Biology subjects

Berry, T.

Publications and source records attributed to Berry, T..

4 recordsLinked to original sources

bioRxiv2026

Preclinical validation of AAV9-TECPR2 gene therapy in a novel knock-in model of TECPR2-related disorder

TECPR2-related disorder is a rare, autosomal recessive neurodevelopmental and neurodegenerative disease characterized by early-onset motor dysfunction, sensory- and autonomic neuropathy, and progressive neurological decline with early mortality. Currently, there are no effective treatments for individuals affected by this debilitating condition. To advance our understanding of disease mechanisms and explore therapeutic strategies, we developed and then characterized a knock-in (KI) mouse model carrying the human TECPR2 c.1319delC frameshift mutation. TECPR2-KI mice exhibit a subset of disease-relevant phenotypes, most prominently abnormal gait, along with reduced body weight and altered tactile sensitivity. We additionally observe a reduction in acoustic startle responses, consistent with dysfunction of brainstem-associated sensorimotor pathways. Histopathological analyses reveal progressive accumulation of axonal spheroids in the dorsal column nuclei, together with abnormalities in autophagy-related markers, features previously reported in individuals with TECPR2-related disorder. To assess the therapeutic potential of gene replacement, we delivered TECPR2 via intracisternal infusion of AAV9/TECPR2 in neonatal KI mice. Gene therapy restored mechanosensory function, normalized gait and startle responses, maintain autophagic homeostasis, and partially reduced axonal pathology. These findings demonstrate that TECPR2-associated deficits are not only replicable in this new mouse model but are also amenable to postnatal intervention. Our study introduces a genetically accurate murine model of TECPR2 deficiency, identifies brainstem-associated phenotypes, and provides preliminary evidence supporting the feasibility of AAV9-mediated TECPR2 gene delivery, establishing a foundation for future translational research in a currently untreatable disease. One-Sentence Key MessageTECPR2 deficiency disrupts brainstem sensory-motor circuits, impairing autophagy and tactile, gait, and startle function and is prevented by neonatal AAV9.

neuroscience↗

bioRxiv2026

Functional genomics identifies therapeutic options, biomarkers, and resistance mechanisms for high-grade gliomas

High-grade gliomas (HGGs) are aggressive tumors with poor outcomes and limited treatment options. Here, we combined genomic and transcriptomic tumor profiling with drug testing in a patient-derived 3-dimensional culture model to identify individualized treatments and predictive biomarkers. Activity of single agents targeting frequently dysregulated glioma pathways was relatively poor ex vivo and generally reflected historical patient data. However, compounds targeting PI3K, epigenetic, and survival/senescence signaling were effective in some cases. Drug sensitivity correlated with transcriptional rather than genomic features and suggested heterogeneity as a resistance mechanism. Bromodomain and extraterminal domain inhibition was particularly effective in tumors enriched in the mesenchymal transcriptional subtype, promoted proneural transition, and was overcome by upregulated PI3K signaling. Notably, combinations were largely effective, with 6 strategies exhibiting stronger efficacy than corresponding single agents in most cases (58-77%). This study identifies HGG vulnerabilities and associated biomarkers, resistance mechanisms, and effective combination strategies that warrant further clinical validation. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=171 SRC="FIGDIR/small/701806v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@cdb75corg.highwire.dtl.DTLVardef@1c133e6org.highwire.dtl.DTLVardef@1365153org.highwire.dtl.DTLVardef@11543a4_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Functional impact of the hyperduplication genomophenotype in high copy number endometrial cancer

High copy number endometrial cancers (HCNEC) are dominated by excessive duplications scattered across the genome, termed here as the HyperDuplication GenomoPhenotype (HDGP). Although correlated with cancer progression, its biological significance and implications for therapy have not yet been established. We identified locations and sizes of duplications in 171 endometrial cancer cases and designated 71 HCNEC cases as HDGP. We also investigated the response to the pan-ERBB inhibitor afatinib in a subset of HDGP-EC cases with ERBB2/ERBB3 duplications using a patient-derived three-dimensional culture model. Our analysis demonstrates that beyond tandem duplications there is a more general pattern involving coordinated duplication of multiple distant regions of the genome, demonstrating preferential selectivity to over-expressed potential oncogenes within a broad network. This suggests that HDGP increases tumor fitness and resistance to therapy by perturbing important gene networks in concert rather than only driver genes, suggesting a mechanistic basis for the ineffectiveness of targeted drugs in these patients and highlighting the need for combination therapies in these highly aggressive cases.

genomics↗

bioRxiv2021

Dispersal syndrome and landscape fragmentation in the salt-marsh specialist spider Erigone longipalpis

Dispersal and its evolution play a key role for population persistence in fragmented landscapes where habitat loss and fragmentation increase the cost of between-habitat movements. In such contexts, it is important to know how variation in dispersal and other traits is structured, and whether responses to landscape fragmentation are aligned with underlying dispersal-trait correlations, or dispersal syndromes. We therefore studied trait variation in Erigone longipalpis, a European spider species specialist of (often patchy) salt marshes. We collected spiders in two salt-marsh landscapes differing in habitat availability. We then reared lab-born spiders for two generations in controlled conditions, and measured dispersal and its association with various key traits. E. longipalpis population densities were lower in the more fragmented landscape. Despite this, we found no evidence of differences in dispersal, or any other trait we studied, between the two landscapes. While a dispersal syndrome was present at the among-individual level (dispersers were more fecund and faster growing, among others), there was no indication it was genetically driven: among-family differences in dispersal were not correlated with differences in other traits. Instead, we showed that the observed phenotypic covariations were mostly due to within-family correlations. We hypothesize that the dispersal syndrome is the result of asymmetric food access among siblings, leading to variation in development rates and carrying over to adult traits. Our results show we need to better understand the sources of dispersal variation and syndromes, especially when dispersal may evolve rapidly in response to environmental change.

ecology↗