Bivalent Lentiviral-Based Gene Therapy Might Decrease Costs in Sickle Cell Disease

The results of a recently published study in Molecular Therapy: Methods & Clinical Development describe a new bivalent lentiviral-based gene therapy approach for sickle cell disease (SCD).¹ Theoretically, such an approach might ultimately decrease costs of production of SCD gene therapies, potentially improving access to these life-changing treatments.

With the recent approvals of two gene products for SCD, autologous hematopoietic cell transplantation with gene therapy is poised to dramatically transform outcomes for patients. However, the costs of these therapies are high, estimated at $1 million to $3 million, a sum that includes both extensive medical costs from myeloablative transplant and production costs of the specific gene-therapy product and incorporating it into patients’ blood stem cells.¹

Exagamglogene autotemcel (exa-cel) uses the genome-editing technology CRISPR/Cas9 to interrupt the BCL11A gene, ultimately resulting in increased production of gamma globulin and fetal hemoglobin.² In contrast, lovotibeglogene autotemcel (lovo-cel) uses a lentiviral-vector approach to produce an adult-type hemoglobin with anti-sickling characteristics.³ Both approaches require the production of a relatively large amount of gene therapy product for effective results.

Donald B. Kohn, MD, is a pediatric bone marrow transplant physician and a professor of pediatrics and microbiology, immunology, and molecular genetics at the University of California, Los Angeles (UCLA); graduate researcher Kevyn L. Hart, also at UCLA, is first author of the paper. Working with other colleagues, they developed the new bifunctional lentiviral vector.¹

Dr. Kohn said that making viral vectors using globin has been challenging for the industry because the gene is very large and includes many regulatory elements. Larger vectors result in decreased titers, as well as decreased infectivity into the patient’s stem cells. All of this contributes to increased costs of production.

“One of our goals was to decrease the size of our lentiviral vector, increasing the titer and also increasing gene transfer,” Ms. Hart, who is a PhD candidate, said. “By doing that, we might be able to treat more patients per batch of virus that’s produced, bringing down the price per patient.”

Dr. Kohn pointed out a drawback in the approach of decreasing the lentiviral vector size. In so doing, they lost some regulatory elements of the gene, somewhat decreasing the gene expression per vector copy, but their overall approach compensates for this effect. Dr. Kohn noted that their lentiviral vector introduced a version of an anti-​sickling mutation that might be more potent than that found in lovo-cel, based on their differing structures.⁴

Additionally, David A. Williams, MD, co-first author Boya Liu, PhD, and other colleagues at Boston Children’s Hospital at Harvard Medical School added another element — two microRNA-​adapted short hairpin RNAs (shmiRs). These target two genes involved in the production of fetal hemoglobin: BCL11A (also targeted in exa-cel) and ZNF410. The former increased fetal hemoglobin by about 30% in clinical trials, and adding the ZNF410 shmiR may increase fetal hemoglobin by an additional 10%.^5,6

Researchers in the current study explored multiple vector possibilities, but the version with these two shmiRs and the anti-sickling mutation produced the best results. Using hematopoietic stem and progenitor cells from human SCD donors modified with the vector, they found that all hematologic parameters improved compared to controls, with significant reduction in the sickling of red blood cells produced in vitro.

Using the Berkely mouse SCD model, they also found that the vector ameliorated SCD features. It induced a high level of anti-sickling hemoglobin with significant improvements in hematocrit and reticulocyte percentages, as well as a 30% increase in the expression of anti-sickling hemoglobin per number of vector copies.¹

The early stage of these investigations is an inherent limitation of the results, and further studies would be needed before the approach could reach the clinic. However, the gene therapy space is quite competitive, Ms. Hart said; in addition to the two approved products, multiple additional gene therapy approaches are under development. These include base-editing approaches and even in vivo approaches that might one day deliver gene therapies directly without necessitating removal of patients’ stem cells.

“I think if this project can get funding, it would be a really good lentiviral vector because right now it has potentially the best efficacy of any SCD gene therapy product in the market,” Ms. Hart said.

Any conflicts of interest declared by the authors can be found in the original article.

References

1. Hart KL, Liu B, Brown D, et al. A novel high-titer, bifunctional lentiviral vector for autologous hematopoietic stem cell gene therapy of sickle cell disease. Mol Ther Methods Clin Dev. 2024;32(2):101254.
2. Frangoul H, Locatelli F, Sharma A, et al. Exagamglogene autotemcel for severe sickle cell disease. N Engl J Med. 2024;390(18):1649-1662.
3. Kanter J, Thompson AA, Pierciey FJ Jr, et al. Lovo-cel gene therapy for sickle cell disease: treatment process evolution and outcomes in the initial groups of the HGB-206 study. Am J Hematol. 2023;98(1):11-22.
4. Levasseur DN, Ryan TM, Pawlik KM, et al. Correction of a mouse model of sickle cell disease: lentiviral/antisickling beta-globin gene transduction of unmobilized, purified hematopoietic stem cells. Blood. 2003;102(13):4312-4319.
5. Liu B, Brendel C, Vinjamur DS, et al. Development of a double shmiR lentivirus effectively targeting both BCL11A and ZNF410 for enhanced induction of fetal hemoglobin to treat β-hemoglobinopathies. Mol Ther. 2022;30(8):2693-2708.
6. Esrick EB, Lehmann LE, Biffi A, et al. Post-transcriptional genetic silencing of BCL11A to treat sickle cell disease. N Engl J Med. 2021;384(3):205-215.