Auditory hair cell-specific deletion of p27Kip1 in postnatal mice promotes cell-autonomous generation of new hair cells and normal hearing.

Hearing in mammals relies upon the transduction of sound by hair cells (HCs) in the organ of Corti within the cochlea of the inner ear. Sensorineural hearing loss is a widespread and permanent disability due largely to a lack of HC regeneration in mammals. Recent studies suggest that targeting the retinoblastoma (Rb)/E2F pathway can elicit proliferation of auditory HCs. However, previous attempts to induce HC proliferation in this manner have resulted in abnormal cochlear morphology, HC death, and hearing loss. Here we show that cochlear HCs readily proliferate and survive following neonatal, HC-specific, conditional knock-out of p27(Kip1) (p27CKO), a tumor suppressor upstream of Rb. Indeed, HC-specific p27CKO results in proliferation of these cells without the upregulation of the supporting cell or progenitor cell proteins, Prox1 or Sox2, suggesting that they remain HCs. Furthermore, p27CKO leads to a significant addition of postnatally derived HCs that express characteristic synaptic and stereociliary markers and survive to adulthood, although a portion of the newly derived inner HCs exhibit cytocauds and lack VGlut3 expression. Despite this, p27CKO mice exhibit normal hearing as measured by evoked auditory brainstem responses, which suggests that the newly generated HCs may contribute to, or at least do not greatly detract from, function. These results show that p27(Kip1) actively maintains HC quiescence in postnatal mice, and suggest that inhibition of p27(Kip1) in residual HCs represents a potential strategy for cell-autonomous auditory HC regeneration.

Factors Involved in Anti-VEGF Treatment Decisions for Neovascular Age-Related Macular Degeneration: Insights from Real-World Clinical Practice.

Background: Anti-vascular endothelial growth factor (anti-VEGF) agents are widely prescribed for the treatment of neovascular age-related macular degeneration (nAMD). Although studies have investigated patient choice of anti-VEGF agent, little is known regarding factors that influence physician preference of anti-VEGF agent for their patients. Objective: To describe physician rationale and challenges in prescribing anti-VEGF treatments for patients with nAMD. Methods: Data were drawn from the Adelphi Real World nAMD Disease Specific Programme™, a cross-sectional survey with retrospective data capture of physicians and their patients with nAMD in the United States between October 2021 and May 2022. Physicians (n = 56) reported data for up to 13 consecutively consulting patients (n = 451), including current anti-VEGF treatments used, factors affecting physicians' choice of anti-VEGF agent and treatment strategy, and restrictions on specific agents. Results: Most physicians prefer employing a "treat-and-extend" treatment strategy, over "fixed interval" or "pro re nata" strategies. However, in routine clinical practice, "treat-and-extend" was reported for less than half of nAMD-diagnosed eyes. Top factors influencing physician choice of anti-VEGF agent and treatment strategy included maximizing clinical benefit (eg visual acuity gains and fluid control), patient convenience, and reducing out-of-pocket costs. However, physicians also reported facing substantial roadblocks in prescribing their choice of anti-VEGF agent, including restrictions on approved agents and gaps in insurance coverage. Persistent fluid was the most common physician-selected reason for switching a patient away from an anti-VEGF agent. Conclusion: Physicians face barriers to prescribing their preferred anti-VEGF agents in real-world healthcare settings. Overcoming these challenges may improve treatment outcomes for patients with nAMD.

People with wet age-related macular degeneration (wet AMD) have problems with their eyesight that can lead to blindness if left untreated. Eye doctors (ophthalmologists) use a class of medicine called anti-VEGF agents to treat people with wet AMD. However, eye doctors often face challenges in prescribing their anti-VEGF agent of choice. We surveyed eye doctors to determine the reasons why they preferred some anti-VEGF agents over others, as well as the barriers to prescribing these anti-VEGF agents. Eye doctors reported that they usually choose a specific anti-VEGF agent because it leads to better vision, has lower cost for people with wet AMD, or may reduce the number of appointments needed for people with wet AMD. Eye doctors also noted that they face challenges in treating people with wet AMD, including restrictions and limited insurance coverage for certain anti-VEGF agents. Solving these problems could help eye doctors use their medicine of choice and improve eyesight even more when they treat people with wet AMD.

In Vivo Interplay between p27Kip1, GATA3, ATOH1, and POU4F3 Converts Non-sensory Cells to Hair Cells in Adult Mice.

Hearing loss is widespread and persistent because mature mammalian auditory hair cells (HCs) are nonregenerative. In mice, the ability to regenerate HCs from surrounding supporting cells (SCs) declines abruptly after postnatal maturation. We find that combining p27Kip1 deletion with ectopic ATOH1 expression surmounts this age-related decline, leading to conversion of SCs to HCs in mature mouse cochleae and after noise damage. p27Kip1 deletion, independent of canonical effects on Rb-family proteins, upregulated GATA3, a co-factor for ATOH1 that is lost from SCs with age. Co-activation of GATA3 or POU4F3 and ATOH1 promoted conversion of SCs to HCs in adult mice. Activation of POU4F3 alone also converted mature SCs to HCs in vivo. These data illuminate a genetic pathway that initiates auditory HC regeneration and suggest p27Kip1, GATA3, and POU4F3 as additional therapeutic targets for ATOH1-mediated HC regeneration.