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An Assessment of the Therapeutic Landscape for the Treatment of Heart Disease in the RASopathies

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Abstract

The RAS/mitogen-activated protein kinase (MAPK) pathway controls a plethora of developmental and post-developmental processes. It is now clear that mutations in the RAS-MAPK pathway cause developmental diseases collectively referred to as the RASopathies. The RASopathies include Noonan syndrome, Noonan syndrome with multiple lentigines, cardiofaciocutaneous syndrome, neurofibromatosis type 1, and Costello syndrome. RASopathy patients exhibit a wide spectrum of congenital heart defects (CHD), such as valvular abnormalities and hypertrophic cardiomyopathy (HCM). Since the cardiovascular defects are the most serious and recurrent cause of mortality in RASopathy patients, it is critical to understand the pathological signaling mechanisms that drive the disease. Therapies for the treatment of HCM and other RASopathy-associated comorbidities have yet to be fully realized. Recent developments have shown promise for the use of repurposed antineoplastic drugs that target the RAS-MAPK pathway for the treatment of RASopathy-associated HCM. However, given the impact of the RAS-MAPK pathway in post-developmental physiology, establishing safety and evaluating risk when treating children will be paramount. As such insight provided by preclinical and clinical information will be critical. This review will highlight the cardiovascular manifestations caused by the RASopathies and will discuss the emerging therapies for treatment.

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Funding

This work was supported by NIH grant R01HL134166 to AMB.

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  1. Department of Pharmacology, Yale University School of Medicine, SHM B226D, 333 Cedar Street, New Haven, CT, 06520-8066, USA

    Jae-Sung Yi, Sravan Perla & Anton M. Bennett

  2. Yale Center for Molecular and Systems Metabolism, Yale University, New Haven, CT, 06520, USA

    Anton M. Bennett

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JSY, SP, and AMB contributed equally to this work.

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Yi, JS., Perla, S. & Bennett, A.M. An Assessment of the Therapeutic Landscape for the Treatment of Heart Disease in the RASopathies. Cardiovasc Drugs Ther 37, 1193–1204 (2023). https://doi.org/10.1007/s10557-022-07324-0

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