Strategic Plan RFI
ASGCT response to National Institute for Deafness and Communications Disorders RFI
Submitted March 31, 2020
1. What are the most significant scientific discoveries in hearing and balance, taste and
smell, and voice, speech, and language that have occurred in the past five years? (Please
provide references to scientific journal articles, if applicable.)
The American Society of Gene & Cell Therapy (ASGCT) is appreciative of this opportunity to
provide input on NIDCD’s strategic priorities. ASGCT is a nonprofit professional membership
organization comprised of more than 3,500 scientists, physicians, and other professionals
working in gene and cell therapy in settings such as universities, hospitals, and biotechnology
companies. Our comments focus on the importance of research funding for gene therapy due to
its considerable potential to treat hearing and balance disorders with significant unmet need.
While genetic factors contribute to almost half of all cases of deafness, treatment options for
genetic forms of deafness are limited. The genetics of congenital balance disorders are poorly
understood, but multiple examples demonstrating dramatic recovery of balance phenotypes in
mutant mice treated with gene therapy highlight the potential of this relatively unexplored space.
The most significant discoveries in the past five years include the successful application of gene
therapy using adeno-associated viral (AAV) vectors to the inner ear. Zinn et al. first described
the synthetic vector AAVAnc80 (2015, doi:10.1016/j.celrep.2015.07.019). In turn Landegger et
al. (2017, doi:10.1038/nbt.3781) first reported using a serotype of AAVAnc80 to successfully
transduce cochlear hair cells, followed by Nist-Lund et al. (2019, doi:10.1038/s41467-018-
08264-w). Gyorgy et al. (2018, doi:10.1016/j.omtm.2018.11.003) reported successful cochlear
transduction in mice utilizing an AAV9 capsid variant. These reports suggested that existing
AAV-based gene therapy technologies could be adapted to the inner ear.
The development of strategies for restoring hearing and balance in mouse models has been
reported in a number of recent studies. Askew et al. (2015, doi:10.1126/scitranslmed.aab1996)
and Nist-Lund et al. (2019, doi:10.1038/s41467-018-08264-w) attained positive results via gene
addition in mice with TMC-type mutations. Gene addition was also utilized with some success in
mice with CLRN1 mutations, associated with Usher syndrome type 3A (Geng et al., 2017,
doi:10.1038/s41598-017-13620-9). Across two academic groups, remarkable hearing rescue was
achieved in in congenitally deaf, Otoferlin-deficient mice using a dual AAV approach to deliver
this large gene (Akil et al., 2019, doi:10.1073/pnas.1817537116; Al-Moyed et al., 2019,
doi:10.15252/emmm.201809396). These studies serve as proof of principle that the inherent
inefficiencies of dual AAV approaches can be overcome in the closed compartment of the ear
and are now being developed as therapeutics by several companies. In an alternate approach,
Shibata et al. (2016, doi:10.1016/j.ajhg.2016.03.028) were able to prevent hearing loss in TMC1
mice via RNA interference. On the gene editing side, Gao et al. (2018, doi:10.1038/nature25164)
and Gyorgy et al. (2019, doi:10.1038/s41591-019-0500-9) found CRISPR/Cas9 gene editing to be effective on genetic hearing loss in mice with a dominantly inherited form of genetic
deafness.
It was a breakthrough that Yoshimura et al. (2019; doi:10.1016/j.ymthe.2018.12.014) and Akil et
al. (2019; doi:10.1073/pnas.1817537116) successfully applied gene therapy to adult mice.
Previous studies were of gene therapies for neo-natal mice, whose hearing does not develop fully
for several weeks after birth; since human hearing develops in utero, the ability to use gene
therapy successfully in mature murine ears was a significant step toward its translation to human
subjects.
Notably, the first clinical trial for hearing loss began in 2014, targeting the Atoh1 transcription
factor. The trial, sponsored by Novartis and completed in December 2019, tested Atoh1 gene
therapy for individuals with severe-to-profound unilateral or bilateral hearing loss to regenerate
hair cells (ClinicalTrials.gov Identifier: NCT02132130). The trial’s initial findings will assist the
field in prioritizing endpoints and target populations for the next wave of regenerative
therapeutics.
2. What are the unmet needs in current research and training that may impact hearing and
balance, taste and smell, and voice, speech, and language?
Vector refinement and development for gene therapy are at the forefront of unmet needs in
hearing research. Gene and cell therapies for hearing and balance disorders would particularly
benefit from additional research into vectors with more efficient transduction capability, as well
as evaluation of specific promoters for different cochlear cell types. It will also be important to
determine which genes have multiple isoforms and what role they play; expanded knowledge of
those isoforms specific to the inner ear is essential for effective gene therapy. Exploration
outside the realm of conventional AAVs, which make up the majority of vectors used in hearing
gene therapy research, may expand researchers’ toolboxes to include synthetic AAVs, other
types of viral vectors, or vectors that are non-viral in nature. Additionally, more research is
needed on the development of base editors and guide RNAs (gRNAs) to correct missense
mutations, as well as on development and targeting of prime editors and prime editing guide
RNAs (pegRNAs) to correct insertion-deletion mutations. Research on utilizing gRNAs and
pegRNAs in dividing cells would be especially beneficial.
The impact of preexisting immunity to common vectors in the inner ear is a key unknown for
hearing gene therapies; insufficient data exist to determine how preexisting immunity may
interfere with cochlear gene therapy administration. Whereas the disqualifying immune response
threshold for systemic intravenous administration is relatively well understood, further research
is required to determine levels for the unique environment of the inner ear.
Lack of relevant cell lines and in vitro cell models is another significant unmet need in current
hearing and balance research. In addition, gene therapy research is impossible without effective
preclinical models. ASGCT members believe it is critically important that improved, wellcharacterized animal models be developed for hearing and balance disorders, including common
hereditary hearing disorders. Needs include the development of improved mouse models to support preclinical proof-of-concept studies, as well as non-rodent models for translational and
bridging studies. Very few non-rodent models and/or human tissue proxies can be used to bring
products from animal models to humans in an effective manner. Although there has been striking
success in transducing the cochlea in a nonhuman primate (Ivanchenko et al., 2020,
doi:10.1016/j.heares.2020.107930), many more vectors need to be tested and toxicity evaluated.
Gene therapies for sensorineural forms of hearing loss would also benefit from more thorough
natural history studies of human hereditary deafness and balance disorders. Such research would
help determine the most effective treatment window for therapeutic intervention. Natural history
studies could also illuminate the cochlea’s transcriptome, enabling researchers to correlate
genotype with phenotype in specific hearing disorders, identify treatable patient populations, and
rationally design clinical trials. Particularly lacking is an understanding of the progression of
histopathology in humans, which will be essential to identifying diseases with a viable treatment
window. Since many mutations likely result in rapid deterioration of the ear prior to birth in
humans, a concerted effort to collect more human temporal bone data will be key to advancing
new therapeutics for patients. As patient identification and natural history understanding
improves, a number of other issues may need to be addressed, including appropriate endpoints to
demonstrate clinically meaningful benefit for various disorders and age groups.
3. Describe the opportunities in hearing and balance, taste and smell, and voice, speech,
and language that may be realized in the next five years.
Gene therapies, including gene editing, have the potential to address a wide variety of genetic
hearing and balance disorders. Like the eye, which was the target of the first in vivo gene therapy
to receive FDA approval in the United States, the ear presents a small, enclosed environment that
exists in relative isolation from other body systems. For this reason, high concentrations of a
therapeutic can be delivered to target cells with minimal systemic exposure, offering an ideal
setting for development of gene therapies.
Current genetic testing research has made clear the large number of genes that relate to hearing
loss, which is both an opportunity and a challenge. Research on gene therapy for hearing loss has
the potential to grow significantly with the development of effective tools and innovative
therapies, and researchers have made great progress toward proof-of-concept studies. The safety
and efficacy findings from ongoing and upcoming clinical trials of gene therapy for the ear may
assist in the identification of additional potential genetic hearing and balance disorders for which
gene therapy may be beneficial.
Techniques as varied as stem cell grafting, induced cell differentiation, and other approaches to
hair-cell repair are in early exploratory phases. The development of mutation-agnostic gene
therapy approaches would be a monumental advance. Other early studies have explored
stimulating and regenerating synapses in cases of hidden hearing loss, in which an individual can
pass a standard hearing test but cannot differentiate sounds in a noisy environment. As varied
therapeutic avenues are discovered, entirely novel techniques may also be developed.
At a physiological level, much is still unknown about the functionality and development of the
inner ear, particularly in individuals with congenital hearing loss. It is critical that researchers have access to high-quality otopathologic data, like that stored at the three national otopathology
laboratories. Patient registries would also be an effective way to illuminate population size
within each diagnosis.
4. What are the greatest challenges or barriers to progress in hearing and balance, taste
and smell, and voice, speech, and language?
While most genes associated with hearing loss are small enough to be packaged in a single AAV,
there are a number that are too large. Studies in the last year have demonstrated some success
with cochlear dual-vector delivery in mouse models (Akil et al., 2019,
doi:10.1073/pnas.1817537116; Al-Moyed et al., 2019, doi:10.15252/emmm.201809396). Other
techniques could include a gene-editing approach, which has shown early results (Gao et al.,
2018, doi:10.1038/nature25164; Gyorgy et al., 2019, doi:10.1038/s41591-019-0500-9), or
miniaturizing the gene. The challenge of packaging capacity will need to be overcome across
gene therapy disciplines. Additionally, some gene therapies will require development of postadministration safeguards, in which a genetic off switch is activated to prevent indiscriminate
gene expression. Therapeutic transgenes expressed in non-target cells could lead to safety
concerns, and this will need to be better understood as hearing gene therapies are developed.
The isolation that makes the ear attractive for gene therapy also makes it difficult to access. This
therapeutic accessibility “blind spot” impacts the ability to track therapeutic response and match
the right patient with the right therapeutic approach, and impedes clinical trial design for many
ear diseases. Imaging might involve a surgical probe approach, electrophysiological screening, or
other techniques, but the sheer visual impassability of the inner ear has been a challenge for
developing pharmacologic therapies, including gene therapies. The development of less invasive
delivery of gene therapies to the inner ear could also be beneficial, either through simplified
surgical approaches or through delivery systems that do not require injection directly into the
cochlear fluid space.
As in all fields, nonhuman models and human tissue proxies are imperfect corollaries for human
biology. Mice, for example, develop hearing in a similar manner but on an entirely different time
course than humans, so may have limited utility beyond the proof-of-concept stage if an
investigational therapy is administered before the postnatal maturation of the cochlea (which is
prenatal in humans and nonhuman primates). Cultured human inner ear hair cells are an effective
study subject when available, but they are difficult to culture and are extremely short-lived.
Cochlear and inner ear organoids, which have come far in the last half decade (Roccio & Edge,
2019, doi:10.1242/dev.177188), are useful for drug screening but have innate limitations for
more advanced research. Developing additional, and in some cases more accurate, mouse models
in terms of reflecting the phenotype in humans, could be necessary to support further research.
The availability of larger animal models of genetic hearing loss could also help facilitate
translational activities.
ASGCT appreciates your consideration of these comments. Please do not hesitate to contact us if
you have questions