Skip to main content

Applying Genomics to Clinical Problems - Therapeutics

A white paper for the National Human Genome Research Institute

Submitted by: Harry Dietz, M.D., and Christopher Austin, M.D.
View All Comments on this White Paper


There is great potential, even expectation, that advances in genetics and genomics will fuel a revolution in disease prevention and treatment. Both the intramural scientific and extramural funding arms of the National Human Genome Research Institute (NHGRI) have contributed substantially to this goal through initiatives that have developed critical foundation tools (e.g. the human genome sequence and haplotype map) and provided access to enabling technologies (e.g. the NIH Chemical Genomics Center; NCGC). It is anticipated that the path forward will be informed by consideration of the architecture for prior success in transformational application of basic science inquiry to clinical practice.

Common themes include the calculated or fortuitous intersection between lines of basic inquiry focused on both mechanisms of disease and strategies to modify physiologic and/or inherently pathologic events; the need for prioritization of initiatives based upon public health burden or evident opportunity; the importance of the development of infrastructure and the forging of alliances between academia, industry and patients; and the need for physician and public education for the responsible testing and introduction of new therapies and the productive management of expectations. In this light, it is anticipated that the mission of NHGRI to contribute to the development of novel therapeutic strategies will be facilitated by consideration of the following questions:

1. How can we improve efforts to define the mechanistic underpinnings of disease predisposition, initiation, and/or progression?
  • While it is clear from precedent that positional strategies for disease gene identification add the potential for quantum leaps in understanding of basic biologic and disease processes, can these strategies be refined, tailored or directed to identify the therapeutically "targetable" mechanisms of disease? Given the major gene effects and relative homogeneity of etiology inherent to Mendelian disorders, are such disease processes inherently more "targetable" and/or tractable in clinical trials? If so, can the use of Mendelian disorders to interrogate complex disease traits be expanded? What are the opportunities relevant to specific gaps in knowledge? Alternatively, will single gene or pathway perturbations sufficient to cause disease be informative for predispositions that contribute to late-onset disease? Are the pathways defined by predisposing alleles more amenable to pharmacologic and/or environmental modification than those defined by major gene effects? Do the answers to these questions depend upon the disease in question? If so, can rules be established?

  • Can we expand the use of modifier genes, pathways or events to direct the development of therapeutic strategies? To what extent and under what circumstances should such studies be restricted to people? Does relevance of therapeutic observations made in animal models to the human condition require the involvement of common pathways, genes or even genotypes? What can we learn from therapeutic effects in animal models that do not translate to people?

  • Can expression profiling or proteomics be used to define the "targetable" mechanisms of disease? Are the results informative in the absence of specific hypotheses based upon at least minimal knowledge regarding etiology or pathogenesis? Can cultured cells adequately mimic the complex interplay between genetic predisposition, time and both productive and contributory secondary effects? What is the optimal source of cells or tissues to be analyzed? To what extent can "accessible" cells or tissues substitute for the ideal reagents based upon the distribution of disease manifestations? Do the answers to these questions vary for different disease processes and can rules be established?

  • Can we develop a catalog of signatures for different disease processes and will this inform elucidation of pathogenesis for diseases of unknown etiology? Is this best accomplished using patient samples with defined mutations and/or mechanisms, natural or induced animal models, siRNA-mediated gene silencing or environmental/chemical perturbations? How well does induced gene silencing (siRNA or mouse knockouts) recapitulate events seen with haploinsufficiency or dominant-negative alleles? How well will disease signatures correlate with therapeutic responses? Will inclusion of signatures for predisposed patients, animals or experimental states that escape disease inform the development of new therapies?

2. Can we better define therapeutic agents in order to expand their application?
  • Can we develop an informative catalog of pathways or events that are influenced by different therapeutic agents? Should this effort be limited to FDA-approved drugs? If not, how should other interventions be prioritized? Can nutritional or environmental restrictions or exposures be productively incorporated?

  • How do we best utilize small molecule, siRNA, and perhaps other approaches (e.g. aptamers) to determine general principles of small molecule-target interactions, gene involvement in physiologic pathways, and potential beneficial or harmful effects of moduclation of these targets and pathways?

3. What are the critical gaps in infrastructure?
  • Are existing patient populations (e.g. unified by disease, genotype or response to therapy), patient samples (e.g. DNA, cell lines, surgical specimens) and study results (e.g. genome-wide association studies) being collected in a way that maximizes the potential, efficiency and incentive for sharing?

  • How do we best expand the repertoire of surrogate markers for use in therapeutic screens or clinical trials? Are experts in imaging or biomarker development adequately invested and integrated into this process?

  • How useful are current animal models for interrogating pathogenesis or therapeutic trials? Should there be more investment in the development of an allelic series of targeted mutations, as opposed to predominant reliance on null alleles? What are the strengths and limitations of murine models and what other species should receive greater development?

  • How do we critically assess the composition of small molecule and other therapeutic libraries? How do we increase access to these resources?

  • How do we harness human variation in the United States health system for use in important scholarly research (including pharmacogenetics) that maximizes power and efficiency while minimizing risk and the perception of risk to the participants?

4. What are the synergistic relationships needed to catalyze progress and how are they best developed?
  • How do we promote productive interactions in translational research between conventional and unconventional academic disciplines and industry? Will specific meetings or journals that highlight the process of translational research and bring diverse disciplines to the table facilitate this process? What about funding opportunities that either encourage or require unconventional partnerships (e.g. academia-industry, basic-clinical science, basic-applied science)? Is there added value to industry to establish such relationships before the phase of clinical trial? If so, are there untapped funding opportunities from industry?

  • How do we facilitate collaboration between genetic/genomic disease experts and small molecule/siRNA screening and probe development experts to efficiently develop chemical probes for definition of gene/pathway function and testing of therapeutic hypotheses in physiological systems?

  • For the vast majority of rare disorders that will not support the current model of private sector-based therapeutic development, how should we most efficiently develop clinical candidate compounds that could be entered into clinical trials? For example, if a parent compound shows potential in an academia-based screen for a rare disorder, how do we facilitate the medicinal chemistry and other aspects of product development needed to realize maximal potential? Are there business models involving government or patient foundation support that pharmaceutical companies would find attractive? What can we learn from overt success stories regarding the development of therapeutics for rare disorders (e.g. enzyme replacement therapies)?

5. What are the opportunities and obstacles regarding human clinical trials?
  • How can we promote and support clinical trials for rare genetic disorders? Should there be clinical trials networks that are provided infrastructure and discretional funding that allow rapid movement on promising developments (e.g. the Pediatric Heart Network of the National Heart, Lung and Blood Institute)?

  • How do we develop standards regarding if a therapeutic intervention is adequate for a clinical trial (e.g. saves the liver but not the brain)? How can such standards be monitored and enforced?

  • How do we ensure that every sponsored clinical trial will achieve maximal impact? Should it be a requirement that every trial will include the collection, storage and potential distribution of patient samples in order to further elucidate disease mechanisms and the molecular basis for variation in therapeutic response? Should every trial incorporate an initiative to explore pharmacogenomics?

6. What educational initiatives will be needed to maximize progress in the development and responsible application of therapeutic advances?
  • How can patients and physicians be made aware of therapeutic advances? How do we incorporate the concept of individual variation in therapeutic response? How do we prepare them for this type of information?

  • What social and behavioral practices or biases will limit acceptance or utilization of novel therapeutic practices? How can these be recognized, manipulated and/or managed in a manner that promotes beneficial health practices?

  • How can physicians and patients be informed about and protected from ineffective or inadequately validated commercial products or services?

  • How do we present progress in a manner sensitive to patient's needs and hopes while avoiding hype? How do we best shape public expectations?

Top of page

Last Reviewed: March 15, 2012