A single dose of the investigational gene therapy LentiGlobin for sickle cell anemia restored blood cells to their normal shape and eliminated severe, painful vaso-occlusive events for 3 years in some patients, according to findings presented by John F. Tisdale, MD, of the National Institute of Health’s National Heart, Lung and Blood Institute and colleagues at 2021 American Society of Hematology (ASH) Annual Meeting. The findings were also published in The New England Journal of Medicine.

“People with sickle cell disease live in constant fear of the next pain crisis,” said coauthor Markus Y. Mapara, MD, PhD, professor of medicine at Columbia University Vagelos College of Physicians and Surgeons. “This treatment could give people with this disease their life back. We hope this therapy will also be successful in younger patients so they can grow up without experiencing pain crises and live longer.”

Sickle cell disease is caused by a mutation in the β-globin gene that leads to the production of abnormal sickle hemoglobin. LentiGlobin therapy (bb1111; lovotibeglogene autotemcel) involves autologous transplantation of hematopoietic stem and progenitor cells transduced with the BB305 lentiviral vector encoding a modified β-globin gene. The therapy allows patients to produce the antisickling hemoglobin HbAT87Q and decreases the proportion of abnormal sickle hemoglobin in the bloodstream.

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All 35 patients with sickle cell anemia who received LentiGlobin infusion in this phase 1 to 2 trial experienced engraftment. In the 24 months before enrollment, the patients experienced a median of 3.5 vaso-occlusive events per year (range, 2.0 to 13.5).

Complete resolution of severe vaso-occlusive events occurred in all 25 evaluable patients over a median follow-up of 17.3 months (range, 3.7 to 37.6). Median total hemoglobin level increased from 8.5 g/dL at baseline to 11 g/dL or more between 6 and 36 months after infusion. HbAT87Q accounted for at least 40% of total hemoglobin and was distributed across a mean of 85% (SD ±8%) of red blood cells. Markers of hemolysis were also reduced after therapy, the researchers noted.

Three patients had transient nonserious adverse events related or possibly related to gene therapy; all resolved within 1 week.

One limitation of this gene therapy is that patients’ marrow must first be conditioned with high-dose chemotherapy to eliminate old stem cells and make room for the modified stem cells, a process known as conditioning. Researchers are currently working on less toxic approaches to conditioning. “The eventual goal will be to give this treatment as early as possible, well before patients develop organ damage and other complications of sickle cell disease,” said Dr Mapara. “But before we can do this, we need to find a safer alternative to chemotherapy for conditioning strategies, such as antibodies.”

The study was funded by Bluebird Bio. Some study author(s) declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

Other Research on Sickle Cell Disease

Additional studies presented at the 2021 ASH Annual Meeting and recently published in the literature provide new insights into the cognitive impact of sickle cell disease, and recently published studies describe a mobile health tool for disease self-management in adults, sex-based differences in clinical outcomes, and systemic complications of the disease. Click on the following topics for more news:

Tisdale J, et al. Polyclonality strongly correlates with biological outcomes and is significantly increased following improvements to the phase 1/2 HGB-206 protocol and manufacturing of LentiGlobin for sickle cell disease (SCD; bb1111) gene therapy. Presented at ASH 2021; December 11-14, 2021. Abstract 561.

Kanter J, Walters MC, Krishnamurti L, et al. Biologic and clinical efficacy of LentiGlobin for sickle cell disease. N Engl J Med. 2021 Dec 12. doi:10.1056/NEJMoa2117175

Columbia University Irving Medical Center. Experimental gene therapy reverses sickle cell disease for years. December 13, 2021. Accessed December 28, 2021. https://www.cuimc.columbia.edu/news/experimental-gene-therapy-reverses-sickle-cell-disease-years