Daily Respiratory Research Analysis
Analyzed 172 papers and selected 3 impactful papers.
Summary
Analyzed 172 papers and selected 3 impactful articles.
Selected Articles
1. Base editing and nanoparticle transfection of airway cell types essential for treatment of cystic fibrosis.
This preclinical study corrects a common CFTR splice mutation in primary CF airway cells using CRISPR base editor RNAs delivered by polymeric nanoparticles, achieving clinically meaningful functional rescue. Single-cell profiling shows widespread restoration of CFTR transcripts across airway cell types and enrichment of CFTR-expressing ionocytes. The nonviral platform demonstrates translational promise for CF patients unresponsive to modulators.
Impact: Demonstrates durable correction of a high-need CF genotype with a scalable, nonviral delivery—an essential step toward airway gene editing therapies. Provides mechanistic and functional validation across airway cell types.
Clinical Implications: If safety and durability are confirmed in vivo, this approach could offer a disease-modifying option for approximately 10% of CF patients who lack effective CFTR modulators, and potentially other respiratory epithelial disorders.
Key Findings
- CRISPR base editor RNAs corrected CFTR 3120+1G>A in primary CF airway cells with functional CFTR rescue to clinically meaningful levels.
- Single-cell RNA-seq showed broad increases in CFTR transcripts across airway epithelial subsets, with enrichment of CFTR-expressing ionocytes and goblet cells.
- Polymeric nanoparticles enabled efficient nonviral delivery of base editors and reporter RNA; vitronectin dominated the in vivo corona but did not enhance delivery when preincubated.
Methodological Strengths
- Use of primary CF airway cells with single-cell RNA sequencing to map cell-type–specific rescue.
- Demonstration of functional CFTR correction and nonviral nanoparticle delivery across immortalized and primary cultures.
Limitations
- Preclinical in vitro/air–liquid interface models; absence of in vivo human airway delivery and long-term durability/safety data.
- Potential off-target editing and immune responses to nanoparticles or editor components not fully characterized.
Future Directions: Evaluate in vivo airway delivery, durability, and safety (off-targets, immunogenicity), and expand to additional CFTR genotypes and large-animal models before early-phase clinical trials.
Cystic fibrosis (CF) is a life-limiting genetic disorder caused by deleterious variants in the CFTR gene that results in altered mucus impairing the airway epithelia. Durable correction of these variants in airway cells remains a therapeutic challenge for about 10% of individuals unresponsive to CFTR modulators. A common disease-causing CFTR splice site variant, 3120+1G>A, was corrected in primary CF airway cells using base editor RNAs. Single-cell RNA sequencing revealed a remarkable increase in detectable CFTR transcript in most CF airway epithelial cell types resulting in notable enrichment of CFTR-expressing ionocytes and secretory goblet cells. Progenitor basal cell subtypes were edited, but they decreased as a fraction of total cells and CFTR-expressing cells compared with unedited cells. CRISPR base editors delivered by polymeric nanoparticles (PNPs) facilitated functional rescue of CFTR to clinically meaningful levels in immortalized and primary airway cells. PNPs delivered GFP-encoding RNA to progenitor airway cells in fully differentiated airway cultures. Vitronectin was a major component of the PNP corona that formed in vivo, but preincubation with vitronectin did not enhance delivery. Together, these findings validate a scalable, nonviral platform with compelling translational promise for treating CF and other respiratory diseases involving respiratory epithelial cell dysfunction.
2. Time to diagnosis and treatment of obstructive sleep apnoea using mandibular jaw movement monitoring versus polysomnography: an open-label, multicentre, randomised, controlled trial.
In a multicentre open-label RCT (n=849), AI-supported mandibular jaw movement monitoring achieved noninferior 3-month daytime sleepiness improvement versus PSG while significantly shortening time to diagnosis and treatment. Earlier treatment translated into earlier improvement in sleepiness, with comparable adherence and patient-reported outcomes.
Impact: Provides randomized evidence for a scalable at-home diagnostic pathway that can relieve PSG bottlenecks and accelerate OSA care. Aligns with healthcare system needs for timely diagnosis and treatment initiation.
Clinical Implications: Healthcare systems can integrate AI-supported MJM monitoring to triage suspected OSA, reducing wait times to diagnosis and PAP initiation without compromising patient-reported outcomes.
Key Findings
- AI-supported MJM monitoring was noninferior to PSG for reducing Epworth Sleepiness Scale scores at 3 months post-diagnosis.
- Time to diagnosis and time to treatment were significantly shorter with MJM than with PSG, enabling earlier symptomatic improvement.
- Quality of life, work productivity, and early PAP adherence were comparable between arms.
Methodological Strengths
- Prospective, multicentre randomized controlled design with hierarchical co-primary endpoints.
- Real-world, at-home diagnostic pathway evaluated against gold-standard PSG.
Limitations
- Open-label design and single-country setting may limit generalizability; device-specific implementation (Sunrise).
- Primary outcome focused on patient-reported sleepiness rather than cardiorespiratory endpoints.
Future Directions: Assess long-term cardiovascular and metabolic outcomes, cost-effectiveness, and performance in diverse healthcare systems and high-risk subgroups.
BACKGROUND: Obstructive sleep apnoea (OSA) is often underdiagnosed, highlighting the need for scalable diagnostic alternatives. The SUNSAS study compared a new device for at-home diagnosis of OSA (artificial intelligence [AI]-supported analysis of mandibular jaw movements [MJM]) with polysomnography (PSG) for time to diagnosis and treatment, and patient-reported outcomes. METHODS: This prospective, multicentre, randomised, controlled, open-label study was conducted in France (October 2021-October 2024). Adults aged 18-80 years with suspected OSA were randomised (1:1) to undergo diagnostic testing using MJM monitoring (Sunrise) or PSG. Primary endpoints were assessed using hierarchical testing: 1. daytime sleepiness (Epworth Sleepiness Scale [ESS] score) at 3 months post-diagnosis and time to diagnosis; 2. time to treatment; and 3. daytime sleepiness at 3 months post-randomisation. Secondary endpoints included quality of life (Short Form-36, Quebec Sleep Questionnaire), work productivity (Work Productivity and Activity Impairment questionnaire), and positive airway pressure therapy adherence at 3 months after treatment initiation. FINDINGS: Of 849 participants randomised (58·7% male, median age 50 years, body mass index 28·0 kg/m INTERPRETATION: OSA diagnosis based on MJM monitoring with AI-supported analysis is noninferior to PSG in reducing daytime sleepiness at 3 months after diagnosis, while significantly accelerating time to diagnosis and treatment initiation, resulting in earlier improvement in daytime sleepiness. FUNDING: Sunrise, with support from the French Ministry of Health through the
3. Mammary and respiratory infection of sheep with H5Nx clade 2.3.4.4b viruses with milk-mediated transmission to lambs.
In sheep experimentally infected with H5N1/H5N5, intramammary inoculation caused mastitis with high milk viral loads and milk-mediated transmission to lambs, which could back-spread infection to uninoculated mammary glands. Nonlactating sheep exposed by aerosol developed transient respiratory infection. In vitro replication in sheep mammary epithelial cells supports mammary tropism.
Impact: Reveals previously unrecognized milk-mediated transmission of H5Nx in a ruminant model, redefining surveillance and biosecurity strategies in dairy systems and informing zoonotic spillover risk assessments.
Clinical Implications: For veterinary and public health, enhance surveillance of mastitis and milk in ruminant outbreaks, update biosecurity for lactation management, and consider targeted testing of milk as part of containment.
Key Findings
- Intramammary H5N1/H5N5 inoculation in lactating sheep led to mastitis, high milk viral loads, and transmission to suckling lambs with subsequent spread to uninoculated mammary glands.
- Aerosol exposure in nonlactating sheep caused transient respiratory infection with low-level replication and seroconversion.
- Both viruses replicated in sheep mammary epithelial cells in vitro, supporting mammary tropism and a milk-mediated transmission route.
Methodological Strengths
- In vivo infection model comparing mammary versus aerosol exposure across genotypes with serologic confirmation.
- In vitro validation of viral replication in target mammary epithelial cells to support mechanistic pathway.
Limitations
- Animal study with unspecified sample sizes; generalizability to other ruminants and field settings requires caution.
- Human zoonotic implications are inferential; no direct human exposure data.
Future Directions: Quantify shedding dynamics, dose-response in milk; assess cross-species risk including farm workers; evaluate control measures (milk pasteurization, lactation biosecurity) in outbreak simulations.
H5Nx clade 2.3.4.4b viruses are evolving rapidly, expanding host ranges and threatening animal and public health. In the US, genotype B3.13 dominates dairy outbreaks, while D1.1 is linked to fewer cases. In the UK, an asymptomatic ewe infected with genotype DI.2 raised concerns about ruminant susceptibility. We inoculated lactating and nonlactating sheep with D1.1 (H5N1) and A6 (H5N5) viruses. Intramammary inoculation in lactating sheep caused clinical mastitis, high viral loads in milk, and transmission to suckling lambs, which further spread infection to the uninoculated mammary glands. Both ewes and their lambs seroconverted. Aerosol exposure of nonlactating sheep led to transient respiratory infection, with low-level viral replication, and seroconversion. In vitro, both viruses replicated in sheep mammary epithelial cells. These findings establish sheep as a viable ruminant model for H5N1 and H5N5 infection and highlight previously unidentified transmission dynamics, including milk-mediated and lamb-to-ewe spread, relevant for surveillance and biosecurity in ruminant populations.