Digital twins of the spleen to accelerate the design and development of new therapies in sickle cell disease - The spleen clears the blood by removing the altered red blood cells (RBCs) at the cost of splenic congestion and anemia in sickle cell disease (SCD). In infants with SCD, accumulation of normal and sickled RBCs in the spleen is central in acute splenic sequestration or subacute hypersplenism (ASSC/HS), major complications that often require splenectomy. Even without splenectomy, the spleen in SCD patients has been thought to become non-functional (autosplenectomy) early in childhood. However, our recent results indicated that approximately half of adult patients with SCD in France still retain some extent of splenic function. Further, in SCD children with ASSC/HS, swollen spleens clear stiff RBCs from the circulation so effectively that poorly deformable RBCs in circulation are as rare as in control subjects with a normal spleen. These recent findings strongly suggest that ASSC/HS may be managed by improving the deformability or reducing sickling of RBCs. This hypothesis, if confirmed, is expected to reduce the indication of splenectomy, preserve splenic function, mitigate anemia, and improve the quality of life for children with SCD. Curative treatments involving stem cell and gene therapy have made significant progress recently, but their implementation will not be universal. Four more affordable medications have been approved by the FDA for treating SCD, but none has a fully curative effect. Herein, we propose to conduct a comprehensive and integrated clinical, microfluidics, and computational investigation to explore the effects and mechanisms of voxelotor, one of the FDA-approved SCD drugs, and its equivalents, with the main aims of reducing spleen congestion, alleviating anemia and preserving splenic function in pediatric and adult SCD patients. While the clinical studies will assess the efficacy of voxelotor in protecting the organ function in vivo, phenotypic screening, microfluidics, and computational studies based on digital twins will identify new drugs and provide the mechanistic rationale to support the clinical and screening findings. Specifically, we propose to achieve our goal through three Aims. In Aim 1, we will assess the ability of the voxelotor to decongest the spleen and screen new drugs displaying this effect. In Aim 2, we will perform an in vitro investigation of the efficacy of voxelotor, its successor GBT601, and newly identified drugs through spleen-mimetic microfluidic chips to unravel the potential mechanisms of these drugs for protecting the splenic function. In Aim 3, we will build digital twins of the spleen to efficiently predict the patient-specific efficacy of voxelotor, GBT601, and newly identified drugs in preserving the spleen function. In summary, we will develop a new integrated clinical-microfluidics-computational framework to explore the impact of existing and new drugs in preserving the splenic function with the promise of improving the quality of life for the majority of SCD patients. This framework will have a broader impact as the filtering function of the spleen likely impacts hemolysis and vaso-occlusion in other organs, such as liver and lungs.
