In adulthood, our hearts generally can’t grow again in response to injury. Emory cardiology researchers Ahsan Husain and Nawazish Naqvi and their colleagues have been chipping away at this biological edifice in animal models, demonstrating that it is possible to remove constraints that prevent the heart from growing new muscle cells.
Husain and Naqvi’s teams accomplished this by combining the thyroid hormone T3 — already FDA approved — with siRNA-based inhibition of an enzyme called DUSP5. Their latest paper, published in the journal Theranostics, applies the combination in an animal model of drug-induced heart failure.
The anticancer drug doxorubicin is notorious for its cardiotoxicity, yet it is a mainstay of treatment for breast cancer in adults and several types of cancer in children. Cardiotoxicity affects a fraction of breast cancer patients treated with doxorubicin (20 percent in some studies) and severely impacts mortality and quality of life.
In the mouse model, doxorubicin generates severe heart failure, with a 40 percent drop in left ventricular ejection fraction (LVEF), a measure of the heart’s pumping capacity. In response to the combination of T3 and DUSP5 siRNA, a large increase in LVEF is seen. The researchers also report that the treatment has a marked effect on the health of the animals, restoring their activity levels, grooming and posture. See the video for an example of a mouse heart treated with the T3/DUSP5 siRNA combination.
The results are potentially applicable to other situations when doctors would want to regrow or repair cardiac muscle. Husain reports plans for a clinical study in patients with drug-induced or other forms of heart failure, supported by a generous gift from the Atlanta-based ten Broeke Family Foundation.
The way Husain’s team delivers the critical part of the combination therapy — small interfering RNA (siRNA), sometimes known as silencing RNA — may sound adventurous. However, given examples of the same delivery agents for other diseases and the progress of other siRNA-based drugs such as Onpattro/patisiran, which is now FDA approved for polyneuropathy associated with hereditary amyloidosis, it’s easier to envision similar approaches reaching the clinic.
In a previous Scientific Reports paper, Husain’s group showed that heart muscle cells in young adult mice can respond to thyroid hormone, but only part of the organ does so. DUSP5 is what’s holding back the rest of the heart, inhibiting proliferation signals triggered by thyroid hormone. In the more recent report, uninjured mouse hearts treated with the combination therapy over 7 days also increase their numbers of cardiac muscle cells (about 25 percent).
When used clinically, it would be important to avoid stimulating uncontrolled growth. The Emory researchers checked that the combination treatment is specific for cardiomyocytes, not affecting other cell types in the heart like fibroblasts or other organs (lung/kidney/liver), and that it does not generate arrhythmia in the mice.
The co-first authors of the Theranostics paper are assistant research scientist Lin Tan and cardiology research fellow Nikolay Bogush, with Emory co-authors John Calvert and W. Robert Taylor, and contributions from Robert Graham of Victor Chang Cardiac Research Institute in Australia.
This research was supported by grants from Emory University’s Department of Medicine, the Carlyle Fraser Heart Center and Emory University Hospital Midtown. The work was also supported by he National Heart Lung and Blood Institute (HL079040, HL127726, HL098481, T32HL007745, HL092141, HL093579, HL094373 and HL113452), the American Heart Association (13SDG16460006; 17GRNT33670975), the Fondation Leducq Transatlantic Network, National Health and Medical Research Council, Australia (APP1074386), R.T. Hall estate, and the Australian Research Council Stem Cells Australia Special Initiative in Stem Cell Science grant (SR1101002).