hair cell regeneration
The Expression and Roles of the Super Elongation Complex in Mouse Cochlear Lgr5+ Progenitor Cells
Super Elongation Complex might play important roles in regulating inner ear progenitors and regulating hair cell regeneration.
High-throughput screening on cochlear organoids identifies VEGFR-MEK-TGFB1 signaling promoting hair cell reprogramming
VEGFR-MEK-TGFB1 signaling crosstalk as a potential target for hair cell regeneration and hearing restoration.
The Hunt for Drugs That Promote Ear Hair Cell Regeneration
“Nanjing University researchers use cochlear organoids to identify drugs that can promote the regeneration of hair cells”
Research Progress on the Mechanism of Cochlear Hair Cell Regeneration
Front. Cell. Neurosci., 29 March 2021 | https://doi.org/10.3389/fncel.2021.660748
Transcription Factor Reprogramming in the Inner Ear: Turning on Cell Fate Switches to Regenerate Sensory Hair Cells
Non-mammalian vertebrates can restore their auditory and vestibular hair cells naturally by triggering the regeneration of adjacent supporting cells. The transcription factor ATOH1 is a key regulator of hair cell development and regeneration in the inner ear. Following the death of hair cells, supporting cells upregulate ATOH1 and give rise to new hair cells. However, in the mature mammalian cochlea, such natural regeneration of hair cells is largely absent. Transcription factor reprogramming has been used in many tissues to convert one cell type into another, with the long-term hope of achieving tissue regeneration. Reprogramming transcription factors work by altering the transcriptomic and epigenetic landscapes in a target cell, resulting in a fate change to the desired cell type. Several studies have shown that ATOH1 is capable of reprogramming cochlear non-sensory tissue into cells resembling hair cells in young animals. However, the reprogramming ability of ATOH1 is lost with age, implying that the potency of individual hair cell-specific transcription factors may be reduced or lost over time by mechanisms that are still not clear. To circumvent this, combinations of key hair cell transcription factors have been used to promote hair cell regeneration in older animals. In this review, we summarize recent findings that have identified and studied these reprogramming factor combinations for hair cell regeneration. Finally, we discuss the important questions that emerge from these findings, particularly the feasibility of therapeutic strategies using reprogramming factors to restore human hearing in the future.
Here is a sneak preview of an upcoming podium presentation from Will McLean (Frequency Therapeutics) about hearing restoration and FX-322:
In less than two weeks from today, the 44th Annual ARO MidWinter Meeting will begin.
It is a virtual conference.
On Monday, February 22, 2021, Will McLean (Frequency Therapeutics) will give a podium presentation at this virtual conference.
Here is a copy of McLean’s podium abstract:
Preclinical/Clinical Translational Evidence for a Potential Hearing Restoration Therapeutic, FX-322
Background: Cochlear hair cell loss in mammals is permanent because progenitor cells fail to divide and differentiate on their own. Previous work has shown that the two compounds in FX-322 enhance the regenerative potential of mouse and human progenitor cells in vitro. This multi-group collaboration assessed the pharmacodynamic (PD) and restorative potential of FX-322 in a mouse noise-induced hearing loss (NIHL) model, cochlear pharmacokinetics (PK) of intratympanically injected FX-322 in guinea pigs, perilymph concentrations in patients undergoing cochlear implantation, and a safety study of FX-322 in patients with permanent sensorineural hearing loss (SNHL).
Methods: PD effects were first assessed in a NIHL mouse model to assess the therapeutic potential of FX-322. PK studies with FX-322 were performed in guinea pigs to calibrate a well-established computer model predicting drug distribution over the length of the cochlea with time. The animal PK model was extended to humans by analysis of perilymph samples collected from subjects undergoing cochlear implant surgery. A double-blinded, placebo-controlled, safety trial in patients with permanent/stable SNHL was conducted to assess the systemic safety, plasma PK, and effects on otoscopy, audiometry, and word testing (WR, WIN). The trial enrolled 23 patients with medical histories consistent with either NIHL or sudden SNHL. Treatment was a single unilateral intratympanic dose and patients were monitored overnight for safety, PK and PD over a 90-day period.
Results: Animal PD – A single intratympanic injection of FX322 was associated with increased hair cell counts and improved auditory function compared to placebo in mice with NIHL within one month after treatment. Guinea Pig PK – FX-322 concentrations in samples taken from the RW niche were found to decrease with time, with elimination half-times under 1 hour. The highest drug concentration was observed in the basal regions. Human PK – Intraoperative middle ear contents and perilymph were analyzed for FX-322 approximately 1 hour into surgery for cochlear implant subjects (n=7). While some subjects had anatomical features that have been speculated to impair drug entry, such as mucosal folds or bony overhangs, FX-322 was quantified in all samples analyzed. Human Safety and PD – FX-322 was associated with a favorable safety profile. In FX-322-treated subject ears WR and WIN improved over the duration of the study while placebo-treated subject ears did not.
Conclusions: Both preclinical and clinical PK analyses suggest that FX-322 was able to achieve therapeutically active levels in the extended high frequency region of the cochlea. Preclinically, this was associated with an increase in hair cell counts and auditory brainstem response thresholds. The present work provides the first evidence that a novel potential therapeutic, FX-322, is associated with clinically meaningful improvements in speech recognition in subjects with permanent and stable SNHL, and larger clinical studies are underway.
The source of this “podium abstract” is the Association for Research in Otolaryngology (ARO)’s 44th Annual Mid-Winter Meeting event website.
Here is a link to the
official PDF copy of the February 22, 2021 FX-322 podium presentation [EDIT #1: the link does not work, removed] (uploaded online by ARO’s event organizers… who have once again done a superb job organizing all of the presentations, speakers, podiums, posters, and more, into a friendly and searchable format *even when some links don’t work!).
What’s “new” here?
For readers who have been closely following FX-322 updates… there is nothing truly “new” in this presentation preview. However, we do not know what other data or information or announcements will be shared alongside this presentation. Perhaps we will also get a press release on Monday, February 22 which gives us more substantial “news” *fingers crossed*…
RE: FX-322 updates…
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Macrophages respond rapidly to ototoxic injury of lateral line hair cells but are not required for hair cell regeneration
View ORCID ProfileMark E. Warchol, Angela Schrader, View ORCID ProfileLavinia Sheets