Sickle Cell Disease in 2023: Laying the Foundation for Future Breakthroughs

Despite arising from alterations in just one gene (beta-globin), sickle cell disease (SCD) manifests in a plethora of complex, varied, and challenging-to-manage phenotypes. Globally, there are more than 7.5 million individuals living with SCD, with unacceptably high mortality concentrated in lower-income countries.¹  Common complications include vasculopathy, vaso-occlusion leading to periodic pain episodes, and damage to end-organs — all of which can lead to strokes, renal disease, bone osteonecrosis, and cardiopulmonary disease. This culminates in a high rate of healthcare utilization, significant morbidity, diminished quality of life, and ultimately, a shortened lifespan.

SCD was initially described over a century ago in 1910. Despite this, research and therapeutic development in SCD has historically been hampered by inadequate/disparate funding.²  Thankfully, the landscape is changing as policy-makers, patients and family members, advocacy organizations, researchers, and pharmaceutical companies all place a heavy emphasis on improving the lives of individuals living with SCD.

The year drew to a close with an incredible breakthrough in SCD management: approval by the U.S. Food and Drug Administration (FDA) of the first gene therapies for SCD after a decade of painstaking research and clinical trials. Two products were approved in early December: Exagamglogene autotemcel (exa-cel), a CRISPR-based gene therapy, and lovotibeglogene autotemcel (lovo-cel), a lentiviral based gene therapy. The enthusiasm for these therapies is tempered by the unknown long-term side effects and durability of the edited cells, uncertainty about affordability and access (a likely, major barrier to widespread adoption), and the effects of myeloablative conditioning on fertility.

Novel, alternative gene editing approaches for SCD are also in various stages of clinical development, portending more curative-intent options in the future.^{3, 4}  One of the most innovative approaches relies on a non-integrating, prime-editor-expressing viral vector after granulocyte colony-stimulating factor (G-CSF) mobilization to correct the beta-globin gene mutation in vivo in a mouse model of SCD.⁵  If further developed, this approach may obviate or reduce the need for chemotherapy, expanding the eligibility pool and improving the safety of gene editing for SCD.

The exuberant focus on curative-intent therapies often overshadows other interesting and foundational research necessary for further advances in SCD treatment. Erica M. Sparkenbough, PhD, and colleagues established that coagulation factor XII contributes to inflammation and thrombin generation in a mouse model of SCD, further demonstrating factor XII inhibition as a potential target for reducing thrombosis and vaso-occlusion in SCD.⁶  In their recent study, Huihui Li, PhD, and colleagues highlighted the role of iron hemostasis and the gut microbiome in acute vaso-occlusion episodes in SCD mice, suggesting the need for further study of iron restriction as a novel therapy for SCD.⁷  Building on previous work linking the endocannabinoid pain modulator 2-arachidonoylglycerol (2-AG) to hyperalgesia in SCD, Iryna Khasabova, PhD, and colleagues demonstrated that maintaining physiological levels of 2-AG reduces hyperalgesia in SCD mice, a promising and unique target for treating chronic pain in SCD.⁸ 

On the epidemiology front, the Global Burden of Disease Study 2021 yielded the most comprehensive assessment of SCD burden to date using data from over 200 countries. Their recent report highlighted the rising population of individuals living with SCD over the past two decades, which has increased from 5.46 million to 7.74 million, largely due to population growth in the Caribbean and the western and central regions of sub-Saharan Africa. Importantly, this study documents the disparate outcomes of SCD worldwide, particularly in mortality rates for children under 5.¹  Studies like this are critical for policymakers and stakeholders in improving SCD outcomes globally.

For this year’s best, I must spotlight the growing emphasis on improving reproductive health during SCD management. In a poignant article, Lydia Pecker, MD, and colleagues argued that inadequate access, knowledge, and counseling surrounding assisted reproductive technologies contributes to health disparities in SCD and is a barrier for individuals considering curative-intent therapies.⁹  A recent study demonstrated suboptimal contraception counseling and STI management in transitioning adolescents and young adults with SCD.¹⁰  To improve awareness and education for women with SCD, ASH collaborated with the CDC, the Foundation for Women & Girls with Blood Disorders, and the Sickle Cell Reproductive Health Education Directive to release fact sheets on preconception, prenatal, and postpartum care.^11–13  These efforts will, over time, improve fertility and pregnancy outcomes in people living with SCD.

Overall, 2023 has been another year of steady progress in SCD and transformative breakthroughs. The future has never been brighter for individuals living with SCD, as the combined efforts of key stakeholders and patients continually yields tangible progress for those living with SCD.