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Report of the Molecular Therapies for Auditory/Vestibular Disease Workshop

September 7, 2005
Bethesda North Marriott Hotel and Conference Center
Bethesda, Maryland

The NIDCD held a workshop to discuss the current and future state of molecular therapy development in auditory and vestibular disease. The purpose of the workshop was to discuss and identify research opportunities that will advance/translate targeted molecular approaches into clinical treatments. The workshop, organized by Nancy Freeman, Ph.D., Division of Extramural Research, NIH-NIDCD, and chaired by Douglas Brough, Ph.D., Genvec Inc., brought together a group of investigators with expertise in auditory and vestibular biology, pharmacokinetics, clinical gene therapy, and FDA regulatory topics specific to molecular therapeutic approaches.

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. Brough then moderated the day's agenda and discussion period. Each speaker was given a 30-minute time slot that included ~5–10 minutes for discussion.

Discussion Overview and Research Opportunities

The last decade of molecular and genetic research has increased our understanding of basic processes and diseases within the auditory and vestibular systems. The field is now positioned to advance targeted therapeutics for diseases affecting these sensory systems. Potential restoration of auditory/vestibular function by the delivery of a targeted gene, drug or other synthetic/biological compound presents a unique opportunity to combine both basic scientific research with the simultaneous development of a potential clinical therapeutic. Basic biological research must continue in identifying genes and signaling cascades important to the scientific information base, but must be broadened to integrate issues of inner ear and vestibular pathology, homeostasis, delivery, and immunology specific to a targeted therapy scenario. Further, vector delivery systems, whether biologically based or other, need continued advancement to address issues of efficacy, cellular and system toxicity. Importantly, truly relevant disease model systems which mimic real time auditory/vestibular dysfunction needs to be developed and tested in therapeutic treatment environment, wherein lead molecules can be selected and appropriate safety and efficacy studies conducted.

To aggressively move molecular based therapies to the marketplace, clear milestones should be established. Optimistically, now is the time to streamline federal oversight hurdles to therapy development and to make targeted therapy development more attractive. For NIH/NIDCD, this means continued access to funding availability and to specific review panels that address the needs of translational research. To this end, there will need to be a paradigm shift from hypothesis-driven research to task-and-descriptive efficacy research.

At present, there has been no specific drug or other cellular therapeutic developed for the ear and thus large pharmaceutical companies remain uninterested. This creates an opportunity to develop new outreach programs to foster joint collaborative ventures between large and small biotechnology and pharmaceutical companies, and federal agencies to streamline and fastrack pharmaceutical therapeutic development for inner ear and vestibular disease. Key areas of interest include development of clinically relevant models that can be used for lead molecule selection and safety studies for specific clinical applications. The next stage will be the support for critical phase I clinical trials to test safety of new therapies. All of this is now possible and should be considered a major area for NIDCD interest in the near term.

Research Opportunity Highlights:

  • Basic Research
    The science behind molecular therapeutics in the auditory/vestibular systems is extremely strong. A decade of research funding to understand the molecular genetic pathways of development and potential disease in the ear has proven very fruitful. The workshop highlighted work from several investigators that clearly demonstrated the advances made in this area. Researchers working in the ear and the adjoining vestibular system are truly well positioned to advance models for basic research. Because the auditory and vestibular systems are subject to diverse diseases, it is important to analyze their different microenvironments as potentially therapeutic targets. Examples for consideration are epidermal delivery, outer membrane mucosa, and biofilms as putative targets for delivery of drugs and small molecules for treatment of middle ear infections. There is a lack of good biomarkers and a general lack of understanding the overall role of the vascularization process and how these interface with infection and disease of the auditory system. At specific cellular levels, advances in hair cell regeneration point to key molecular advances that are unique for the inner ear. In particular, the science behind the ability of one gene (atonal) to induce a differentiated cell to change into a complex new cell is exciting. This observation provides a hope that additional basic research will help develop one of the first inner ear therapies. To this end, researchers must continue to aggressively explore combinatorial approaches between other molecules/cell populations in combination with targeted gene delivery approaches. In areas of hardware implants, pre- and post treatment with selected molecules may facilitate better biological and functional recovery.

    Conclusion: The efforts in basic research to uncover the molecular and genetic processes of ear disease should continue with the advancement of key programs into clinical testing. The continuation of discovery research into every aspect of molecular mechanism should be done with simultaneous advancement of appropriate concepts into the clinic.

  • Importance of relevant disease models
    The auditory and vestibular systems are dynamic and non-static environments. There is a need to continue to develop clinically relevant model systems that realistically mimic injury time/duration and rescue of function. For example, analyzing the end outcome such as cell death will mostly likely involve different cellular participants than those involved in a neuroprotective process, thus key demarcation of onset, progression and time-dependent effects of hearing loss or vestibular afflictions will be critical in development of relevant disease models.

    Conclusion: Continued development is needed of relevant models that mimic trauma, genetic, and disease scenarios in auditory and vestibular systems. Development must be done with consideration of future clinical milestones that must be met to acquire a useable treatment.

  • Auditory/Vestibular Programs are an unmet medical need and 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 serious debilitating condition with devastating effects on quality of life and economic impacts on society. The disease is a common sensory defect in humans, affecting normal communication in 10 percent of people aged 65 years or older and in 50 percent of those greater than 80 years old. Approximately 28 million Americans, or about one in every ten people suffer from some hearing loss. The numbers of patients suffering from balance disorders are growing. Vestibular disorders occur frequently and can affect people of all ages. A common cause of balance dysfunction is due to ototoxcity caused by pharmaceutical drugs or infection. As a result, these patients lose their vestibular sensory hair cells and at present, there are no treatments available. Because auditory and vestibular sensory dysfunctions are not terminal diseases, they have a lessened mortality risk factor commonly associated with other diseases and thus represent an attractive candidate for therapeutic development. Several different opportunities for molecular therapies exist for potential clinical delivery in the near future. One example being transdifferentiation induced by atonal gene expression. Participants continued to summarize efforts from both biotech industry and academia that illustrated successful ways to translate research concepts into clinical therapeutic trials. In all cases, efforts were poised to select a lead molecule and move to phase 1 trial as quickly as possible to assess safety in people. In most cases clinical trials showing efficacy follow demonstration of drug safety in phase I; however, several phase 1 trials have indicated that the overall concept may provide enough efficacious therapeutic response to move forward to a clinical therapeutic for the treatment of inner ear disease. Participants were reminded of other possible clinical targets, for example, the middle ear, and how each represents an interesting possible clinical target worthy of consideration for translational research.

    Conclusion: The market potential for targeted therapies in these disease areas could be vast. Clinical indications need to described and translational research supported to advance the first molecular therapies to auditory/vestibular systems. Appropriate safe clinical approaches with a well-defined clinical population will advance translational research.

  • Importance of delivery technology
    Approaches within the inner ear will require proper delivery technology. Clinically relevant approaches to reach the inner ear and middle ear are currently available and are relevant for drug delivery. Several panelists clearly envisioned the feasibility for delivery into the inner ear. While delivery device development is important to the field, it should not be a prohibitive metric to move forward other approaches to human testing stages. Alternatives to device delivery were also discussed with discussion of biodegradable polymers and other compounds to deliver the vector/targeted gene over time. Continued development is needed for ways to incorporate gene delivery systems in these materials and to understand marked release rates of virus from these preparations for extended periods of time. Again, issues of immune response, biological effects and the potential readministration effects of the vector need to be explored. The panelists also discussed the importance in accessibility issues between the auditory and vestibular systems, and in specific cases, vestibular treatments may not have as much difficulty with delivery.

    Conclusion: Continued efforts are needed to generate devices for drug delivery to the ear to expand accessibility of delivery. Clinical advances are needed in exploring relevant models wherein existing surgical techniques can be translated into specific therapeutic applications.

  • Pharmacology in drug design and safety
    Pharmacokinetics is a key component in advancing drugs and other small molecule biologics into the ear. The impact is in selection of clinical candidates, the label for the use of the therapeutic (dose, toxicity, efficacy), formulation selection, quality control and performance, animal model selection, in vitro/in vivo correlative assays, mechanism (ADME), which all lead to the optimized dose for the therapeutic. Specific to targeted gene delivery systems using the adenovirus, full toxicological assessment in the appropriate animal model should be performed. Issues to be addressed should be general assessment of full body biodistribution of the virus, systemic toxicity (in the form of the acute and chronic immune response to the virus (and the transgene) ) and other side effects that may arise from the treatment in a dose dependent manner. Other vectors used or being considered for gene delivery will also have the same toxicity concerns and similar criteria would need to be met. The adenovirus as a vector for gene delivery to the auditory and vestibular systems appears to work well; only short-term expression appears to be necessary for stimulation of hair cell growth. However, other vectors/agents may offer longer-term expression and perhaps transduce other targets in the auditory system and should be explored further. Targeting the adenovirus can be achieved by several methods (serotyping, PEGylation, crosslinking to monoclonal antibodies, etc.). Participants recognized that optimization for gene transfer via delivery and formulation methods would continue to be important. Combinatorial approaches between delivery systems and introduced molecules may provide a needed back door when/if a potential "rescue" may be needed; it can offer an "escape hatch" for the discontinuation of therapy.

    Conclusion: Aspects of pharmacokinetics will be critical for successful translational of ear/vestibular therapies. Animal models developed specifically for the clinical application will be important in lead molecule selection and safety evaluation.

  • The FDA as partner to translate drugs, biologics, into therapies
    The FDA is a critical component in the successful translation of new discoveries into clinical applications. Understanding the regulations and working with the FDA is an ongoing process to reach a clinical application. Experienced participants with successful translation experiences confirmed and highlighted that several different gene transfer applications have moved forward through the FDA by working directly with the agency. Several different areas need to be considered when thinking of moving this aspect of the translational component forward:
    • design the trial with an eye to the future. The purpose of the phase 1 trial is safety, but where possible design the trial to gain other relevant information, such as clinical activity, functional activity, duration, level of transgene expression, vector biodistribution, immune responses.
    • product development does not stop at the phase 1. Design the trial to consider product stability when used and intended and for the future, development of assays to measure potency, characterization of the drug for purity, and scale-up for treatment of a larger patient population.

    Conclusion: The FDA is a partner to move forward translational research in the ear. Clinical approaches should consider design aspects that could move the program into the future. The FDA and NIH need a more streamlined partnership in moving biologics into applied therapeutics.