Is Regenerative Therapies Working?

The purpose of the workshop was to discuss and identify research opportunities that will advance/translate targeted molecular approaches into clinical applications. The working meeting was organized by Nancy Freeman, Ph.D., Division of Scientific Programs, NIH-NIDCD, and co-chaired with Stefan Heller, Ph.D., Stanford University. The meeting brought together investigators with diverse expertise in auditory and vestibular biology, stem cell research, clinical gene therapy, and commercial development to discuss and assess potential research toward the advancement of native/biological therapeutic approaches for hearing/balance deficiencies.

The meeting began with opening remarks from NIDCD director, James Battey, Jr., M.D., Ph.D., who welcomed the panelists and attending guests. Dr. Freeman provided the scope and purpose to the workshop panel, and Dr. Heller then presented and moderated the day’s agenda and discussion period. Each speaker was given a 15-minute time slot with ~5 minutes for discussion with the intent of keeping commentary focused and specific to goals and challenges. In addition, several months before the meeting, the panel utilized a private blog to share and exchange ideas and commentary.

The Discussion Summary and Research Opportunities

The NIDCD continues to host working group meetings in the area of hair cell regeneration in the pursuit of driving research discoveries into clinical application. Hearing/balance disorders have complex disease etiologies and most likely, there will be multiple design treatment approaches rather than single-source therapeutic solutions. While decades of molecular and genetic research have increased our basic understanding of disease processes within the auditory and vestibular systems, there remain long-standing challenges; with each discovery are new sets of challenges emphasizing the importance of continued support of this research area. Basic biological research must continue in efforts to identify genes and signaling cascades important to the inner ear and vestibular development, pathology, homeostasis, delivery, and immunology, but it remains imperative to identify within a functional context between normal and diseased states. In addition, vector delivery systems, whether biologically based or other, need continued advancement to address issues of efficacy, cellular and system toxicity, and access to identifiable tissue delivery sites. Importantly, the need for truly relevant disease model systems which mimic real-time auditory/vestibular dysfunction needs to be developed and tested in a treatment environment where appropriate safety and efficacy studies can be measured. Many of these issues are not new and were identified in previous working group meetings, and while much has been gained in research since that time, there remain large knowledge gaps in the translatability of auditory/vestibular research information to targeted biologic therapeutics.

The NIDCD auditory/vestibular programs remain an unmet medical need and are poised for clinical research. At present, there are no targeted drug- or cell-based therapies available to treat hearing loss or balance disorders. Hearing loss is a seriously debilitating condition with devastating effects on quality of life and economic impacts on society. The disease is a common sensory defect in humans that affects normal communication with approximately 17% of American adults suffering from some hearing loss, and the number of patients suffering from vestibular/balance disorders growing. Vestibular disorders occur frequently and can affect people of all ages. There was recognition that several different opportunities for molecular therapies exist for potential clinical delivery shortly and recognized the need for a true success paradigm as was witnessed in the visual system. Implementation of these needs demands steady funding for research, improved numbers of new investigators, and relevant scientific expertise for the review of hair cell regeneration applications.

Continued Research Needs and Opportunities

  • Relevant Disease Models
    There continues to be a critical need for the development of clinically relevant disease model systems that realistically mimic injury, time/duration, and rescue of function. The translatability of research data into a real-time disease perspective remains imperative in understanding the overall function of the disease process. Thus key demarcation of onset, progression, and time-dependent effects of hearing loss or vestibular afflictions will be critical in the development of relevant disease and treatment models.

    Conclusion: Continued development is needed of functionally relevant models that mimic trauma, genetic, and disease scenarios in auditory and vestibular systems. The NIDCD continues to support various animal models with focused paradigms toward auditory and vestibular discoveries. Development must be done with consideration of future clinical milestones that must be met to acquire a relevant treatment.

  • Molecular and Basic Research
    There continues to be a lack of comprehensive molecular and genetic data sets to give a full understanding of involved pathways and the regulatory differences of those pathways between normal and diseased states, comparative age determinant stages, and the development of specific cell types (hair cells, support cells, etc.). There could be helpful information to be gleaned on front-end molecular protection studies. Although there have been significant advances in these areas, the complete thoroughness of omic/informatical approaches and data network maps remain sparse. There is a need for unified open databases for a common depository of this information. In addition, functional models (mammalian and non-mammalian) and assays need to be refined and further developed by the implementation of novel technologies for cell and genetic manipulations as well as imaging and functional analyses.

    Conclusion: Continued comprehensive profiling at the molecular level to understand genes and proteins and their regulation between diseased and normal states, and to understand the translatability of that information to the human condition if using animal model systems. There is a specific need for the continued development/refinement of molecular tools such as in vitro/in vivo comparative assays and advanced genetic tools, for the improvement of cell and genetic manipulation. There should be recognized that many significant applications submitted to the NIH could be weighted heavily toward descriptive as a multitude of critical missing data sets is derived from profiling assays.

  • Cellular Systems
    Cell-based assays and investigative in vitro models can be very helpful for the functional characterization of candidate signaling pathways for development, functional maturation of inner ear tissue, ototoxicity, regeneration, and aging. In vitro models, if defined properly and interpreted with taking into account the specific limitations, can expedite the translation of basic research findings into more specific disease models.

    Conclusion: Continued development is needed of cell-based assays for basic laboratory, high-throughput (HTTP), or high-content, as well as disease-specific research. Therapy development, in some cases, can initially be more efficiently done in cell culture. These cell-based systems should be conducive to animal studies and translational approaches.

  • Delivery Targets and Agent Technology
    There continues the need for transforming and delivery agents such as recombinant nucleic acids, viruses, stem/progenitor cells, biodegradable polymers, and the varying possible combinations of multiple agents. Continued development is needed for ways to incorporate transformatively and agent delivery systems and to understand measurable efficacy for extended periods. Issues of the immune response, biological effects, and the potential re-administration effects of external agents need to be explored. In addition, delivery and/or transforming agents will dictate criteria for the delivery site. Continued investigation to determine optimal delivery sites and targets (e.g. perilymph, endolymph, stria vascularis, etc.) is needed in combination with differing accessibility issues depending on the individual and deliverable agent. Because of accessibility issues between the auditory and vestibular systems, there could be possible advantages to vestibular treatments.

    Conclusion: Continued efforts are needed to investigate delivery agents to the ear, particularly in the context of accessible delivery sites. Concurrently, clinical advances are needed in exploring relevant models wherein existing surgical techniques could be translated into the delivery of therapeutic agents.

  • Inspiring Novel Approaches with New Basic/Clinical Investigators
    The area of hair cell regeneration is a very small component of the overall NIDCD research portfolio and should be increased if regeneration is a field of promise. Attracting new and novel investigators with novel technology with the intention of developing creative and innovative approaches has the potential to move the field forward. Particularly in tight budgetary times, it could be an opportunity to attract new basic and clinical investigators to the field. Hair cell regeneration has been a challenging research area, but the chances that clinical interventions are possible are likely to increase in future years. Retention and recruitment of bright young investigators from other fields could be a major strategy where the investment could be highly beneficial for the future.

    Conclusion: A novel initiative to support novel and creative ideas from junior investigators. These could be senior postdocs, clinician scientists, and/or assistant professors with less than 5 years on the job. The explicit goal would be to attract young investigators who might have no track record working on auditory/vestibular-related problems and to tackle some of the biggest challenges in the field with creative novel approaches.