DRUG DISCOVERY PLATFORM
Dilated cardiomyopathy, in which the heart becomes dilated and the muscle walls thin, is a major cause of heart failure hospitalizations and death, and the most common reason for heart transplantation. About 25 to 50 percent of dilated cardiomyopathy is inherited, and an estimated 1 in 2,500 to 3,000 people are affected with FDCM, although the true extent of the disease may be larger. No current therapies are targeted at FDCM or specific mutations, and none prevent decline in asymptomatic patients.
GENE THERAPY PLATFORM
In patients who have had an MI, the affected part of the heart becomes non-functional, due primarily to loss of cardiomyocytes. Because cardiomyocytes are post-mitotic and do not divide, a regenerative approach is needed to replace lost cardiomyocytes and restore cardiac function.
In response to an MI, fibroblasts (connective tissue cells) proliferate, inducing scarring and fibrosis. Cardiac fibroblasts are the most abundant cell type in the heart, comprising up to 50 percent of cardiac cells following an MI. As such, they represent a reprogrammable pool of cells residing within the site of the injury. With the goal of regenerating new heart muscle cells in vivo to improve heart function, we have designed our lead program to reprogram cardiac fibroblasts into cardiomyocytes in vivo to repair the heart and directly improve its ability to pump blood.
Our cardiomyopathy drug discovery platform is based on advances in the genetics of FDCM, which has been linked to more than 50 genes, and includes two approaches:
We have developed a unique model – human iPSC-derived cardiomyocytes – that enables identification of novel targets, and high-throughput screening of novel compounds, including gene therapies and traditional therapies such as small molecules. In 2006, groundbreaking science showed it was possible to create human induced pluripotent stem cells (iPSCs), which have the unique capacity to become any type of cell found in the body, including cells of the heart. These cells offer an unprecedented tool for observing and manipulating human heart cells as a model system for drug discovery and development. We have used CRISPR technology to create more than 20 iPSC lines representing human FDCM mutations, which impair the ability of cardiac cells to beat. We are screening cardiomyocytes derived from these human iPSCs to identify drug targets and optimize leads.
We have also made iPSC-derived cardiomyocytes from individuals with DCM and are characterizing them to understand the broader population of DCM and potentially identify additional disease-causing mutations. We are further using these patient-specific human cells to determine the applicability of targets identified from our screens in genetically defined FDCM to the broader DCM patient population and to test the activity of our novel small molecules and biologic therapeutics to treat DCM of unknown genetic cause.
Sarcomere proteins, which generate movement and force within cardiomyocytes, are often mutated in FDCM. One approach to developing DCM therapeutics has been to individually target these components of the sarcomere in an effort to overcome their specific force-generating deficits. Tenaya’s unique approach is to identify novel targets acting downstream of a variety of mutant proteins to ultimately develop drugs that are effective across multiple genotypes by correcting processes on which various etiologies converge.
We have promising early medicinal chemistry efforts on two distinct classes of compounds that each may address multiple FDCM mutations. We also have promising early in vivo data from one compound in a small animal model of DCM. We plan to nominate a development candidate from our cardiomyopathy drug discovery platform in 2019.
Tenaya has developed in-house capabilities to explore the use of viral vectors – both AAV and non-integrating lentiviral vectors (NILV) – to deliver different types of genetic material to targeted cells in the heart. The Gene Therapy Platform is initially being used to optimize the delivery and expression of transcription factors for the Regeneration Platform, but the science has very broad applicability to address heart disease of different etiologies, including for orphan diseases as well as for highly prevalent conditions.
We have created novel AAV vectors with the ability to preferentially target specific cells of the heart, including cardiac fibroblasts and cardiomyocytes.
We are also creating novel synthetic promoters to enable more targeted expression of genetic material in relevant heart cells, which can improve the efficacy of our drug candidates as well as minimize the chances for off-target effects of the therapeutic approach.
As most heart disease is not monogenic in nature, we have done considerable “cassette engineering” work on multi-cistronic vectors to optimize the size, order and expression of multiple genes in a single viral vector.
Tenaya has also established early in-house manufacturing capabilities, including process development and analytical development for AAV vectors.
Our scientific approach involves replacing the fibrotic region of the heart by regenerating new cardiomyocytes to help improve the heart’s performance and pumping capacity. We are using novel AAV vectors to introduce genes into cardiac fibroblasts that direct these resident cells to convert into cardiomyocytes, ultimately generating new heart muscle at the site of injury, which could potentially improve heart function. The genes that we introduce include novel combinations of transcription factors – genes that control cellular identity and function – to produce cardiomyocytes and improve the heart’s performance.
These improvements can be measured by conventional techniques, such as echocardiography or MRI, to quantify how forcefully the heart muscle is beating and how much blood is being pumped. We have demonstrated in vivo efficacy in a mouse model of MI, showing significant reduction of scar area and improved cardiac output.
We are conducting ongoing preclinical research to optimize this novel in vivo cardiac reprogramming approach. We believe that using specialized viral vectors to deliver the genes directly to the damaged area of the heart via local delivery to permanently reprogram fibroblasts into cardiomyocytes could potentially have a durable effect. We intend to nominate a development candidate for this one-time gene therapy in 2019.