Lonafarnib improves cardiovascular function and survival in a mouse model of Hutchinson-Gilford progeria syndrome

Clinical trials have demonstrated that lonafarnib, a farnesyltransferase inhibitor, extends the lifespan in patients afflicted by Hutchinson-Gilford progeria syndrome, a devastating condition that accelerates many characteristics of aging and results in premature death due to cardiovascular sequelae. The US Food and Drug Administration approved Zokinvy (lonafarnib) in November 2020 for treating these patients, yet a detailed examination of drug-associated effects on cardiovascular structure, properties, and function has remained wanting. In this paper, we report encouraging outcomes of daily post-weaning treatment with lonafarnib on the composition and biomechanical phenotype of elastic and muscular arteries as well as associated cardiac function in a well-accepted mouse model of progeria that exhibits severe perimorbid cardiovascular disease. Lonafarnib resulted in 100% survival of the treated progeria mice to the study end-point (time of 50% survival of untreated mice), with associated improvements in arterial structure and function working together to significantly reduce pulse wave velocity and improve left ventricular diastolic function. By contrast, neither treatment with the mTOR inhibitor rapamycin alone nor dual treatment with lonafarnib plus rapamycin improved outcomes over that achieved with lonafarnib monotherapy.

 

Comments：

This paper reports the effects of daily post-weaning treatment with lonafarnib, a farnesyltransferase inhibitor, on the cardiovascular structure, properties, and function in a mouse model of progeria. Progeria is a genetic disorder that causes accelerated aging and premature death due to cardiovascular complications. The study found that lonafarnib treatment resulted in 100% survival of the treated mice to the study endpoint, with improvements in arterial structure and function, leading to a significant reduction in pulse wave velocity and improvement in left ventricular diastolic function.

The study also evaluated the effects of rapamycin, an mTOR inhibitor, alone and in combination with lonafarnib, but found that neither treatment improved outcomes over lonafarnib monotherapy. These findings suggest that lonafarnib may be an effective treatment for cardiovascular complications in progeria patients and highlight the importance of examining drug-associated effects on cardiovascular function in clinical trials.

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