Biology subjects

Ranganathan, M.

Publications and source records attributed to Ranganathan, M..

4 recordsLinked to original sources

bioRxiv2026

Safe Redosable Low-Immunogenic In Vivo CAR-T Therapy for B Cell Malignancies and Solid Tumors

In vivo CAR-T cell therapy eliminates manufacturing complexities associated with ex vivo autologous approaches, but safety concerns have limited adoption. We developed viroVbot, a next-generation in vivo CAR-T platform, by combining computational immunogenicity prediction (CIMMEXTM) with envelope engineering. Screening 22,562 glycoprotein sequences, we identified 641 vesiculovirus homologs, from which we selected Piry virus glycoprotein (PIRYV) as the optimal candidate. PIRYV exhibited lower MHC-epitope density, reduced human seroprevalence, with decreased T cell activation compared to VSV-G. To enhance targeting specificity, we engineered receptor-binding-deficient PIRYV (ePIRYVRBD) displaying CD3/CD7 nanobodies for T cell-selective transduction. To maximize safety, we engineered CAR-TRAP producer cells to eliminate unwanted B cell transduction and incorporated machine learning-optimized T cell-specific promoters that restrict CAR activation exclusively to lymphocytes. Additional modifications suppressed hepatocyte expression and prevented phagocytic uptake. In humanized xenograft models, viroVbot3 generated potent BCMA/CD19 specific CAR-T responses against multiple myeloma and Claudin18.2-targeting gastric cancer, demonstrating sequential redosing with alternative envelopes. Critically, viroVbot3 exhibited minimal off-target organ biodistribution with CAR expression restricted to T lymphocytes. These findings establish viroVbot as a low-immunogenic platform for scalable in vivo CAR-T manufacturing with capability for sequential redosing across hematologic and solid tumors.

bioengineering↗

bioRxiv2020

Analysis of Circulating Exosomes Reveals a Peripheral Signature of Astrocytic Pathology in Schizophrenia

BackgroundThere is considerable interest in identifying peripheral biomarkers that reflect neuropathological changes in schizophrenia. Extracellular vesicles, including exosomes can cross the blood brain barrier with their contents intact and their cargo, including lipids, proteins and genetic materials can be assayed peripherally. Circulating exosomes have been studied in other neurodegenerative disorders, but there is scarce data in schizophrenia. MethodsWe examined neuropathology relevant protein biomarkers in circulating exosomes from patients with schizophrenia and age and gender matched healthy controls using methods consistent with the recommended "Minimal information for studies of extracellular vesicles 2018" (MISEV2018) guidelines. Nanoparticle tracking analysis was used to determine the size and concentration of exosomes. Exosomal membrane marker (CD9) and specific target cargo proteins (glial fibrillary acid protein[GFAP], synaptophysin and -II-spectrin) immunopositivity was examined using Western blot analyses and band intensity quantified. ResultsNo group differences were observed between schizophrenia and control samples in plasma exosomal concentration and size or in CD9 or calnexin positivity. Exosomal GFAP concentration was significantly higher and -II-spectrin expression significantly lower in schizophrenia samples and there were no group differences observed for exosomal synaptophysin concentration. ConclusionsOur results demonstrate for the first time, a differential pattern of exosomal protein expression in schizophrenia compared to matched healthy controls, consistent with the hypothesized astro-glial pathology in this disorder. These results warrant further examination of circulating exosomes as vehicles of novel peripheral biomarkers of disease in schizophrenia and other neuropsychiatric disorders.

neuroscience↗

bioRxiv2019

Single-cell Transcriptome Mapping Identifies Common and Cell-type Specific Genes Affected by Acute Delta9-tetrahydrocannabinol in Humans

Delta 9-tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis, is also known to modulate immune response in peripheral cells. The mechanisms of THCs effects on gene expression in human immune cells remains poorly understood. Combining a within-subject design with single cell transcriptome mapping, we report that administration of THC acutely alters gene expression in 15,973 human blood immune cells. Controlled for high inter-individual transcriptomic variability, we identified 294 transcriptome-wide significant genes among eight cell types including 69 common genes and 225 cell-type specific genes affected by acute THC administration, including those genes involving not only in immune response, cytokine production, but signal transduction, and cell proliferation and apoptosis. We revealed distinct transcriptomic sub-clusters affected by THC in major immune cell types where THC perturbed cell type-specific intracellular gene expression correlations. Gene set enrichment analysis further supports the findings of THCs common and cell-type specific effects on immune response and cell toxicity. We found that THC alters the correlation of cannabinoid receptor gene, CNR2, with other genes in B cells, in which CNR2 showed the highest level of expression. This comprehensive cell-specific transcriptomic profiling identified novel genes regulated by THC and provides important insights into THCs acute effects on immune function that may have important medical implications.

genetics↗

bioRxiv2018

Rapamycin, an Immunosuppressant and mTORC1 Inhibitor, Triples the antidepressant Response Rate of Ketamine at 2 Weeks Following Treatment: A double-blind, placebo-controlled, cross-over, randomized clinical trial

BACKGROUNDKetamine exerts rapid and robust antidepressant effects thought to be mediated by activation of the mechanistic target of rapamycin complex 1 (mTORC1). To test this hypothesis, depressed patients were pretreated with rapamycin, an mTORC1 inhibitor, prior to receiving ketamine.\n\nMETHODSTwenty-three patients suffering a major depressive episode were randomized to oral rapamycin (6 mg) or placebo, each was followed 2 hours later by ketamine 0.5 mg/kg in a double-blind cross-over design with treatment days separated by at least 2 weeks. Depression severity was assessed using Montgomery-[A]sberg Depression Rating Scale (MADRS). Antidepressant response was defined as a MADRS improvement of 50% or more.\n\nRESULTSOver the two-week follow-up, we found a significant treatment by time interaction (F(8,245) = 2.02, p = 0.04), reflecting prolonged antidepressant effects post rapamycin+ketamine treatment. At 2 weeks, we found a significantly higher response rate following rapamycin+ketamine (41%) compared to placebo+ketamine (13%, p = 0.04). However, rapamycin pretreatment did not alter the acute effects of ketamine.\n\nCONCLUSIONUnexpectedly, pretreatment with rapamycin prolonged rather than blocked the acute antidepressant effects of ketamine. This observation raises questions about the role of mTORC1 in the antidepressant effects of keta-mine, raises the possibility that rapamycin may extend the benefits of ketamine, and thereby potentially sheds light on mechanisms that limit the duration of ketamine effects. The supplementing of ketamine with rapamycin may be a treat-ment strategy for reducing the frequency of ketamine infusions during maintenance treatment.

neuroscience↗