Reprogramming Heart Fibroblasts into Heart Muscle Cells Goes to Human Trials

Last month, this blog reported on the conversion of heart-based fibroblasts into heart muscle cells after a heart attack in living, laboratory animals by means of gene therapy. Another researcher has utilized a different strategy to achieve the same result. This work has also provided the means for biotechnology companies to begin clinical trials using this very strategy.

Scar formation (fibrosis), prevents the regeneration of heart muscle and creates a scar that does not contract. The loss of contractile function leads to heart failure and death. Therapeutic goals for these conditions include limiting scar formation.

To that end, Eric C. Olson and his colleagues from UT Southwestern were able to introduce four genes (GATA4, HAND2, MEFC2, and TBX5) into heart-based fibroblasts and convert them into beating heart muscle cells. To do this, Olson and his army of graduate students, technicians, and postdoctoral research fellows made genetically engineered viruses that encoded the four genes (collective known as GHMT).  When the GHMT-viruses were injected into mouse hearts after a heart attack, the four genes reprogrammed the fibroblasts into heart muscle cells in tissue culture and inside living animals.  Furthermore, when GHMT is introduced into fibroblasts after a heart attack, the fibroblasts do not make scar tissue, but heart muscle.

Olson and his team also used techniques that allowed them to trace cells and their descendents.  These techniques showed that the heart muscle that formed after the heart attack were the result of cells that had been infected by the engineered viruses (that is, they contained viral DNA).  Thus the new heart muscle came about because the virally-infected fibroblasts turned into heart muscle that began to beat.  Also, heart imaging also showed that infection of the heart with GHMT viruses greatly boosted heart function after a heart attack in comparison to control heart that were infected by the viruses that did not contain GHMT.

Can such a technology make it way to clinical trials?  Fortunately, Eric Olson is not only chairman of the Molecular Biology department as UT Southwestern, but he is also co-founder of a medical technology company known as LoneStar Heart Inc.  Olson’s company hopes to extend his findings in laboratory animals and eventually gain approval to begin human clinical trials.  Olson noted, “These studies establish proof-of-concept for in vivo cellular reprogramming as a new approach for heart repair. However, much work remains to be done to determine if this strategy might eventually be effective in humans. We are working hard toward that goal.”

LoneStar Heart is capitalizing on previous work by Olson and others in his laboratory that have established that the delivery of the four previously mentioned genes increases heart regeneration in laboratory animals and in cultured human heart cells.  LoneStar Heart is currently trying to complete the animal studies required before the Food and Drug Administration will consider permitting a human clinical trial

Lonestar Heart, however, has other products that might play a role in treating the hearts of patients whose hearts have started to enlarge. Heart enlargement results when the heart is overworked and it reacts to this overwork by enlarging. The enlargement stretches the heart and makes the walls of the heart thinner. The result is that the heart does not beat in a coordinated fashion, and patients with enlarged hearts are at risk for irregular heart beats or sudden cardiac death.

To address enlargement of the heart, LoneStar Heart has made a product called Algisyl-LVR that is a biopolymer that stiffens when it is injected into the heart. Injection of Algisyl-LVR into the walls of a heart that has enlarged thickens the heart wall without interfering with heart function. The artificial thickening of the heart walls decreases the stress on the heart and helps reverse heart enlargement. Algisyl-LVR is presently being tested in Europe in clinical trials under the product name AUGMENT-HF.  These remarkable products will hopefully be on the market before long.