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Published on: September 12, 2019
Multi-Omic, Histopathologic, and Clinicopathologic Effects of Once-Weekly Oral Rapamycin in a Naturally Occurring
Victor N Rivas1,2, Joanna L Kaplan1, Susan A Kennedy3
1Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616, USA.
Insights
This study explored rapamycin
Area of Science:
- Veterinary Cardiology
- Pharmacology
- Molecular Biology
Background:
- Hypertrophic cardiomyopathy (HCM) is the most common heart disease in cats, affecting up to 15% of the feline population.
- Currently, limited therapeutic options exist for treating feline HCM, necessitating research into disease-modifying interventions.
- Previous studies suggested rapamycin's potential for beneficial cardiac remodeling in cats with subclinical HCM.
Purpose of the Study:
- To investigate the tissue-, urine-, and plasma-level proteomic and transcriptomic effects of oral delayed-release rapamycin in cats with hereditary HCM.
- To evaluate the safety and tolerability of intermittent low and high doses of rapamycin in a feline research colony.
- To explore the dose-responsive effects of rapamycin on myocardial hypertrophy and autophagy.
Main Methods:
- A pilot study involving 9 cats with naturally occurring hereditary HCM.
- Administration of two doses of delayed-release oral rapamycin (0.15 mg/kg and 0.30 mg/kg) once weekly for eight weeks.
- Analysis of tissue, urine, and plasma proteomic profiles, alongside tissue transcriptomic analysis.
Main Results:
- Rapamycin was found to be safe and well-tolerated in cats at both tested doses over eight weeks.
- Transcriptomic analysis indicated dose-responsive suppression of myocardial hypertrophy and stimulation of autophagy.
- Proteomic differences suggested potential anti-coagulant, cellular remodeling, and metabolic effects of rapamycin.
Conclusions:
- Rapamycin demonstrates promising disease-modifying potential for feline hypertrophic cardiomyopathy, with observed effects mirroring human studies.
- The findings support further investigation into rapamycin as a therapeutic agent for feline HCM.
- Future research should focus on validating the relationship between rapamycin treatment and observed gene expression and protein abundance changes.
Abstract:
Hypertrophic cardiomyopathy (HCM) remains the single most common cardiomyopathy in cats, with a staggering prevalence as high as 15%. To date, little to no direct therapeutical intervention for HCM exists for veterinary patients. A previous study aimed to evaluate the effects of delayed-release (DR) rapamycin dosing in a client-owned population of subclinical, non-obstructive, HCM-affected cats and reported that the drug was well tolerated and resulted in beneficial LV remodeling. However, the precise effects of rapamycin in the hypertrophied myocardium remain unknown. Using a feline research colony with naturally occurring hereditary HCM (n = 9), we embarked on the first-ever pilot study to examine the tissue-, urine-, and plasma-level proteomic and tissue-level transcriptomic effects of an intermittent low dose (0.15 mg/kg) and high dose (0.30 mg/kg) of DR oral rapamycin once weekly. Rapamycin remained safe and well tolerated in cats receiving both doses for eight weeks. Following repeated weekly dosing, transcriptomic differences between the low- and high-dose groups support dose-responsive suppressive effects on myocardial hypertrophy and stimulatory effects on autophagy. Differences in the myocardial proteome between treated and control cats suggest potential anti-coagulant/-thrombotic, cellular remodeling, and metabolic effects of the drug. The results of this study closely recapitulate what is observed in the human literature, and the use of rapamycin in the clinical setting as the first therapeutic agent with disease-modifying effects on HCM remains promising. The results of this study establish the need for future validation efforts that investigate the fine-scale relationship between rapamycin treatment and the most compelling gene expression and protein abundance differences reported here.
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