Biomedical subjects

Devesh Sharma

Publications and source records attributed to Devesh Sharma.

2 recordsLinked to original sources

PubMed2026

The emergence of putative epistatic mutations and iSNVs in SARS-CoV-2 XBB.1.16 variants linked with alteration in immunogenic determinants.

The SARS-CoV-2 XBB variants have been proposed to evolve towards immune evasion against vaccination or natural infection, which may contribute to higher transmissibility. The XBB.1.16 independently emerged due to accumulation of two important substitutions, E180V and T478R in the spike protein. Its pseudoviral infectivity and evasion of humoral immunity were similar to XBB.1 and XBB.1.5. In March 2023, XBB.1.16 had outcompeted other dominant XBB variants in India, which indicate a potential growth advantage. Here, intra-host single nucleotide variations (iSNV) and mutations were screened in SARS-CoV-2 genomes in closely related individuals at two time points: at symptoms onset, and during recovery. The prominence of putative epistatic iSNVs (E180V, G184V, G252V, D253G, and P521S/T) in XBB.1.16 variants were detected during the recovery phase. E180V exhibits mutational constellations with the G252V and P521T in a subset of samples, and this pattern was also detected in contemporary SARS-CoV-2 genomes. Higher order protein structural predictions suggested that the putative epistatic interactions among E180V, G184V, and G252V, D253G may be associated with S protein folding and structural stability. This study involving genomics and computational analyses highlights the potential role of these putative epistatic interactions in immune evasion, which may have contributed to dominance of XBB variants.

Humans↗

PubMed2026

Combinatorial base editing couples disease correction with lineage amplification in hematopoietic stem and progenitor cells.

First-generation genome editing therapies have largely focused on correcting or compensating for pathogenic variants. However, as these approaches enter the clinic, emerging biological constraints limit maximal therapeutic impact. Because globin genes are activated late during erythroid differentiation, genome-corrected hematopoietic stem and progenitor cells (HSPCs) gain little selective advantage in the bone marrow. Here, we establish a strategy that links therapeutic genome edits to an erythroid fitness-enhancing allele to amplify the output of clinically relevant cells. We develop a multiplex base editing strategy that couples fetal hemoglobin (HbF) reactivation with erythroid lineage expansion. Introduction of a naturally occurring erythropoietin receptor truncation (tEPOR) associated with benign erythrocytosis increased erythroid cell production without impairing viability or differentiation. Combinatorial editing of tEPOR together with the BCL11A erythroid enhancer and HBG1/2 promoters in healthy donor, sickle cell disease, and β-thalassemia HSPCs synergistically increased erythroid proliferation and HbF expression beyond single base-edited or Casgevy-treated controls. Multiplex base-edited HSPCs retained long-term lineage repopulation and engraftment capacity in vivo, establishing a modular strategy that pairs disease correction with lineage amplification to improve therapeutic potency.

Journal Article↗