Early Translational III
Heart disease is a leading cause of mortality. The underlying pathology is typically loss of heart muscle cells that leads to heart failure. Because heart muscle has little or no regenerative capacity after birth, current therapeutic approaches are limited for the over 5 million Americans who suffer from heart failure. Our recent findings regarding direct reprogramming of a type of structural cell of the heart, called fibroblasts, into cardiac muscle-like cells using just three genes offers a novel approach to achieving cardiac regeneration. 50% of cells in the human heart are cardiac fibroblasts, providing a potential source of new heart muscle cells for regenerative therapy. We simulated a heart attack in mice by blocking the coronary artery, and have been able to reprogram existing mouse cardiac fibroblasts in to new muscle by delivering the three genes into the heart. We found a significant reduction in scar size and an improvement in cardiac function that persists after injury. The reprogramming of cells in the intact organ was more complete than in cells in a dish. We now propose to develop the optimal gene therapy approach to introduce cardiac reprogramming genes into the heart, to establish the optimal delivery approach to administer virus encoding cardiac reprogramming factors that results in improvement in cardiac function in a preclinical model of cardiac injury, and to establish the safety profile of in vivo cardiac reprogramming in a preclinical model.
Statement of Benefit to California:
This research will benefit the state of California and its citizens by helping develop a new therapeutic approach to cardiac regeneration. Heart disease is a leading cause of death in adults and children in California, but there is no current treatment that can promote cardiac regeneration. This proposal will lay the groundwork for a clinical trial that could result in generation of new heart muscle cells from within the heart. If successful, there is potential economic benefit in terms of productive lives saved and in the commercialization of this technology.
The goal of this development candidate (DC) proposal is to utilize a recently described technology (direct reprogramming) to convert cardiac fibroblasts into cardiac myocytes in vivo for the treatment of acute myocardial infarction (AMI). The applicant plans to select a vector (the DC) to optimize specificity and delivery of reprogramming genes and determine the best route of administration. Additionally, the team will establish the safety and efficacy profile of in vivo reprogramming using their optimized vectors and delivery route in a clinically relevant animal model of acute myocardial infarction. Objective and Milestones - Reviewers found the objective of reprogramming activated fibroblasts after AMI excellent and considered the target product profile reasonable and appropriate. - A panelist noted that the milestones, while well written, would benefit from more quantitative measures of success. Rationale and Significance - If successfully developed, this novel and innovative approach to cardiac regeneration holds transformative potential and could fulfill a huge unmet medical need in heart disease. - Because of the prevalence of heart disease, even an incremental improvement over current approaches could have substantial clinical impact. Research Project Feasibility and Design - Reviewers expressed enthusiasm for this application, which they praised as innovative, ground-breaking and clearly written. - The application provides compelling preliminary evidence that the team can both reprogram resident cardiac fibroblasts to cardiomyocytes and improve cardiac function post AMI. - The pivotal criticisms of the application relate to vectorology. The applicant proposes to examine the suitability of two different vector types. Reviewers expressed technical and safety concerns that could hinder successful translation of the direct cardiac reprogramming technology. - Vector Specificity: Direct reprogramming of non-cardiac fibroblasts and other cells presents a safety risk, as the proposed reprogramming vectors are neither fibroblast, nor organ specific. Fibroblast specific vectors have not been achieved in the field but the applicant will attempt to identify vector serotypes that have higher selectivity for cardiac fibroblasts over cardiac myocytes. - Carrying Capacity: One of the proposed vector types has limited carrying capacity and at least 3 separate viruses, transfected at equal efficiencies, will be needed to target a single cell for reprogramming. This presents a substantial technical hurdle. - Clinical data indicates one of the selected vectors can result in long-term gene expression; this is unnecessary for direct reprogramming and may present further safety risks. - Reviewers noted that alternative vectors, including that utilized in the preliminary data could prove to be a superior development candidate for this indication. Qualification of the PI (Co-PI and Partner PI, if applicable) and Research Team - The PI is a world-class physician scientist with a proven commitment to and track record in this area of work. - Reviewers praised the group, calling it a dream team, and noting that each member brings unique expertise to the proposal. They did note that the program would benefit from consultation with additional vector experts to consider alternative gene delivery strategies. - The budget is focused and appropriate Collaborations, Assets, Resources and Environment - All assets and personnel required for the program are available to the investigators. Responsiveness to the RFA - Reviewers found the proposed DC novel and the program responsive to the RFA.
- A motion was made to move this application into Tier 1, Recommended for Funding. During the discussion, the panel reiterated enthusiasm for the novel and promising biologic concept in the proposed program and noted that feasibility concerns regarding the selected gene delivery vector lowered the application’s score.
- The GWG discussed the possibility of successfully achieving a development candidate using alternative vector strategies, given the high degree of enthusiasm for the biological concept and the potential impact of translating these findings. A reviewer suggested that the team assembled by the PI has the expertise to address the issue. However, the panel remained concerned that achieving a viable development candidate was very uncertain given the significant roadblocks to identifying a suitable vector. The GWG therefore advised as a condition for funding that the applicant consult additional vector specialists with translational and clinical experience to select a more appropriate vector to move this program towards the clinic. The motion carried.