Center for Precision Medicine and Rare Heart Disease

Much of the necessary methodology exists; however, the power of the Center for Precision Medicine is its dynamic platform that engages creative participation of scientists, clinicians, technology developers, data scientists, patient groups, and others. This initiative will also require new resources; these should not compete with support of existing programs, especially in a difficult fiscal climate. With enough resources and a strong, sustained commitment of time, energy, and ingenuity from the scientific, medical, and patient communities, the full potential of precision medicine can ultimately be realized to give everyone the best chance at good health.

The Center for Precision Medicine will provide unique opportunities to collaborate with the NIH, including but not limited to the Therapeutics for Rare and Neglected Diseases (TRND) Program. With an open environment, permitting the involvement of established experts on a given disease, the TRND program is designed to enable certain promising compounds to be taken through the preclinical development phase — a time-consuming, high-risk phase that pharmaceutical companies refer to as the “the valley of death.” Besides accelerating the development of drugs to treat rare and neglected diseases, the TRND program is designed to identify molecularly distinct subtypes of some common diseases, which may lead to new therapeutic possibilities, either through the development of targeted drugs or the repurposing of drugs by identifying subgroups of patients likely to benefit from them.

The Center for Precision Medicine will also collaborate with existing tissue banks and biorepositories on campus at UCMC - an important step toward linking them to clinical outcomes. Such a resource will allow for a much broader assessment of the clinical importance of genetic and “omic” variations across a range of conditions. The Center for Precision Medicine will also be a touch point for the CCTST Program- one of 46 centers funded by the NIH Clinical and Translational Sciences Award program and potentially the Mark O. Hatfield Clinical Research Center (the country's largest research hospital, in Bethesda, MD) to translate basic research findings into clinical applications. The Hatfield Center can provide specialized diagnostic services for rare and neglected diseases, offer a state-of-the-art manufacturing facility for novel therapies, and pioneer clinical trials of other innovative biologic therapies, such as those using human embryonic stem cells or induced pluripotent stem cells.

The Center for Precision Medicine will also collaborate with existing tissue banks and biorepositories on campus at UCMC - an important step toward linking them to clinical outcomes. Such a resource will allow for a much broader assessment of the clinical importance of genetic and “omic” variations across a range of conditions. The Center for Precision Medicine will also be a touch point for the CCTST Program- one of 46 centers funded by the NIH Clinical and Translational Sciences Award program and potentially the Mark O. Hatfield Clinical Research Center (the country's largest research hospital, in Bethesda, MD) to translate basic research findings into clinical applications. The Hatfield Center can provide specialized diagnostic services for rare and neglected diseases, offer a state-of-the-art manufacturing facility for novel therapies, and pioneer clinical trials of other innovative biologic therapies, such as those using human embryonic stem cells or induced pluripotent stem cells.

Real progress will come when clinically beneficial new products and approaches are incorporated into clinical practice. To this end, the following milestones will be the focus of our efforts:

1. Integrate data to construct a knowledge network of disease
   As data from pilot studies and other sources begin to populate the information commons (Central Command for Precision Medicine Center), substantial effort should go into integrating these data with the results of basic biomedical research in order to create a dynamic, interactive knowledge network. This network, and the Information Commons itself, should leverage state-of-the-art information technology to provide multiple views of the data appropriate to the varying needs of different users such as basic researchers, clinicians, or outcomes researchers. The incorporation of electronic medical records into the health care system and the advent of inexpensive ways of collecting health information could also create opportunities to integrate data for the information commons more efficiently. Pilot studies, including those conducted in health care settings, would help scientists figure out how to integrate molecular data with medical histories and health outcomes in the ordinary course of clinical care. These studies would address the institutional, cultural, and regulatory barriers to widespread sharing of individuals' molecular profiles and health histories while still protecting patients' rights. Much of the initial work necessary to develop the information commons should take the form of observation studies, which would collect molecular and other patient data during the normal course of treatment.
2. Initiate a process within appropriate federal agencies to assess the privacy issues associated with the research required to create the information commons.
   Because privacy issues associated with genetic information have been studied extensively, this process need not start from scratch. However, investigators who wish to participate in the pilot studies discussed above—and the Institutional Review Boards who must approve their human-subjects’ protocols—will need specific guidance on the range of informed-consent processes appropriate for these projects.
3. Ensure data sharing.
   Widespread data sharing is essential to the success of each stage of creating a new disease taxonomy. Most fundamentally, information on how gene sequence translates to symptoms must be broadly accessible so that a wide diversity of researchers can mine them. Data sharing standards that respect individual privacy concerns while enhancing the deposition of data into the Information Commons should be created. These standards should provide incentives that motivate data sharing over the establishment of proprietary databases for commercial intent.
4. Develop an efficient validation process to incorporate information from the disease knowledge network into a new taxonomy of disease.
   Insights into disease classification that emerge from the Information Commons and the derived knowledge network will require validation of their reproducibility and their utility for making clinical decisions such as selecting appropriate treatment, before adoption into clinical use. The speed and complexity with which such validated information emerges will undoubtedly accelerate and will require novel decision support systems for use by all stakeholders.
5. Incentivize partnerships.
   A new taxonomy incorporating molecular data could become self-sustaining by accelerating delivery of better health through more accurate diagnosis and more effective and cost-efficient treatments. However, to cover initial costs associated with collecting and integrating data for the Information Commons, incentives should be developed that encourage public private partnerships involving government, drug developers, regulators, advocacy groups and payers.
   While rare diseases, when considered individually, are indeed uncommon collectively they represent a very important cause of disability, chronic illness, impaired quality of life, health care cost and premature death in both children and adults. In addition to accounting for a disproportionate share of healthcare expenditures in the US, their complexity often leads to inadequate diagnosis and treatment.

A major misconception among physicians, scientists and the American public is that rare diseases of the heart exist in a virtual vacuum. In fact, this is not true. Many fundamental advances in medicine have their origins in the study of rare diseases. For example, the human genome project was stimulated by the identification of a gene responsible for muscular dystrophy. Similarly, the field of epigenetics began with early descriptions of rare diseases and the potential contribution of environmental and psychosocial conditions. Accordingly, the scientific and translational foundation of studying rare heart and lung disease is scalable and can be used to advance the understanding of common diseases, disorders and conditions and train the next generation of researchers.

CDCN's research model. The CDCN has taken a four-step approach to drive forward "omics" research: 1a) The CDCN identified and connected the research community and (1b) provided supportive resources to patients and loved ones. Then, the CDCN turns to the research community (2a) and patient community (2b) to prioritize key research studies into an International Research Agenda as well as collect and centrally store clinical data and tissue samples. With the top priority projects identified, the CDCN solicits funding from patients and loved ones for specific projects. Then, the CDCN provides two mechanisms for funding (3a) investigator-initiated research grants through traditional requests for proposals and (3b) strategically directed research grants where the DRO recruits the top experts within the community or outside of the community to do the studies. 4) Pharmaceutical companies are more eager to contribute tissue samples and funding for clearly defined projects with the greatest likelihood of return.