Intervention to Prevent Acute Lung Injury for Patients with Sickle Cell Disease

Researchers at the University of Pittsburgh have developed an approach to inhibit lung vaso-occlusion and lung injury in SCD beyond the current FDA approved treatment of intravenous P-selectin Ab therapy.

Description

Acute chest syndrome (ACS) is a type of acute lung injury and one of the leading causes of mortality in Sickle Cell Disease (SCD). The etiological mechanisms that trigger ACS remain poorly understood. 10-20% of SCD patients hospitalized with acute systemic painful vaso-occlusive episodes develop ACS within the next few days, which suggests that molecular events surrounding vaso-occlusion contribute to lung injury. This is a major problem for patients and presents an opportunity for the development of therapeutics that can halt the development of ACS. Recent clinical trial has shown a ~50% reduction in hospitalization of SCD patients receiving intravenous P-selectin Ab therapy, suggesting that therapies beyond P-selectin inhibition would be needed to prevent ACS in SCD patients. Researchers at the University of Pittsburgh have developed an approach to ameliorate the remaining (~50%) lung vaso-occlusion associated morbidity in SCD by inhibiting the Gasdermin-D (GSDMD) dependent signaling in leukocytes.

Applications

• Therapeutic for patients with SCD to reduce the occurrence of lung-vaso occlusion, which in turn reduces the likelihood of developing ACS.

Advantages

• Improved outcome for patients with SCD; reduced rates of lung-vaso occlusion.
• Potential to reduce mortality rate for SCD patients.

Invention Readiness

In vivo evidence using P-selectin-deficient SCD mice shows significant amelioration of lung vaso-occlusion and lung Injury following GSDMD-inhibition.

IP Status

https://patents.google.com/patent/WO2023034905A1

Related Publication(s)

Vats, R., Kaminski, T. W., Brzoska, T., Leech, J. A., Tutuncuoglu, E., Katoch, O., Jonassaint, J., Tejero, J., Novelli, E. M., Pradhan-Sundd, T., Gladwin, M. T., & Sundd, P. (2022). Liver-to-lung microembolic NETs promote gasdermin D–dependent inflammatory lung injury in sickle cell disease. Blood, 140(9), 1020–1037. https://doi.org/10.1182/blood.2021014552

Kaminski, T. W., Katoch, O., Li, Z., Hanway, C. B., Dubey, R. K., Alagbe, A., Brzoska, T., Zhang, H., Sundd, P., Kato, G. J., Novelli, E. M., & Pradhan-Sundd, T. (2023). Impaired hemoglobin clearance by sinusoidal endothelium promotes vaso-occlusion and liver injury in sickle cell disease. Haematologica. https://doi.org/10.3324/haematol.2023.283792