Response to Hypoglossal Nerve Stimulation Changes With Body Mass Index and Supine Sleep.

Importance: Hypoglossal nerve stimulation (HGNS) is a potential alternative therapy for obstructive sleep apnea (OSA), but its efficacy in a clinical setting and the impact of body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) on treatment response remain unclear. Objective: To investigate whether HGNS therapy is effective for patients with OSA, whether HGNS can treat supine OSA, and whether there are associations between BMI and treatment response. Design, Setting, and Participants: In this cohort study, adult patients with OSA implanted with HGNS at the Washington University Medical Center in St Louis from April 2019 to January 2023 were included. Data were analyzed from January 2023 to January 2024. Exposure: HGNS. Main Outcomes and Measures: Multivariable logistic regression was performed to assess associations between HGNS treatment response and both BMI and supine sleep. Treatment response was defined as 50% reduction or greater in preimplantation Apnea-Hypopnea Index (AHI) score and postimplantation AHI of less than 15 events per hour. Results: Of 76 included patients, 57 (75%) were male, and the median (IQR) age was 61 (51-68) years. A total of 59 patients (78%) achieved a treatment response. There was a clinically meaningful reduction in median (IQR) AHI, from 29.3 (23.1-42.8) events per hour preimplantation to 5.3 (2.6-12.3) events per hour postimplantation (Hodges-Lehman difference of 23.0; 95% CI, 22.6-23.4). In adjusted analyses, patients with BMI of 32 to 35 had 75% lower odds of responding to HGNS compared with those with a BMI of 32 or less (odds ratio, 0.25; 95% CI, 0.07-0.94). Of 44 patients who slept in a supine position, 17 (39%) achieved a treatment response, with a clinically meaningful reduction in median (IQR) supine AHI from 46.3 (33.6-63.2) events per hour preimplantation to 21.8 (4.30-42.6) events per hour postimplantation (Hodges-Lehman difference of 24.6; 95% CI, 23.1-26.5). In adjusted analysis, BMI was associated with lower odds of responding to HGNS with supine AHI treatment response (odds ratio, 0.39; 95% CI, 0.04-2.59), but the imprecision of the estimate prevents making a definitive conclusion. Conclusions and Relevance: This study adds to the growing body of literature supporting the use of HGNS for OSA treatment. Sleep medicine clinicians should consider informing patients that higher BMI and supine sleeping position may decrease therapeutic response to HGNS. Future research is needed to replicate these findings in larger, more diverse cohorts, which would facilitate the optimization of treatment strategies and patient counseling for HGNS therapy.

Erratum: iTAG an optimized IMiD-induced degron for targeted protein degradation in human and murine cells.

[This corrects the article DOI: 10.1016/j.isci.2023.107059.].

A Degron Blocking Strategy Towards Improved CRL4CRBN Recruiting PROTAC Selectivity.

Small molecules inducing protein degradation are important pharmacological tools to interrogate complex biology and are rapidly translating into clinical agents. However, to fully realise the potential of these molecules, selectivity remains a limiting challenge. Herein, we addressed the issue of selectivity in the design of CRL4CRBN recruiting PROteolysis TArgeting Chimeras (PROTACs). Thalidomide derivatives used to generate CRL4CRBN recruiting PROTACs have well described intrinsic monovalent degradation profiles by inducing the recruitment of neo-substrates, such as GSPT1, Ikaros and Aiolos. We leveraged structural insights from known CRL4CRBN neo-substrates to attenuate and indeed remove this monovalent degradation function in well-known CRL4CRBN molecular glues degraders, namely CC-885 and Pomalidomide. We then applied these design principles on a previously published BRD9 PROTAC (dBRD9-A) and generated an analogue with improved selectivity profile. Finally, we implemented a computational modelling pipeline to show that our degron blocking design does not impact PROTAC-induced ternary complex formation. We believe that the tools and principles presented in this work will be valuable to support the development of targeted protein degradation.

iTAG an optimized IMiD-induced degron for targeted protein degradation in human and murine cells.

To address the limitation associated with degron based systems, we have developed iTAG, a synthetic tag based on IMiDs/CELMoDs mechanism of action that improves and addresses the limitations of both PROTAC and previous IMiDs/CeLMoDs based tags. Using structural and sequence analysis, we systematically explored native and chimeric degron containing domains (DCDs) and evaluated their ability to induce degradation. We identified the optimal chimeric iTAG(DCD23 60aa) that elicits robust degradation of targets across cell types and subcellular localizations without exhibiting the well documented "hook effect" of PROTAC-based systems. We showed that iTAG can also induce target degradation by murine CRBN and enabled the exploration of natural neo-substrates that can be degraded by murine CRBN. Hence, the iTAG system constitutes a versatile tool to degrade targets across the human and murine proteome.