Research on sickle cell disease (SCD) has gained traction in recent years with various approaches aiming to moderate or cure the disorder. However, despite advancing strategies, numerous questions remain unanswered, with a limited number of these focusing on providing a cure.
Individuals with SCD suffer from painful crises and shortened life expectancies owing to a mutation in the haemoglobin subunit beta (HBB) gene, which produces abnormally shaped red blood cells. Current therapies focus on reducing and preventing episodes of crises, with stem cell transplants or bone marrow transplants proving to be the only established methods to cure the disease; however, these techniques are rarely utilized owing to the significant risks, such as the development of graft-versus-host disease (GvHD).
Spanning the last decade, 2021 marks the year with the highest number of SCD clinical studies, with a 32% increase in the number of trials relative to 2020. The general trend over the last 10 years highlights an increase in the number of initiated studies with variability in the year-by-year trends. Furthermore, the Covid-19 pandemic did not significantly affect the level of SCD research, with 2020 showcasing a marginally greater number of trials relative to 2019. This trend differs from other hematological disorders, which experienced one of the greatest proportional numbers of trial disruptions triggered by Covid-19.
Studies focusing on hematological disorders typically necessitate frequent sample collection for analysis; however, outcome measures related to SCD studies generally focus on reducing the occurrence of sickle cell crises as opposed to assessing the efficacy of therapeutics via biomarker concentration analysis, therefore allowing for easier conduct of decentralized studies.
Though 2017 proved to be the year with the lowest number of trial initiations, l-glutamine received regulatory approval by the FDA that year. Prior to this approval, treatment options for SCD proved limited, with the majority of treatment regimens consisting of hydroxyurea and regular blood transfusions, which display safety concerns and carry significant risk, respectively. Following on from the approval of l-glutamine, the number of SCD studies in 2018 showcased an all-time high at that point.
As displayed in Figure 1, non-industry-sponsored trials dominated the research landscape between 2011 and 2018. However, from 2019 onwards, industry-sponsored trials begin to dominate. The increased industry sponsorship during this period may have been due to the spotlight on SCD following the approval of l-glutamine, as preceding decades presented little progress. Historically SCD research had not been prioritized, with the disease population mainly consisting of individuals of sub-Saharan African descent, potentially highlighting a wider racial inequality issue in the pharmaceutical industry.
In 2019, Novartis’ crizanlizumab and Global Blood Therapeutics’ voxelotor received FDA approval. Earlier this month, the National Institute for Health and Care Excellence (NICE) recommended crizanlizumab as treatment for sickle cell disease, a significant milestone as the first new sickle cell therapy available to the National Health Service (NHS) in 20 years, with the candidate proving greater efficacy in treating severe disease relative to hydroxyurea.
While treatment options are improving, they predominantly focus on alleviating or preventing sickle cell crises as opposed to providing a cure. The transformative potential of gene therapy could allow for a breakthrough therapeutic in which the disease-causing mutation could be corrected to allow for a fully functional β-globin gene.
The two greatest obstacles to an effective gene therapy for SCD are gene delivery methods and safety concerns. Viral vectors, notably lentiviral vectors, offer a comparatively effective likelihood of long-term gene expression; however, they are predisposed to random entry into host chromosomes, potentially leading to mutagenesis. These concerns were further highlighted when a Phase I/II and Phase III clinical trial of Bluebird’s LentiGlobin Gene Therapy for Sickle Cell Disease was suspended as two participants were diagnosed with acute myeloid leukemia (AML). The FDA allowed the trial to restart after the findings had failed to show the lentiviral vectors to be mutagenic agents, but nonetheless, the high level of caution mandated by gene therapies is apparent.
Though gene therapy yields transformative potential for SCD, the significant risk must be mitigated by an increase in research funding to expand knowledge of delivery mechanisms and mutagenic properties of viral vectors; the recent increase in industry funding may prove key in the further developments in a cure for SCD.