated virus vectors carrying functional factor VIII (FVIII) and factor IX (FIX) genes to replace the defective genes. Both in vivo and ex vivo approaches have been considered. Currently, the therapies in advanced development all use a recombinant adeno-associated virus vector to deliver the coagulation factor gene to a patient's liver.

Clinical data shows normalization of factor levels in some patients with improvements in bleeding and quality of life, with toxicities limited to transient elevations in liver enzymes. There are several phase III trials currently recruiting patients or following treated patients. Leading hemophilia gene therapy candidates include:

  • BioMarin Pharmaceuticals' valoctocogene roxaparvovec to treat FVIII deficiency
  • Spark Therapeutics' SPK-8011 to treat FVIII deficiency
  • Pfizer's fidanacogene elaparvovec to treat FIX deficiency
  • UniQure's AMT-061 to treat FIX deficiency

A roundup of recent news shows that the race is on to be the first gene therapy entrant in the global hemophilia market. Despite questions about the long-term durability of their product, BioMarin has announced plans to submit valoctocogene roxaparvovec for regulatory review before the end of 2019, while Pfizer has revealed plans to invest an additional $500 million in its gene therapy production facility. Spark Therapeutics, the one company in this space that has already received regulatory approval for a gene therapy product (voretigene neparvovec), has been slowed by issues related to Roche's $4.3 billion bid to acquire the company.

Fanconi anemia is a rare monogenic blood disorder characterized by accelerated decline in hematopoietic stem cells (HSCs). Long-term treatment requires successful bone marrow transplant, which is limited by the availability of a matched donor. A gene therapy that corrects the patient's own HSCs would be an important advance, according to Pamela Becker, MD, PhD, from the Institute for Stem Cell and Regenerative Medicine at the University of Washington and Fred Hutchinson Cancer Research Center.

Dr. Becker has been working on gene therapy for Fanconi anemia for many years now. The work has faced a host of issues, from isolating stem cells that express CD34 to ensuring engraftment of the gene-modified cells and long-term expression. One hurdle is the fear that "clearing out space" for the gene-modified cells using a conditioning regimen might leave patients vulnerable to secondary malignancies.

"Our original protocol included cyclophosphamide preparation before gene-modified cell infusion, but the NIH's Recombinant DNA Advisory Committee recommended against this because of the concern over secondary malignancy," Dr. Becker said. "Without this, we unfortunately had an issue with long-term engraftment."

While her group and others have worked steadily on optimizing procedures for transducing HSCs and perfecting gene-editing techniques to correct CD34-positive cells isolated from patients, alternative procedures appear promising.

"One group in Madrid has successfully transferred the gene, similar to the way we did with a lentiviral vector, into much younger children," Dr. Becker explained.1 "They harvested stem cells in young children with Fanconi anemia and saved them for later when the children became symptomatic, then infused them back. That method worked, although it takes a long time to see an effect."

The scientific and clinical barriers are formidable and highlight the wide variability of technology and techniques needed to find workable gene therapies for different hematologic disorders.

"In Fanconi anemia, we need hematopoietic stem cells that differentiate into all the blood cells so we can correct the neutropenia, anemia, and thrombocytopenia," she continued. "So, we're actually trying to provide the full-length, normal gene to create functionally corrected cells." This is different from approaches in hemophilia, she said, "where investigators are trying to introduce a copy of the gene that encodes for the coagulation factor and have that flow through the bloodstream, such that patients will produce their own clotting factor, as opposed to creating corrected cells."

In SCD, yet another approach is being considered: gene knockout. "They silence the BCL11A gene that switches off fetal hemoglobin,2 which is unaffected by the sickling mutation," Dr. Becker said. "Doing this has been shown to reverse the symptoms of sickle cell disease."

Gene Therapy for Hemoglobinopathies

Beta-thalassemia and SCD are the two most common inherited hemoglobinopathies worldwide. These disorders are caused by mutations in the B-globin gene locus, which results in production of insufficient amounts of or abnormal globin protein. Several advances have enabled gene therapy progress in these conditions, including the discovery of the B-globin locus control region and several transcription factors, which determine hemoglobin switching.3

Beta-thalassemia, an inherited anemia characterized by defective or absent production of the ß chains of hemoglobin, can require lifelong transfusions of donor red blood cells, but even this does not correct ineffective erythropoiesis, and accumulation of systemic iron requires intense iron chelation therapy. While hematopoietic cell transplantation can cure the disease, that option is not available to all patients.

Transfusion-dependent beta-thalassemia was an early candidate for gene therapy. Proof-of-principle studies reported a decade ago used beta globin–expressing lentivirus. These led to larger trials, including one reported in the New England Journal of Medicine in 2018 demonstrating success with LentiGlobin gene therapy.4 In the study, 22 patients with transfusion-dependent beta-thalassemia received gene therapy with autologous CD34-positive cells transduced ex vivo with a beta globin–containing lentiviral vector, which encodes adult hemoglobin with a T87Q amino acid substitution.

After a median of 26 months, all but one of 13 patients who had a non-β0/β0 genotype became transfusion independent. In the remaining nine patients with a β0/β0 genotype, or two copies of the IVS1-110 mutation, the median annualized transfusion volume was decreased by 73%. Three patients discontinued transfusions. Treatment-related adverse events were similar to those seen with autologous hematopoietic cell transplantation.

In a big win for gene therapy, this product, dubbed Zynteglo by its manufacturer Bluebird Bio, received E.U. regulatory approval in June 2019. Approval from the U.S. Food and Drug Administration is expected in 2020. Bluebird is currently working to get Zynteglo treatment centers in Europe up and running, but the effort is being stymied by the therapy's price tag of €1.575 million.

The success seen in beta-thalassemia motivated efforts to extend the therapy to SCD, an autosomal recessive condition resulting from a single base substitution in the beta-globin gene.

Sickle cell affects minority people who may be underinsured or face enormous health care system disparities, according to Dr. Vichinsky, who is also director of the Northern California Sickle Cell and Thalassemia Centers. "When sickle cell patients don't get comprehensive care, they start having proteinuria and renal disease, and if they're not treated for that, they go into renal failure. They also have other issues, including strokes, and are not given transfusions or hydroxyurea or echocardiograms for pulmonary hypertension."

Lentiviral vectors also are popular in the development of gene therapies for SCD, in part because of the vectors' large transgene capacity, stable expression, and safe integration. To date, lentiviral vectors have been successfully used in more than 200 patients with 10 different hematologic disorders.5 Several phase I/II studies are ongoing, along with a few phase III studies.

One exciting approach, a collaboration between Vertex Pharmaceuticals and CRISPR Therapeutics, involves autologous CD34-positive hematopoietic stem and progenitor cells modified using CRISPR/Cas9 to disable BCL11A activity. Earlier this year, it was reported that a 34-year-old American woman had received these CRISPR-modified autologous cells.6

One study Dr. Vichinsky would like to see before gene therapy for SCD hits the clinic is an outcomes trial that directly compares outcomes of patients given evidence-based comprehensive care with those who undergo either allogeneic hematopoietic transplantation or autologous gene-modified treatment.

"Currently, we don't have good long-term data to show that if patients are given comprehensive care, their survival rates aren't better than with transplant," he said. "Of the data we have, the overall survival rates between transplant and chronic transfusion are no different."

Paying for Progress

The high sticker price of gene therapy products incite desperation and anger in patients, clinicians, and politicians alike. They are also a prime testing ground for novel payment models. The pricing model, from the perspective of the pharma companies, is simple: These one-time curative therapies cost more upfront but save payers in the long term by avoiding life-long expenditures.

In the case of Zynteglo for beta-thalassemia, Bluebird Bio has proposed a new installment-based and outcomes-based model, wherein 80% of the therapy's cost will be dependent on performance over a period of up to five years. With a price tag of €1.575 million (about $1.7 million), the treatment will cost about €315,000 per year for five years, but the last four payments will be canceled if the patient does not remain transfusion independent.

All the gene therapies discussed here are for the treatment of relatively rare diseases, with limited patient populations who are appropriate for these therapies. Where the therapy will really gain momentum is with gene therapy for hemophilia, for which the number of patients is far greater than with beta-thalassemia or Fanconi anemia.

An estimated 20,000 individuals in the U.S. have hemophilia, and hemophilia A is about four times more common than hemophilia B. The worldwide incidence of hemophilia is unknown but is estimated at more than 400,000 people.7

Gene therapies for hemophilia are expected to be priced near $1 million, a number tempered by the high cost (~$300,000 yearly) of prophylactic factor replacement therapy.8

And then there is the issue of precedent. If the first gene therapies are priced exorbitantly, the next generations of drugs are likely to be priced in the same range or even higher. â€”By Debra L. Beck


  1. Rio P, Navarro S, Bueren JA. Advances in gene therapy for Fanconi anemia. Hum Gene Ther. 2018;29:1114-23.
  2. EB, Brendel C, Manis JP, et al. Flipping the switch: initial results of genetic targeting of the fetal to adult globin switch in sickle cell patients. Abstract #203. Presented at the 2018 ASH Annual Meeting, December 3, 2018; San Diego, CA.
  3. Ikawa Y, Miccio A, Magrin E, et al. Gene therapy of hemoglobinopathies: progress and future challenges. Hum Mol Genet. 2019 July 29. [Epub ahead of print]
  4. Thompson AA, Walters MC, Kwiatkowski J, et al. Gene therapy in patients with transfusion-dependent β-thalassemia. N Engl J Med. 2018;378:1479-93.
  5. Cavazzana M, Bushman FD, Miccio A, et al. Gene therapy targeting haematopoietic stem cells for inherited diseases: progress and challenges. Nat Rev Drug Discov. 2019;18:447-62.
  6. Scientific American. Despite controversy, human studies of CRISPR move forward in the U.S. Accessed September 10, 2019, from
  7. National Hemophilia Foundation. Fast facts about bleeding disorders. Accessed September 6, 2018, from
  8. Chen SL. Economic costs of hemophilia and the impact of prophylactic treatment on patient management. Am J Manag Care. 2016;22:s126-33.


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