Biology subjects

Challa, R.

Publications and source records attributed to Challa, R..

4 recordsLinked to original sources

bioRxiv2025

Comparative snRNAseq study of C9orf72, SOD1, and sALS spinal cord

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the loss of motor neurons, yet the cell-type specific molecular alterations within the spinal cords are not well characterized. In this study, we conducted deep molecular profiling of spinal cord tissues donated by people living with sporadic, C9orf72, and SOD1-ALS using single-nucleus RNA sequencing (snRNAseq). We observed numerous distinct gene expression patterns and enriched pathways among ALS types. However, when focusing on common features, we identified activation of stress-response and inflammatory pathways in specific microglia subtypes, as well as disrupted vesicle transport and synaptic function in a ventral inhibitory neuronal subtype. Notably, CPLX3, a SNARE regulator, was uniquely expressed in alpha-motor neurons and was commonly downregulated across all ALS types. While this study uncovers the molecular heterogeneity underlying ALS, it also highlights shared pathways within specific cell types, especially in the ventral inhibitory neurons that have been less explored in ALS research.

neuroscience↗

bioRxiv2025

SB 11285, a Novel Canonical Purine-Pyrimidine Cyclic Dinucleotide, is a Systemically Bioavailable STING Agonist for Cancer Immunotherapy

SummarySB 11285, a novel cell-permeable, canonical 3,5, purine-pyrimidine cyclic dinucleotide has been developed as a potent systemically bioavailable STING agonist currently in clinical trials. The stimulator of Interferon genes (STING) pathway, crucial for cytosolic DNA sensing and innate immunity, presents a promising avenue for novel cancer immunotherapies. Discussed here is the discovery and development of SB11285, a potent activator of the STING pathway, belonging to the canonical class of 3,5 purine-pyrimidine (PuPy) cyclic dinucleotides (CDNs). SB11285 exhibits superior potency and cell permeability compared to non-canonical 2,3-CDNs and demonstrates robust antitumor activity in in vivo syngeneic mouse tumor models, resulting in complete tumor regression, and durable immunological memory. Combination with checkpoint inhibitors and cytotoxic agents further enhances its efficacy. The anti-tumor effects of SB 11285 rely on the induction of CD8+ T cells, activated macrophages, and NK cells in the tumor microenvironment (TME), for efficient tumor killing and fostering profound and durable anti-tumor response. Our findings underscore the potential of functionalized canonical 3,5-Pu-Py CDNs, exemplified by SB11285, as safe and potent STING agonists for multiple routes of administration in cancer therapy. Currently, SB11285 administered intravenously (IV), is undergoing evaluation as the first systemically administered CDN analog in human clinical trials across various tumor types.

immunology↗

bioRxiv2025

Spatial transcriptomics reveals heterogeneous cell-cell interactions among brain regions in a cuprizone model consistent with multiple sclerosis lesions

The cuprizone (CPZ) model is widely used for modeling demyelination in multiple sclerosis (MS) and for testing potential remyelination therapies. We integrated single-cell and spatial transcriptomics (ST) to fine map the spatial cellular and molecular responses during de and remyelination. ST revealed global demyelination and neuroinflammation in the brain beyond the corpus callosum, with region-specific differences. We identified oligodendroglia and microglia as two major cell types with significant transcriptomic changes in the model. Ligand receptor pairing analyses predicted growth factor and phagocytic pathway enrichment during demyelination, which is consistent with changes in MS lesions. During remyelination, while mature oligodendrocytes nearly reversed their phenotype back to the control state, microglia remained associated with the demyelination phenotype. Finally, astrocytes in the CPZ model had the greatest preservation of disease-associated modules to MS lesions, while the MOL, OPC, and microglia showed moderate to low preservation, which overall suggested that the CPZ model had moderate translatability to chronically active MS lesions.

neuroscience↗

bioRxiv2021

CellMap: Characterizing the types and composition of iPSC-derived cells from RNA-seq data

Induced pluripotent stem cell (iPSC) derived cell types are increasingly employed as in vitro model systems for drug discovery. For these studies to be meaningful, it is important to understand the reproducibility of the iPSC-derived cultures and their similarity to equivalent endogenous cell types. Single-cell and single-nucleus RNA sequencing (RNA-seq) are useful to gain such understanding, but they are expensive and time consuming, while bulk RNA-seq data can be generated quicker and at lower cost. In silico cell type decomposition is an efficient, inexpensive, and convenient alternative that can leverage bulk RNA-seq to derive more fine-grained information about these cultures. We developed CellMap, a computational tool that derives cell type profiles from publicly available single-cell and single-nucleus datasets to infer cell types in bulk RNA-seq data from iPSC-derived cell lines.

bioinformatics↗