Jaap-Jan Boelens, MD, PhD
Memorial Sloan Kettering Cancer Center, New York

Key Takeaways

  • Long-term data are needed to determine which gene therapy approach is more efficacious because disease severity may warrant greater therapeutic risk-taking if better SCD-reversing outcomes could be achieved.
  • Patients with SCD already have an elevated risk for blood cancers due to the nature of their disease and long-term exposure to low-dose chemotherapy as part of their treatment. Therefore, the risk of adverse effects linked to gene therapy may not be as significant as current data suggest.
  • We are already seeing the benefits of gene therapy for patients with SCD. While no single delivery method has emerged as significantly superior, patients with SCD — especially adults who meet enrollment criteria — are advised to participate in ongoing clinical trials involving gene therapy, given the great need in this population and the tremendous curative potential of this emerging treatment option.

Jaap-Jan Boelens, MD, PhD, is chief of pediatric stem cell transplantation and cellular therapies at Memorial Sloan Kettering Cancer Center in New York, New York. His clinical areas of focus include cord blood-derived cell therapies, rare pediatric blood diseases, lysosomal storage diseases, and immune reconstitution. His research focuses on using cord blood to develop advanced therapies that target blood disorders at the cellular level. His research team is also creating mathematical models that can help to predict how a young patient’s immune system will respond to these treatments. 

Why might reactivating fetal γ-globin yield superior results in reversing SCD compared with boosting β-globin production? What are advantages and disadvantages of each option?

Treatment selection here is based on safety and efficacy considerations not only in the moment but also over the long term, because both approaches could lead to myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and similar chronic adverse events. There is no data as of yet that supports that gene editing to reactivate fetal γ-globin is a safer or more efficacious than ​​lovotibeglogene autotemcel, but again, time will tell us.  
Given these considerations, one could argue that it is worth taking the slightly higher risks posed by gene therapy because without intervention, there will be devastating outcomes. In addition, the long-term safety of both approaches remains unclear in terms of later incidences of MDS and AML. Since gene therapy poses newer options for the treatment of SCD, we have follow-up periods of only a few years reported in the literature. Results of an ongoing phase 1/2 clinical trial of gene therapy using bb1111, also known as lovotibeglogene autotemcel, in adolescents and adults with SCD (ClinicalTrials.gov Identifier: NCT02140554 ) show that there were 2 cases of these 2 cancers. Importantly, previous research shown an increased risk of blood cancer among patients with SCD.1
It is still unclear whether the increased risk of blood cancer among patients with SCD receiving gene therapy is due to the treatment itself or results from exposure to low-dose chemotherapy or an inherited risk of malignancy tied to SCD. In 1 case in which a patient with SCD developed AML about 5.5 years after gene therapy, investigators evaluated possible evidence of treatment-related risk but concluded that it was not likely related to vector insertion.2 Therefore, we cannot definitely tie treatment to other adverse events. In the end, we need to see long-term results from trials of both treatment approaches and balance risks vs efficacy. If we find that performing hematopoietic stem cell transplants that boost β-globin production is safer but only reduces future pain by 50%, then it is worthwhile to use a therapy that carries higher risk but can completely eliminate SCD complications.

Lovotibeglogene autotemcel adverse effects
Adverse effects reported for lovotibeglogene autotemcel include abdominal pain, drug withdrawal syndrome, nausea, and vomiting.

How might CRISPR-Cas9 gene-editing technology reduce the risk of negative side effects associated with gene therapy for patients with SCD?

One of the major benefits of this technology is its targeted action on DNA.3 With lovotibeglogene autotemcel, the virus inserts semi-randomly and might affect an oncogene or another gene that we prefer to remain undisturbed.4 In contrast, CRISPR-Cas9 gene-editing therapy is more specific and thus, in theory, reduces the risk of unintentionally triggering cancer-inducing effects.

Among several different gene-editing approaches — specifically nonhomologous end joining, homology directed repair-mediated knock-in, and single-stranded oligonucleotides-based gene editing — which method seems to offer patients with SCD the best disease-reversing results?

We simply do not know the answer yet because we need to see short-term, intermediate, and long-term clinical trial results. At this point, I would be open to all strategies because each is now under investigation in early-stage clinical trials and supported by sound preclinical data. We hope to know in a few years which approach is best but for now, they all should get a chance unless a patient has excluding factors for a specific trial.

Considering the gene-therapy delivery methods used to treat SCD, would physical delivery, viral vectors, or nonviral agents produce the best combination of disease-reversing results with minimal side effects? Why might a clinician choose one delivery method over another? When would a combination of delivery approaches be warranted?

Again, we do not have an answer to that question because we are still waiting for long-term data. Like most clinicians, I am open to all approaches and I am eager to enroll patients in several promising trials given the great need for improved outcomes in SCD. At this stage of treatment development, the more approaches we evaluate, the better, especially those for adult patients. The goal is to form a complete picture of the risk-benefit balance for all of these techniques and to follow trial participants for at least 15 years. This is key because a technique that is superior at 5 years may ultimately be inferior at 15 years, since there could be many events later in the course of treatment that could make a particular approach less effective or more dangerous.

I am 100% sure that gene therapy will be a curative treatment for patients with SCD, but this will happen gradually; we will not get there all at once.

A recent study of an investigational gene therapy for SCD found that a single-dose gene therapy restored red blood cells to their normal shape and eliminated sickling-related complications for at least 3 years in some patients.4 Can you highlight the results of this clinical trial?

Overall, the results of this ongoing phase 1/2 trial (ClinicalTrials.gov Identifier: NCT02140554) are encouraging. While 43 patients enrolled, there were some challenges and only 35 patients received the study drug. It is not always possible to get the products to patients because many mobilize hematopoietic stem cells poorly and some production yields were low. For patients who received this one-time treatment, vaso-occlusive disease was completely resolved and hemolysis was reduced.4 Patients still had some sickle hemoglobin (HbS) after treatment but the sickle-cell-related complications resolved, so this therapy looks very promising as a potential cure. Certainly, these patients would score their quality of life as being much higher because they did not experience pain-related events or types of events that can lead to hospitalization. Now we have to ask if this treatment will be sufficient to prevent other vascular issues in the future. To answer that question, longer follow-up periods would be useful given that the median follow-up for this study was about 17.3 months.
In 5 to 8 years, several gene-editing products will likely be available in clinical practice. They might not be perfect at launch, but research and development advances will continue to improve them and yield even better outcomes. A long-term perspective is essential as the management of SCD continues to evolve.
We started with transplants for patients with SCD several decades ago. Initially, they were not perfect and were associated with high mortality rates. With advances in research, we made them safer. In the coming years, we should expect to see several licensed gene-editing products approved by the US Food and Drug Administration with reduced toxicity and greater efficacy. The benefits of gene therapy for patients with SCD are already evident and hold the promise of cure for our patients. We just need to be mindful that time, patience, and perseverance may be required to get to this point.

This Q&A was edited for clarity and length.


Jaap-Jan Boelens, MD, PhD, reported relationships with Avrobio, Inc.; BlueRock Therapeutics LP; Omeros Corporation; Race Oncology Ltd; and Sanofi US Services Inc.


1. Brunson A, Keegan THM, Bang H, Mahajan A, Paulukonis S, Wun T. Increased risk of leukemia among sickle cell disease patients in CaliforniaBlood. 2017;130(13):1597-1599. doi:10.1182/blood-2017-05-783233
2. Goyal S, Tisdale J, Schmidt M, et al. Acute myeloid leukemia case after gene therapy for sickle cell diseaseN Engl J Med. 2022;386(2):138-147. doi:10.1056/NEJMoa2109167
3. Park SH, Bao G. CRISPR/Cas9 gene editing for curing sickle cell disease. Transfus Apher Sci. 2021;60(1):103060. doi:10.1016/j.transci.2021.103060
4. Kanter J, Walters MC, Krishnamurti L, et al. Biologic and clinical efficacy of lentiglobin for sickle cell diseaseN Engl J Med. 2022;386(7):617-628. doi:10.1056/NEJMoa2117175

Posted by Haymarket’s Clinical Content Hub. The editorial staff of Rare Disease Advisor had no role in this content’s preparation.

Reviewed September 2022