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Researchers have found a way to better control the preclinical generation of key neurons depleted in Parkinson's disease, pointing toward a new approach for a disease with no cure and few effective treatments. Researchers at the University of Toronto have found a way to better control the preclinical generation of key neurons depleted in Parkinson's disease, pointing toward a new approach for a disease with no cure and few effective treatments. The researchers used an antibody to selectively activate a receptor in a molecular signaling pathway to develop dopaminergic neurons. These neurons produce dopamine, a neurotransmitter critical to brain health. Researchers around the world have been working to coax stem cells to differentiate into dopaminergic neurons, to replace those lost in patients living with Parkinson's disease. But efforts have been hindered in part by an inability to target specific receptors and areas of the brain. "We used synthetic antibodies that we had previously developed to target the Wnt signaling pathway," said Stephane Angers, principal investigator on the study and director of the Donnelly Centre for Cellular and Molecular Biology. "We can selectively activate this pathway to direct stem cells in the midbrain to develop into neurons by targeting specific receptors in the pathway," said Angers, who is also a professor in the Leslie Dan Faculty of Pharmacy and the Temerty Faculty of Medicine, and holds the Charles H. Best Chair of Medical Research at U of T. "This activation method has not been explored before." The study was recently published in the journal Development. Parkinson's disease is the second-most common neurological disorder after Alzheimer's, affecting over 100,000 Canadians. It particularly impacts older men, progressively impairing movement and causing pain as well as sleep and mental health issues. Most previous research efforts to activate the Wnt signaling pathway have relied on a GSK3 enzyme inhibitor. This method involves multiple signaling pathways for stem cell proliferation and differentiation, which can lead to unintended effects on the newly produced neurons and activation of off-target cells. "We developed an efficient method for stimulating stem cell differentiation to produce neural cells in the midbrain," said Andy Yang, first author on the study and a PhD student at the Donnelly Centre. "Moreover, cells activated via the FZD5 receptor closely resemble dopaminergic neurons of natural origin." Another promising finding of the study was that implanting the artificially-produced neurons in a rodent model with Parkinson's disease led to improvement of the rodent's locomotive impairment. "Our next step would be to continue using rodent or other suitable models to compare the outcomes of activating the FZD5 receptor and inhibiting GSK3," said Yang. "These experiments will confirm which method is more effective in improving symptoms of Parkinson's disease ahead of clinical trials." This research was supported by the University of Toronto Medicine by Design program, which receives funding from the Canada First Research Excellence Fund, and the Canadian Institutes of Health Research.

Regenerative Treatment Designed to Increase Drug Exposure Through the Cochlea; Study Results Expected in H2 2023 Frequency’s Lead Hearing Program, FX-322, on Track for Phase 2b Topline Results in Q1 2023 LEXINGTON, MA, USA I December 15, 2022 I Frequency Therapeutics, Inc. (Nasdaq: FREQ), a clinical-stage regenerative medicine company focused on developing therapeutics to activate a person’s innate potential to restore function, today announced that it has dosed a first patient in the Phase 1b study of FX-345, the Company’s second hearing restoration candidate for sensorineural hearing loss (SNHL). FX-345 is a combination of two small molecules and, similar to Frequency’s lead hearing candidate FX-322, is designed to restore inner ear cells needed for hearing. However, FX-345 includes a more potent GSK3 inhibitor, a new chemical entity that may enable targeted drug exposure further into the cochlea. Future clinical studies will determine whether greater cochlear drug exposure can address additional populations of individuals with SNHL. “Advancing FX-345 to the clinic is an exciting milestone as we further our pioneering work to develop regenerative therapeutics for hearing loss. By expanding our hearing pipeline, we hope to better understand the breadth of SNHL types and severities we may be able to treat, and we look forward to FX-345 Phase 1b study data in the second half of next year,” said Frequency’s Chief Executive Officer David L. Lucchino. “I am pleased with our team’s work to advance small molecule drug delivery, enabling us to explore the impact of reaching further into the cochlea to build upon our understanding of how our approach may restore human hearing.” The Phase 1b trial, FX-345-101, is a prospective, randomized, single-blind, placebo-controlled, multicenter study to evaluate the safety of FX-345, administered as a single intratympanic injection, in approximately 36 adults aged 18-67, with adult-onset acquired SNHL. The study is divided into two cohorts, with an initial safety cohort of nine subjects designed to provide a rapid assessment of safety and drug exposure. Pending favorable safety results, a second cohort of 27 subjects will be dosed to continue the safety assessment and evaluate whether FX-345 favorably improves measures of auditory function. Within each cohort, subjects will be randomized 2:1 to receive a single dose of FX-345 or placebo. In pre-clinical studies, pharmacokinetic measures and computer modeling data suggest that FX-345 administration in this trial may result in therapeutically active drug levels in a broad portion of the human cochlea. The Company anticipates delivering clinical results in the second half of 2023. Frequency is also evaluating FX-322, a therapeutic candidate for SNHL, in an ongoing Phase 2b study (FX-322-208). The prospective, randomized, double-blinded, placebo-controlled, multi-center study is designed to evaluate the efficacy of FX-322 on speech perception in subjects aged 18-65 with hearing loss associated with either noise-induced or permanent idiopathic sudden SNHL. The study is fully enrolled with 142 participants and clinical results are expected in the second half of Q1 2023. About Sensorineural Hearing Loss Sensorineural hearing loss is the most common form of hearing loss, typically resulting from damage to sensory hair cells in the cochlea. These cells convert sound waves to signals sent to the brain which are interpreted as speech and sound. Sensory hair cells are lost due to chronic noise exposure, aging, certain viral infections or exposure to drugs that are toxic to the ear. This type of hearing loss impacts around 40 million individuals in the U.S. alone. About Frequency Therapeutics Frequency Therapeutics is leading a new category in regenerative medicine that aims to restore human function – first in hearing loss and then in multiple sclerosis – by developing therapeutics that activate a person’s innate regenerative potential within the body through the activation of progenitor cells. Frequency’s hearing research focuses on cochlear restoration and auditory repair, and its lead asset, FX-322, is a small-molecule combination product candidate that is the first to show statistically significant and clinically meaningful hearing improvements in clinical trials for sensorineural hearing loss. Frequency is also following early restorative signals in MS to develop medicines with similar underlying regenerative science being brought to hearing loss. Headquartered in Lexington, Frequency has an ex-U.S. license and collaboration agreement with Astellas Pharma Inc. for certain hearing loss products, which includes FX-322 and FX-345, as well as additional collaboration and licensing agreements with academic and nonprofit research organizations including Massachusetts Eye and Ear, Mass General Brigham, the Massachusetts Institute of Technology, and the Scripps Research Institute. For more information, visit www.frequencytx.com and follow Frequency on Twitter @Frequencytx. SOURCE: Frequency Therapeutics