The Year’s Best in Sickle Cell Disease

It is ironic to talk about the “best” of 2020 — a truly rotten year. However, the emergence of gene therapy as a treatment for sickle cell disease (SCD) may be a bright spot. Prior to 2018, there was only one U.S. Food and Drug Administration (FDA) –approved drug (hydroxyurea) for the treatment of SCD. The potential for a one-time treatment for SCD has brought with it a new hope for cure for many affected individuals. Gene therapy has come a long way in the past 20 years. Initially, studies in primary immunodeficiency disorders provided proof of concept for gene therapy, raising the possibility that similar methods could be used in hemoglobinopathies. Inadequate vectors and concern for malignancy as well as the precise needs of globin expression prevented progress. The past few years, however, have seen a surge in SCD research and therapy trials. The advocacy efforts of ASH and the National Heart, Lung, and Blood Institute have helped spur the rapid advancement of gene addition and editing techniques and several ongoing clinical trials in 2020.

Gene addition techniques were the original focus of gene therapy in SCD. Initial studies looked at incorporating a functional β-globin transgene into hematopoietic stem cells (HSCs), but the focus on reducing sickle hemoglobin polymerization led researchers to develop a modified β^A-globin sequence with increased anti-sickling activity compared to normal β-globin. This modified sequence, of which LentiGlobin is the most well-known, was described in mouse models by Dr. Robert Pawliuk and colleagues in 2001, where the addition of a modified β-globin gene led to successful expression of vector hemoglobin and improved anemia.¹  However, the large size of the transgene proved difficult, and the finding of the more efficient HIV-based lentiviral vectors for the insertion of a modified gene into HSCs made gene therapy more feasible for SCD.

An ongoing multicenter phase I/II clinical trial for adults with SCD, HGB-206, offers the most data related to gene therapy in SCD, with results from 40 trial participants.^2,3  Dr. Alexis Thompson and colleagues reviewed the most recent results at the 2020 ASH Annual Meeting, presenting an abstract showing results from 32 of 40 patients with a mean of 13 months follow-up data (abstract #677). In eight patients with two years or more follow-up, nearly 90 percent of red blood cells contained the modified β^A-T87Q — a near pancellular expression resulting in reduced HbS expression, improved hemoglobin levels, normalization of hemolysis markers, and resolution of severe vaso-occlusive events. Furthermore, health-related quality-of-life outcomes for patients in this cohort who had more than 12 months post-treatment also show clinically relevant improvements from baseline (2020 ASH Annual Meeting, abstract #365).

Newer yet is the discovery of CRISPR/Cas9, the most well-known form of gene editing. Using this platform, a DNA break is introduced into the BCL11A gene, which normally suppresses the production of fetal hemoglobin, in order to introduce an indel to turn off the suppression. Data from the CLIMB-121 trial using CTX001, an investigational drug in ongoing clinical trials (clinicaltrials.gov: NCT03745287)⁴  was presented in the Plenary Scientific Session at the 2020 ASH Annual Meeting.⁵  These data, which followed two individuals with SCD who were treated with CTX001, demonstrated improved hemoglobin, near pancellular expression of HbF, and lack of pain episodes as much as 12 months postinfusion (abstract #4). Simultaneously, an article published by Dr. Erica Esrick and colleagues presents data on their single-center pilot study using autologous CD34⁺ cells transduced with the BCH-BB694 lentiviral vector, which encodes a short hairpin RNA (shRNA) targeting BCL11A mRNA embedded in a microRNA (shmiR).⁶  This methodology uses another approach to target fetal hemoglobin expression through erythroid lineage–specific knockdown. Their data were on six patients who had received this therapy (BCH-BB694 gene therapy) with a median follow-up of 18 months (range, 7 to 29 months). All of the patients evaluated achieved robust HbF induction with reduced or absent clinical manifestations of SCD.

As if this was not exciting enough, preclinical data from the 2020 ASH Annual Meeting also offers an even more novel gene therapy approach known as adenine base-editing. Adenine base editors (ABEs) can be used to directly eliminate β^S globin, converting the mutant A-T base pair to a G-C base pair to create Hb G-Makassar, a naturally occurring non-pathologic β-globin in in vitro studies, as well as inducing base changes in HB G1/2 promotors with no detectable off targets (Abstracts #1543 and #1545). While these data are preclinical, the potential for their use in vivo continues to increase excitement for potential cure for SCD.

So, what does the future hold? While early clinical results of LentiGlobin, CTX001, and BCH-BB694 are encouraging, patient numbers remain small and data are immature. Long-term safety and efficacy results in larger cohorts are still needed. Furthermore, defining cure in SCD will likely involve a combination of functional as well as hematologic assessments with a defined set of endpoints that can be adapted for all gene therapy trials. In the meantime, new FDA-approved therapies and stem cell transplant trials continue to provide options for improved quality of life and increased survival in SCD. Though gene therapy is a long way from being widely available, the results conveyed to us in 2020 carry possibility and hope: something much needed in SCD care.