Biomedical subjects

Geoffroy Andrieux

Publications and source records attributed to Geoffroy Andrieux.

3 recordsLinked to original sources

PubMed2026

Targeted insertion of an optimized donor DNA is effective in a humanized mouse model of dominant retinitis pigmentosa.

Retinitis pigmentosa (RP) affects 1 in 3,000 individuals worldwide, with 30%-40% of cases inherited as autosomal dominant (AD). Mutations in RHO (RP4) are the most common cause of ADRP. Because most RHO mutations exert gain-of-function or dominant-negative effects, conventional gene supplementation is insufficient, requiring mutant allele inactivation. Allele-specific editing is impractical, as each mutation requires a unique therapeutic strategy. We present a mutation-agnostic, RHO-specific approach using adeno-associated viral vector-mediated homology-independent targeted integration (AAV-HITI). Optimized donor DNA design enables targeted integration and efficient transgene expression from the endogenous RHO locus. In a humanized RP4 mouse model harboring the RHO P23H mutant allele alongside an endogenous wild-type mouse Rho allele, AAV-HITI significantly improves retinal structure, function, and visual acuity up to 1 year post-treatment. Comprehensive molecular analyses characterize on-target editing in mouse retina and off-target editing in a human cell line. These findings establish an effective, human-centric AAV-HITI platform for RP4 and support its evaluation in this and other dominant genetic conditions.

AAV↗

PubMed2025

PUMA-induced apoptosis drives bone marrow failure and genomic instability in telomerase-deficient mice.

Bone marrow failure is a severe complication of human telomere biology disorders and predisposes individuals to secondary leukemia. A deeper understanding of this process could offer significant clinical benefits. Using a preclinical mouse model deficient in the RNA component of the telomerase (mTerc), we demonstrate that bone marrow failure results from excessive apoptosis, predominantly mediated by the pro-apoptotic p53 target PUMA. Genetic ablation of Puma alleviates hematological phenotypes and reduces the risk of lethal bone marrow failure while preserving genomic stability. Mechanistically, PUMA deficiency decreases the sensitivity of hematopoietic cells to lethal stressors, including critically short telomeres. As a consequence, reduced compensatory turnover of hematopoietic progenitors slows down telomere shortening at the population level, delays stem cell exhaustion, and diminishes the acquisition of somatic mutations - ultimately preventing neoplastic transformation. Elevated expression of both p53 and PUMA is also observed in the bone marrow from patients with telomere biology disorders. While apoptosis resistance is traditionally associated with malignant transformation, our findings provide evidence that selective inhibition of PUMA-mediated apoptosis may represent a viable therapeutic strategy to prevent or delay leukemic transformation in this patient population.

Animals↗

PubMed2025

Multidimensional OMICs reveal ARID1A orchestrated control of DNA damage, splicing, and cell cycle in normal-like and malignant urothelial cells.

Epigenetic regulators, such as the SWI/SNF complex, with important roles in tissue development and homeostasis, are frequently mutated in cancer. ARID1A, a subunit of the SWI/SNF complex, is mutated in approximately 20% of all bladder tumors; however, the consequences of this remain poorly understood. Finding truncations to be the most common mutation, we generated loss- and gain-of-function models to conduct RNA-Seq, interactome analyses, Omni-ATAC-Seq, and functional studies to characterize ARID1A-affected pathways potentially suitable for the treatment of ARID1A-deficient bladder cancers. We observed decreased cell proliferation and deregulation of stress-regulated pathways, including DNA repair, in ARID1A-deficient cells. Furthermore, ARID1A was linked to alternative splicing and translational regulation on RNA and interactome levels. ARID1A deficiency drastically reduced the accessibility of chromatin, especially around introns and distal enhancers, in a functional enrichment analysis. Less accessible chromatin areas were mapped to pathways such as cell proliferation and DNA damage response. Indeed, the G2/M checkpoint appeared impaired after DNA damage in ARID1A-deficient cells. Together, our data highlight the broad impact of ARID1A loss and the possibility of targeting proliferative and DNA repair pathways for treatment.

Transcription Factors↗