Pigeonpea improvement: An amalgam of breeding and genomic research

In the past five decades, constant research has been directed towards yield improvement in pigeonpea resulting in the deployment of several commercially acceptable cultivars in India. Though, the genesis of hybrid technology, the biggest breakthrough, enigma of stagnant productivity still remains unsolved. To sort this productivity disparity, genomic research along with conventional breeding was successfully initiated at ICRISAT. It endowed ample genomic resource providing insight in the pigeonpea genome combating production constraints in a precise and speedy manner. The availability of the draft genome sequence with a large‐scale marker resource, oriented the research towards trait mapping for flowering time, determinacy, fertility restoration, yield attributing traits and photo‐insensitivity. Defined core and mini‐core collection, still eased the pigeonpea breeding being accessible for existing genetic diversity and developing stress resistance. Modern genomic tools like next‐generation sequencing, genome‐wide selection helping in the appraisal of selection efficiency is leading towards next‐generation breeding, an awaited milestone in pigeonpea genetic enhancement. This paper emphasizes the ongoing genetic improvement in pigeonpea with an amalgam of conventional breeding as well as genomic research

Triple Therapy for Cystic Fibrosis Phe508del–Gating and –Residual Function Genotypes

BACKGROUND Elexacaftor–tezacaftor–ivacaftor is a small-molecule cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen shown to be efficacious in patients with at least one Phe508del allele, which indicates that this combination can modulate a single Phe508del allele. In patients whose other CFTR allele contains a gating or residual function mutation that is already effectively treated with previous CFTR modulators (ivacaftor or tezacaftor–ivacaftor), the potential for additional benefit from restoring Phe508del CFTR protein function is unclear. METHODS We conducted a phase 3, double-blind, randomized, active-controlled trial involving patients 12 years of age or older with cystic fibrosis and Phe508del–gating or Phe508del–residual function genotypes. After a 4-week run-in period with ivacaftor or tezacaftor–ivacaftor, patients were randomly assigned to receive elexacaftor–tezacaftor–ivacaftor or active control for 8 weeks. The primary end point was the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline through week 8 in the elexacaftor–tezacaftor–ivacaftor group. RESULTS After the run-in period, 132 patients received elexacaftor–tezacaftor–ivacaftor and 126 received active control. Elexacaftor–tezacaftor–ivacaftor resulted in a percentage of predicted FEV1 that was higher by 3.7 percentage points (95% confidence interval [CI], 2.8 to 4.6) relative to baseline and higher by 3.5 percentage points (95% CI, 2.2 to 4.7) relative to active control and a sweat chloride concentration that was lower by 22.3 mmol per liter (95% CI, 20.2 to 24.5) relative to baseline and lower by 23.1 mmol per liter (95% CI, 20.1 to 26.1) relative to active control (P<0.001 for all comparisons). The change from baseline in the Cystic Fibrosis Questionnaire–Revised respiratory domain score (range, 0 to 100, with higher scores indicating better quality of life) with elexacaftor–tezacaftor–ivacaftor was 10.3 points (95% CI, 8.0 to 12.7) and with active control was 1.6 points (95% CI, −0.8 to 4.1). The incidence of adverse events was similar in the two groups; adverse events led to treatment discontinuation in one patient (elevated aminotransferase level) in the elexacaftor–tezacaftor–ivacaftor group and in two patients (anxiety or depression and pulmonary exacerbation) in the active control group. CONCLUSIONS Elexacaftor–tezacaftor–ivacaftor was efficacious and safe in patients with Phe508del–gating or Phe508del–residual function genotypes and conferred additional benefit relative to previous CFTR modulators. (Funded by Vertex Pharmaceuticals; VX18-445-104 ClinicalTrials.gov number, NCT04058353.

Pigeonpea improvement: An amalgam of breeding and genomic research

In the past five decades, constant research has been directed towards yield improvement in pigeonpea resulting in the deployment of several commercially acceptable cultivars in India. Though, the genesis of hybrid technology, the biggest breakthrough, enigma of stagnant productivity still remains unsolved. To sort this productivity disparity, genomic research along with conventional breeding was successfully initiated at ICRISAT. It endowed ample genomic resource providing insight in the pigeonpea genome combating production constraints in a precise and speedy manner. The availability of the draft genome sequence with a large‐scale marker resource, oriented the research towards trait mapping for flowering time, determinacy, fertility restoration, yield attributing traits and photo‐insensitivity. Defined core and mini‐core collection, still eased the pigeonpea breeding being accessible for existing genetic diversity and developing stress resistance. Modern genomic tools like next‐generation sequencing, genome‐wide selection helping in the appraisal of selection efficiency is leading towards next‐generation breeding, an awaited milestone in pigeonpea genetic enhancement. This paper emphasizes the ongoing genetic improvement in pigeonpea with an amalgam of conventional breeding as well as genomic research

Clinical care for primary ciliary dyskinesia: current challenges and future directions

Primary ciliary dyskinesia (PCD) is a rare genetic disease that affects the motility of cilia, leading to impaired mucociliary clearance. It is estimated that the vast majority of patients with PCD have not been diagnosed as such, providing a major obstacle to delivering appropriate care. Challenges in diagnosing PCD include lack of disease-specific symptoms and absence of a single, “gold standard”, diagnostic test. Management of patients is currently not based on high-level evidence because research findings are mostly derived from small observational studies with limited follow-up period. In this review, we provide a critical overview of the available literature on clinical care for PCD patients, including recent advances. We identify barriers to PCD research and make suggestions for overcoming challenges

Losartan Rescues Inflammation-related Mucociliary Dysfunction in Relevant Models of Cystic Fibrosis

Despite therapeutic progress in treating cystic fibrosis (CF) airway disease, airway inflammation with associated mucociliary dysfunction remains largely unaddressed. Inflammation reduces the activity of apically expressed large-conductance Ca -activated and voltage-dependent K (BK) channels, critical for mucociliary function in the absence of CFTR (CF transmembrane conductance regulator). To test losartan as an antiinflammatory therapy in CF using CF human bronchial epithelial cells and an ovine model of CF-like airway disease. Losartan's antiinflammatory effectiveness to rescue BK activity and thus mucociliary function was tested using primary, fully redifferentiated human airway epithelial cells homozygous for F508del and using a previously validated, now expanded pharmacologic sheep model of CF-like, inflammation-associated mucociliary dysfunction. Nasal scrapings from patients with CF showed that neutrophilic inflammation correlated with reduced expression of LRRC26 (leucine rich repeat containing 26), the γ subunit mandatory for BK function in the airways. TGF-β1 (transforming growth factor β1), downstream of neutrophil elastase, decreased mucociliary parameters . These were rescued by losartan at concentrations achieved by nebulization in the airway and oral application in the bloodstream: BK dysfunction recovered acutely and over time (the latter via an increase in LRRC26 expression), ciliary beat frequency and airway surface liquid volume improved, and mucus hyperconcentration and cellular inflammation decreased. These effects did not depend on angiotensin receptor blockade. Expanding on a validated and published nongenetic, CF-like sheep model, ewes inhaled CFTR 172 and neutrophil elastase for 3 days, which resulted in prolonged tracheal mucus velocity reduction, mucus hyperconcentration, and increased TGF-β1. Nebulized losartan rescued both mucus transport and mucus hyperconcentration and reduced TGF-β1. Losartan effectively reversed CF- and inflammation-associated mucociliary dysfunction, independent of its angiotensin receptor blockade

Long-Term Safety and Efficacy of Elexacaftor/Tezacaftor/Ivacaftor in People With Cystic Fibrosis and at Least One F508del Allele: 144-Week Interim Results From a 192-Week Open-label Extension Study

AIMS: In two pivotal Phase 3 trials, up to 24 weeks of treatment with elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was efficacious and safe in patients with cystic fibrosis ≥12 years of age who have at least one F508del allele. The aim of this study is to assess long-term safety and efficacy of ELX/TEZ/IVA in these patients. METHODS: In this Phase 3, open-label, single-arm extension study, participants with F508del-minimal function (from a 24-week parent study; n=399) or F508del-F508del (from a 4-week parent study; n=107) genotypes receive ELX/TEZ/IVA at the same dose (ELX 200 mg once daily, TEZ 100 mg once daily and IVA 150 mg every 12 h). The primary endpoint is safety and tolerability. A prespecified interim analysis was conducted when the last participant reached the Week 144 visit. RESULTS: At the Week 144 interim analysis, mean duration of exposure to ELX/TEZ/IVA in the extension study was 151.1 weeks. Exposure-adjusted rates of adverse events (586.6 events per 100 participant-years) and serious adverse events (22.4 events per 100 participant-years) were lower than in the ELX/TEZ/IVA treatment group in the 24-week parent study (1096.0 events per 100 participant-years and 36.9 events per 100 participant-years, respectively); most participants had adverse events classified as mild (16.4% of participants) or moderate (60.3% of participants) in severity. Fourteen participants (2.8%) had adverse events that led to treatment discontinuation. Following initiation of ELX/TEZ/IVA, participants had increases in per cent predicted FEV(1) (ppFEV(1)), Cystic Fibrosis Questionnaire-Revised respiratory domain score and body mass index, and had decreases in sweat chloride concentration and pulmonary exacerbations rates that were maintained over the interim analysis period. The mean annualised rate of change in ppFEV(1) was +0.07 percentage points (95% CI, -0.12 to 0.26) among the participants. CONCLUSIONS: ELX/TEZ/IVA was generally safe and well-tolerated, with a safety profile consistent with the 24-week parent study. Participants had sustained improvements in lung function, respiratory symptoms, CFTR function, pulmonary exacerbation rates and nutritional status. These results support the favourable safety profile and durable, disease-modifying clinical benefits of ELX/TEZ/IVA.Published version, accepted version (12 month embargo), submitted versionThe article is available via Open Access. Click on the 'Additional link' above to access the full-text