Biology subjects

Goltsman, D. S. A.

Publications and source records attributed to Goltsman, D. S. A..

3 recordsLinked to original sources

bioRxiv2026

Compact adenine base editors to enable therapeutic rescue of Duchenne muscular dystrophy

Adenine base editors (ABEs) have emerged as a powerful gene-editing technology enabling precise and programmable adenine-to-guanine substitutions across the genome. However, their translation into in vivo therapeutics is limited by delivery challenges, as their size exceeds the packaging capacity of adeno-associated virus (AAV). Here, we report the discovery, structural characterization, and engineering of two compact, highly active ABEs built on novel deaminases and Cas9d nucleases, enabling all-in-one, single-vector AAV delivery. Applying these compact ABEs to Duchenne muscular dystrophy (DMD), we demonstrate efficient disruption of conserved splice-acceptor sites at dystrophin exons 45 and 51 in human skeletal muscle cells, enabling therapeutically relevant exon skipping. Together, these ABEs help expand the therapeutic reach of base editing towards diverse tissue types and disease targets.

bioengineering↗

bioRxiv2023

Gardnerella Diversity and Ecology in Pregnancy and Preterm Birth

The vaginal microbiome has been linked to numerous negative health outcomes including preterm birth. Specific taxa, including Gardnerella spp., have been identified as risk factors for these conditions. Historically, microbiome analysis methods have treated all Gardnerella spp. as one species, but the broad diversity of Gardnerella has recently become more apparent. In the present study, we explore the diversity of Gardnerella clades and genomic species in the vaginal microbiome of pregnant women and their impacts on microbiome composition and associations with preterm birth. Shotgun metagenomic sequencing data collected longitudinally from three distinct cohorts of pregnant women were assessed. Relative abundance of Gardnerella clades and genomic species and other taxa was quantified, and associations between Gardnerella clades and signatures of the vaginal microbiome were measured. We also assessed the diversity and abundance of Gardnerella variants in 16S rRNA gene amplicon sequencing data from seven previously conducted studies in differing populations on the vaginal microbiome and preterm birth. Individual microbiomes often contained multiple Gardnerella variants, and the number of clades was associated with increased microbial load. The genus Gardnerella was also associated with increased microbial load, or the ratio of non-human reads to human reads. Taxon co-occurrence patterns matched previously described community structures, and were largely consistent across Gardnerella clades and among cohorts. Some variants previously described as rare were prevalent in other cohorts, highlighting the importance of surveying a diverse set of populations to fully capture the diversity of Gardnerella. The diversity of Gardnerella both across populations and within individual vaginal microbiomes has long been unappreciated, as has been the intra-species diversity of many other members of the vaginal microbiome.1 The broad genomic diversity of Gardnerella has led to its reclassification as multiple species; here we demonstrate the diversity of Gardnerella found within and between vaginal microbiomes. Further studies should investigate the phenotypes of Gardnerella variants that may underlie the mechanisms by which Gardnerella species may differentially shape the vaginal microbiome.

microbiology↗

bioRxiv2018

Metagenomic analysis with strain-level resolution reveals fine-scale variation in the human pregnancy microbiome

Recent studies suggest that the microbiome has an impact on gestational health and outcome. However, characterization of the pregnancy-associated microbiome has largely relied on 16S rRNA gene amplicon-based surveys. Here, we describe an assembly-driven, metagenomics-based, longitudinal study of the vaginal, gut, and oral microbiomes in 292 samples from ten subjects sampled every three weeks throughout pregnancy. 1.53 Gb of non-human sequence was assembled into scaffolds, and functional genes were predicted for gene-and pathway-based analyses. Vaginal assemblies were binned into 97 draft quality genomes. Redundancy analysis (RDA) of microbial community composition at all three body sites revealed gestational age to be a significant source of variation in patterns of gene abundance. In addition, health complications were associated with variation in community functional gene composition in the mouth and gut. The diversity of Lactobacillus iners-dominated communities in the vagina, unlike most other vaginal community types, significantly increased with gestational age. The genomes of co-occurring Gardnerella vaginalis strains with predicted distinct functions were recovered in samples from two subjects. In seven subjects, gut samples contained strains of the same Lactobacillus species that dominated the vaginal community of that same subject, and not other Lactobacillus species; however, these within-host strains were divergent. CRISPR spacer analysis suggested shared phage and plasmid populations across body sites and individuals. This work underscores the dynamic behavior of the microbiome during pregnancy and suggests the potential importance of understanding the sources of this behavior for fetal development and gestational outcome.

microbiology↗