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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.
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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 preventable and/or 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? Since many Mendelian and even some common diseases have their symptomatic or pathophysiologic genesis in childhood, should clinical trials in pediatric populations be an explicit emphasis? Can the use of Mendelian disorders to interrogate complex disease traits be expanded? What are the opportunities relevant to specific gaps in knowledge? Alternatively, are high-penetrance Mendelian disorders too simple to accurately model low-penetrance complex disorders, and 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 systems biology/physiology 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?

  • How do we ensure that gene-environment interactions at various life stages are considered along with the biological, physiological, and behavioral mechanisms that underlie gene variant-disease associations?

  • Concerning genome-wide association studies, how do we deal with the costs and elaborate IT-infrastructural support needed to analyze the computationally intensive data that is typically generated? How can appropriate processes be established that streamline ethics committee approvals and the steps involved in obtaining informed consent documents?
  • 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 modulation of these targets and pathways?

  • How can we best utilize gene therapy, either for the purposes of gene addition or RNAi usage, and how do we best support the development of gene therapy technologies that can apply across diseases?

  • Should there be a cohesive, focused effort to discover therapies for rare conditions?

  • 3. What are the critical gaps in infrastructure?
  • Are existing patient populations (e.g., unified by age, disease, genotype, or response to therapy) and study results (e.g., genome-wide association studies) being collected in a way that maximizes the potential, efficiency, and incentive for sharing? Do exposures and outcomes need to be defined in a more uniform way to allow combining of datasets from different trials? Should efforts be made to develop clinically usable gene-pathway-drug resources to synthesize this information in ways that will be useful to practitioners? What further clinical/epidemiology resources and strategies are needed for the discovery and validation of gene variants (and gene-gene and gene-environment interactions) as determinants of human disease? Should an effort be made to assemble a collection of healthy adult control samples that could be tested for specific variants identified in patients by academic investigators?

  • Are patient samples (e.g., blood samples, immortalized lymphocytes, DNA, surgical specimens, gene expression profiles) being collected and banked 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 animal models should be better developed?

  • How do we critically assess the composition of small molecule and other libraries? Should drugs that have already been approved for some indication, or compounds that are approved only outside the U.S. or tested but not approved, receive special emphasis? How do we increase access to these resources, and do public-private partnerships have a role in this? Can we capture best practices for assay development for high-throughput screening of these libraries, and develop training methods for improving the commoditization of these assay technologies?

  • 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, health systems in academia, the VA and other government agencies, private and not-for-profit systems, 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 that include a genetic component, including those for rare genetic disorders? Should there be clinical trials networks that can provide infrastructure and discretional funding to allow rapid movement on promising developments (e.g., the Pediatric Heart Network of the National Heart, Lung and Blood Institute)? Should there be a partnership program between genetic/genomic experts and clinical researchers in academia and industry to facilitate genomics in clinical trials?

  • How can researchers harness the potential of patient populations self-organizing through social networks and other mediums? How will we design an informed consent process that facilitates patient engagement in research design and that is flexible regarding potential additional uses of contributed samples?

  • Is the regulatory environment sufficient for clinical trials for rare genetic disorders? Could FDA be engaged much earlier in the process? Should FDA develop a review program specific for rare diseases?

  • How do we develop standards regarding whether a therapeutic intervention is adequate in 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? If so, what consent and anonymization is needed to avoid individual or group stigma? Should every trial incorporate an initiative to explore pharmacogenetics? If this is done, how can negative affects from variations in therapeutic response that correlate with existing socially defined groups be avoided? How much emphasis should go into conducting "real world" clinical trials (those in more primary care settings), how should these be designed and funded, when are real world trials appropriate, and how are outcomes data collected and shared?

  • 6. What health care implementation and educational initiatives will be needed to maximize progress in the development and responsible application of therapeutic advances?
  • How can patients and the many practitioners in the health care arena be made aware of therapeutic advances? Can lessons learned in other public health approaches assist in efforts to educate patients and health care professionals? How much emphasis should be placed on web-based resources, including point-of-care education and incorporation of genetic/genomic information into electronic health records? How do we incorporate the concept of individual variation in therapeutic response? How do we prepare them for this type of information?

  • Once the evidence base is established to ensure the validity and utility of novel therapeutic practices, how can we encourage their acceptance or utilization? What barriers exist to widespread adoption? What knowledge or communication strategies are most effective in dispelling fears, misperceptions, or biases? What role do disease-specific organizations have in educating patients about therapeutic advances? How can their educational resources be brought to serve the larger community?

  • 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 patients' needs and hopes while avoiding hype? How do we educate the public to ensure accurate and/or realistic expectations?
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    Last Reviewed: March 19, 2012