Gene Therapies for SCD, Beta Thalassemia Need Further Development Despite Promising Results

The use of gene therapy to treat beta-globinopathies, including beta thalassemia and sickle cell disease (SCD), is rapidly becoming a reality. The gene therapy Zynteglo was recently approved to treat transfusion dependent beta thalassemia, and other products are showing promising results in clinical trials for SCD.

Current gene therapies for hemoglobinopathies include two main approaches: gene addition and genome editing. In gene addition, a lentiviral vector delivers to the patient cells one or more copies of a gene or a sequence ultimately responsible for the synthesis of a therapeutic hemoglobin. In genome editing, a protein able to modify a specific DNA sequence can ultimately lead to the expression of a curative gene.

Although these approaches seem to be very effective, the clinical results so far are also teaching us that further development of these techniques is necessary. In the case of Zynteglo, several viral genomic integrations are required to successfully treat patients affected by beta thalassemia. Therefore, vectors that can express higher levels of the therapeutic gene could decrease the number of integrations and be intrinsically safer. This may also positively affect the cost of vector production, which now represents a major obstacle to the use of this drug in many countries.

In genome editing, the leading drug is based on a technology that requires a double strand DNA break in the cells of the patient. This is concerning, as it may lead to additional mutations and chromosome rearrangement that can cause cancer (chromothripsis). Advanced technologies aiming to target the genome by base editing or prime editing do not require a double strand DNA break and may eliminate or prevent these potential issues.

In each case (gene addition and genome editing), myeloablation is required before these genetically modified cells are infused into the patients. Myeloablation not only leads to infertility, but, together with the stress that the hematopoietic stem cells undergo during their selection and activation, may also result in clonal hematopoiesis and leukemia. Therefore, novel approaches to limit or modify myeloablation are extremely desirable. This will not only simplify the recovery of the patients, but also reduce clinical cost.

The ultimate and most desirable therapy, however, should completely eliminate the need for myeloablation and cell selection (presently required to modify the cells in vitro for both gene addition and genome editing). This will happen when novel technologies are able to directly deliver particles with material that will genetically modify the diseased cells in vivo. This “in vivo gene therapy” will ultimately eliminate many of the side effects associated with the current technologies, likely abate the cost of the treatment, and increase accessibility to the many patients that cannot currently afford these therapies.

Dr. Rivella is the Kwame Ohene-Frempong Chair on Sickle Cell Anemia and a professor of pediatrics at the Children's Hospital of Philadelphia, as well as a member of ASGCT.