< Program

Technology Update Session

Session 3B
Preclinical Development of AK-OTOF: A Genetic Medicine for Otoferlin Gene-Mediated Hearing Loss
Michelle D. Valero, PhD, Akouos, Inc.

Millions of people worldwide have disabling hearing loss due to mutations in one of their genes that result in loss of expression or generation of an incorrect version of a protein required for hearing. The otoferlin gene (OTOF) encodes otoferlin, a protein critical for afferent signaling at the inner hair cell (IHC) synapse; individuals with biallelic mutations in OTOF typically present with congenital, Severe to Profound sensorineural hearing loss that can be identified early through newborn hearing screening that includes auditory brainstem response testing. Recent advances in both gene therapy and delivery to the intracochlear space support the potential to restore hearing in individuals with OTOF-mediated hearing loss by enabling IHCs to produce otoferlin using a one-time, local administration of AK-OTOF (AAVAnc80-hOTOF). Here, we describe the preclinical development strategy and key nonclinical studies that support the translation of AK-OTOF, an investigational genetic medicine, and an investigational delivery device, designed for intracochlear administration, to clinical development.The approach to deliver genetic medicines to the inner ear, including the design of a dual adeno-associated viral (AAV) vector, the Akouos delivery device, and an intracochlear administration procedure, was evaluated in in vitro studies, as well as in in vivo studies in otoferlin knock-out (Otof -/-) mice and non-human primates (NHPs). Nonclinical studies were conducted to inform the design of clinical investigation of AK-OTOF, including demonstration of biological plausibility by the intended clinical route of administration, evaluation of intervention window (with respect to otoacoustic emission [OAE] status), identification of biologically active dose levels, assessment of onset and durability of functional recovery, and evaluation of safety. Results from these studies indicate that a one-time intracochlear administration of AK-OTOF to mice and NHPs results in robust expression of full-length otoferlin protein in the target IHCs (and not in other cell types). The Otof -/- mouse phenotype supports its utility for preclinical development, including determination of biologically active dose levels of AK-OTOF that restored auditory function by 2 weeks post-administration, and through at least 6 months post-administration (the longest survival duration evaluated), and determination of potential for restoration of auditory function based on status of cochlear integrity (as evaluated by OAEs). Evaluation of safety and otic tolerability of AK-OTOF was conducted in both NHPs and mice; no adverse effects were observed in clinical pathology, otic pathology, systemic histopathology, and/or cochlear / auditory function, demonstrating that AK-OTOF was systemically and locally well tolerated. The strategy employed for preclinical development of AK-OTOF, leading to FDA clearance for a clinical trial in pediatric individuals with OTOF-mediated hearing loss, can serve as an exemplary path to achieving the broader goal of developing precision genetic medicines with the potential to restore, improve, and preserve high-acuity physiologic hearing for individuals worldwide who live with disabling hearing loss. Referral for genetic testing is critical for a definitive establishment of the underlying cause and to facilitate identification of individuals who may benefit from precision genetic medicines for genetic forms of hearing loss, such as OTOF-mediated hearing loss.

Michelle Valero received her PhD in Neurobiology from the University of Texas in San Antonio and then trained with Dr. Charles Liberman as a postdoctoral fellow at Massachusetts Eye and Ear. As Senior Director and Head of the Anatomy and Physiology Team at Akouos, Inc, she now leads a diverse team of nonclinical scientists responsible for testing the efficacy and safety of product candidates from early discovery through IND-enabling studies.