ObjectivesStudy of currently approved drugs and exploration of future clinical development pipeline therapeutics for cystic fibrosis, and possible limitations in their use.MethodsExtensive literature search using individual and a combination of key words related to cystic fibrosis therapeutics.Key findingsCystic fibrosis is an autosomal recessive disorder due to mutations in CFTR gene leading to abnormality of chloride channels in mucus and sweat producing cells. Respiratory system and GIT are primarily involved but eventually multiple organs are affected leading to life threatening complications. Management requires drug therapy, extensive physiotherapy and nutritional support. Previously, the focus was on symptomatic improvement and complication prevention but recently the protein rectifiers are being studied which are claimed to correct underlying structural and functional abnormalities. Some improvement is observed by the corrector drugs. Other promising approaches are gene therapy, targeting of cellular interactomes, and newer drugs for symptomatic improvement.ConclusionsThe treatment has a long way to go as most of the existing therapeutics is for older children. Other limiting factors include mutation class, genetic profile, drug interactions, adverse effects, and cost. Novel approaches like gene transfer/gene editing, disease modeling and search for alternative targets are warranted.

Consanguineous Pakistani pedigrees segregating deafness have contributed decisively to the discovery of 31 of the 68 genes associated with nonsyndromic autosomal recessive hearing loss (HL) worldwide. In this study, we utilized genome-wide genotyping, Sanger and exome sequencing to identify 163 DNA variants in 41 previously reported HL genes segregating in 321 Pakistani families. Of these, 71 (43.6%) variants identified in 29 genes are novel. As expected from genetic studies of disorders segregating in consanguineous families, the majority of affected individuals (94.4%) are homozygous for HL-associated variants, with the other variants being compound heterozygotes. The five most common HL genes in the Pakistani population are SLC26A4, MYO7A, GJB2, CIB2 and HGF, respectively. Our study provides a profile of the genetic etiology of HL in Pakistani families, which will allow for the development of more efficient genetic diagnostic tools, aid in accurate genetic counseling and guide application of future gene-based therapies. These findings are also valuable in interpreting pathogenicity of variants that are potentially associated with HL in individuals of all ancestries. The Pakistani population, and its infrastructure for studying human genetics, will continue to be valuable to gene discovery for HL and other inherited disorders.

Atherosclerosis is one of the leading causes of mortality and morbidity worldwide. Chemokines and their receptors are implicated in the pathogenesis of atherosclerosis. CXCL12 is a member of the chemokine family exerting a myriad role in atherosclerosis through its classical CXCR4 and atypical ACKR3 (CXCR7) receptors. The modulatory and regulatory functional spectrum of CXCL12/ CXCR4/ACKR3 axis in atherosclerosis spans from proatherogenic, prothrombotic and proinflammatory to atheroprotective, plaque stabilizer and dyslipidemia rectifier. This diverse continuum is executed in a wide range of biological units including endothelial cells (ECs), progenitor cells, macrophages, monocytes, platelets, lymphocytes, neutrophils and vascular smooth muscle cells (VSMCs) through complex heterogeneous and homogenous coupling of CXCR4 and ACKR3 receptors, employing different downstream signalling pathways, which often cross-talk among themselves and with other signalling interactomes. Hence, a better understanding of this structural and functional heterogeneity and complex phenomenon involving CXCL12/CXCR4/ACKR3 axis in atherosclerosis would not only help in formulation of novel therapeutics, but also in elucidation of the CXCL12 ligand and its receptors, as possible diagnostic and prognostic biomarkers. KEY MESSAGES1. The role of CXCL12 per se is proatherogenic in atherosclerosis development and progression. 2. The CXCL12 receptors, CXCR4 and ACKR3 perform both proatherogenic and athero-protective functions in various cell types 3. Due to functional heterogeneity and cross talk of CXCR4 and ACKR3 at receptor level and downstream pathways, regional boosting with specific temporal and spatial modulators of CXCL12, CXCR4 and ACKR3 need to be explored.

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