Neurologic & Ophthalmic - American Society of Gene & Cell Therapy

Neurologic & Ophthalmic Gene & Cell Therapy
Summary by Anne Messer, PhD
Gene and Cell Therapies for Auditory and Olfactory Disorders
Co-Chairs: Jodi L. McBride, PhD and Anne Messer, PhD
Gene and cell therapies for auditory and olfactory disorders are promising approaches for
human therapeutics. Although the field is relatively new, a combination of genetic and
environmental perturbations in humans can be modeled sufficiently to optimize
parameters, and establish proof of concept to move the most promising corrections
forward clinically.
Jeffrey Holt, PhD, gave an excellent introduction to the auditory system, and the sensory
transduction process, including dysfunctions. His lab is particularly focused on the
tension-controlled calcium channels, TMC1 and 2. Tmc1 is expressed in hair cells, and
knockout mice have been produced to mimic a genetic disorder that causes deafness in
humans. Gene replacement in vitro demonstrated rescue of function. In vivo work with
AAV1 is in progress. The availability of TMC2 knockouts (which appear to primarily
affect the vestibular system) and double knockouts provides additional opportunities to
model, understand, and correct this critical set of pathways in the auditory system.
Larry Lustig, MD, presented AAV1-mediated restoration of hearing in vesicular
glutamate transporter 3 (VGLUT3) knockout mice. The acoustic brainstem response can
be fully corrected, and the readily-measured startle response is partially corrected. Dr.
Lustig presented data on several parameters that affect the degree and persistence of
correction, including viral titer, route of administration, and age of treatment. P1
treatment was the most effective and long-lasting. Round window membrane delivery of
virus appears to be as effective as a cochleostomy at this early age of delivery.
The third presentation on auditory correction strategies described cell, rather than gene,
therapy. Marcelo Rivolta, MD, starts with human embryonic stem cells (hESCs), which
can be directed to otic epithelial or otic neuronal progenitors, using FGF3 or FGF10.
The former further differentiate with tissue signals as hair or ganglion cells, while the
latter form only the ganglion neurons. When transplanted into a gerbil deafness model,
the cells can survive and form functional connections offering partial correction.
Olfaction is another sensory organ that is vulnerable to genetic and environmental
damage, with some severe effects on safety and nutrition. Jeffrey Martens presented
studies using adenovirus to correct the cilliary protein IFT88 in olfactory sensory
neurons. Delivery of this gene into knockout mice improved their feeding behavior and
body weights, via transduction of mature neurons. This general approach is applicable to
multiple important ciliated cell types.

The variety of targets and approaches covered by the speakers illustrate the strong
potential for gene and cell therapy to impact a wide range of human sensory disorders.