From Pages to Practice

By Ann Cheung, MD, MBA, MS

Published November 17, 2023


Sickle cell disease (SCD) is the most common monogenic disorder caused by a point mutation in the HBB gene, which encodes β-hemoglobin. The resulting substitution of valine for glutamic acid modifies the erythrocyte morphology such that it is predisposed to polymerization and hemolysis in deoxygenated and acidotic states. Erythrocyte polymerization induces vaso-occlusion, leading to a cascade of downstream effects including ischemic tissue damage and multiorgan pathology. Complications can include cerebrovascular disease, chronic pain, acute chest syndrome, functional hyposplenism, and renal disease, resulting in reduced life expectancy in patients with SCD.

Disease-modifying therapies for patients with SCD are limited. Currently, allogeneic hematopoietic stem cell transplantation (HSCT) is the only cure. Gene editing through clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 offers the potential for another cure that bypasses some risks associated with allogeneic HSCT. In an effort to increase fetal hemoglobin (HbF) levels, which have been found to reduce complications of SCD, CRISPR-Cas9 editing has been used in the form of exagamglogene autotemcel (exa-cel) to inhibit the downregulation of HbF production by disrupting BCL11A expression. The FDA is currently reviewing exa-cel for use in patients aged 12 years and older with severe SCD.

Sharma et al. also used CRISPR-Cas9 to inhibit the fetal-to-adult hemoglobin switch in patients with severe SCD. The researchers evaluated the safety and adverse-effect profile of OTQ923, an autologous, ex vivo, CRISPR-Cas9-edited CD34+ hematopoietic stem cell product in three patients with severe homozygous SCD. The patients received autologous OTQ923 after myeloablative conditioning and were followed for 6 to 18 months. During follow up, all patients experienced successful engraftment, stable hemoglobin levels, and elevated HbF levels as a percentage of total hemoglobin and HbF cells as a percentage of total red blood cells. No off-target genetic events were observed, and more importantly, participants experienced fewer SCD-related complications.

These findings support the potential for gene editing and add to the short list of treatments for SCD. OTQ923 shows promise as a treatment that can bypass some challenges of allogeneic HSCT, which include finding a suitable HLA-matched donor and lifelong immunosuppression to avoid graft-versus-host disease. However, myeloablative conditioning is debilitating and HSCT is costly and not easily accessible. Although long-term follow-up in more patients is needed, discussions between providers and patients about gene-editing therapies for SCD will require shared decision-making to determine whether autologous HSCT is the best treatment for individual patients.

Read the following NEJM Journal Watch summary for more details of this study.

CRISPR/Cas9-Edited Gene Therapy for Sickle Cell Disease

Anjali A. Sharathkumar, MBBS, MD, MS, reviewing Sharma A et al. N Engl J Med 2023 Aug 31

Gene therapy remains an attractive option for cure of sickle cell disease (SCD), as the disease is caused by a single point mutation in the beta-globin gene. This industry-funded phase 2/3 interventional study evaluated the safety and tolerability of OTQ923 — an autologous, ex vivo, CRISPR/Cas9-edited, CD34+ cellular product — in the treatment of SCD. OTQ923 prevents the fetal-to-adult hemoglobin switch by inhibiting the interaction of transcription factors with regulatory elements in the γ-globin promoters (HBG1/HBG2) that are responsible for this switch.

Three young adults with severe SCD received standard-of-care treatment with hydroxyurea and red cell exchange prior to receiving a single infusion of OTQ923. Follow-up ranged from 6 to 18 months. The key observations were as follows:

  • Adequate hematopoietic stem cells (CD34+) could be mobilized after hydroxyurea was discontinued for 2 to 8 months prior to collection of stem cells.

  • Successful engraftment with neutrophils and platelets occurred within the same timeframe as that of genetically unmodified CD34+ selected grafts (18 to 26 days).

  • The genetically modified CD34+ cells retained normal trilineage differentiation ability.

  • During follow-up, all three patients had desired hematologic parameters:

    • Total hemoglobin levels ranged from 10.5 to 11.0 g/dL.

    • Fetal hemoglobin as a percentage of total hemoglobin ranged from 19.0% to 26.8%.

    • Fetal hemoglobin cells as a percentage of red cells ranged from 69.7% to 87.8%.

  • Adverse events were related to the stem cell transplant conditioning regimen.

  • Participants continued to have SCD-related complications, but at a lower rate, and did not require red cell transfusions.

  • No off-target genetic events were observed.

Comment: This study shows promising short-term safety, efficacy, and durability of the CRISPR/Cas9-edited gene therapy, OTQ923, for the treatment of SCD. Of note, red cell fetal hemoglobin levels were insufficient to inhibit sickle hemoglobin polymerization completely; consequently, SCD complications could not be eradicated. Considering the outcomes and risks of stem cell transplant, disease-modifying novel therapeutics (voxelotor or pyruvate kinase activator) may be more attractive options than gene therapy.

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Ann Cheung, MD, MBA, MS is a 2023–2024 NEJM Editorial Fellow. She is currently a pediatric hospitalist at Tufts Medical Center and Lowell General Hospital, where she also completed her pediatric hospital medicine fellowship training.