Biology subjects

Houser, D.

Publications and source records attributed to Houser, D..

3 recordsLinked to original sources

bioRxiv2026

Development of a Fully Non-Viral 1XX-enhanced BCMA CAR-T Cell Therapy for Multiple Myeloma

Multiple myeloma (MM) is a clonal plasma cell malignancy characterized by bone marrow infiltration, monoclonal immunoglobulin production, and microenvironmental dysregulation that leads to systemic organ damage. The advent of B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapy has induced unprecedented responses and durability for patients with relapsed/refractory MM. These outcomes are rarely observed with prior salvage strategies, although relapse remains the predominant long-term challenge for most patients. The two currently approved BCMA CAR-T cell products use viral vectors to semi-randomly insert the CAR gene, which results in heterogeneous genomic composition and variability in efficacy, safety, and product consistency. To address these challenges, we integrated targeted CRISPR genome engineering with precise CAR transgene insertion at the T-cell receptor alpha constant (TRAC) locus, 1XX CAR signaling architecture to enhance potency and durability, and non-viral manufacturing with a single-stranded DNA repair template to improve efficiency and yield. This approach confers physiological CAR expression, reduces insertional mutagenesis, and improves persistence by mitigating tonic signaling and exhaustion. Our GMP manufacturing process consistently achieved high CAR integration (37.7-72.7%) and yields across all full-scale runs and met predefined release criteria for identity, purity, safety, and quality. In NSG mouse models of MM, the UCCT-BCMA-1 product exhibited exceptionally potent tumor control, CAR-T cell expansion 100-1000-fold greater than that of lentiviral constructs, and durable clearance of myeloma cells after multiple rechallenges. These findings establish a CRISPR-edited, fully non-viral manufacturing platform for next-generation 1XX-BCMA CAR-T therapies with enhanced persistence, safety, and efficacy. One Sentence SummaryCRISPR-engineered, TRAC-targeted 1XX-BCMA CAR-T therapy with improved safety, potency, and persistence in relapsed and refractory multiple myeloma.

cancer biology↗

bioRxiv2024

Bending Unwinds DNA

DNA is under high bending and torsional strain in many biological contexts 1,2, but elastic limits of tightly bent DNA under simultaneous torsional strain are not fully understood 3-22. We synthesized DNA circles with all possible radii of curvature between r {approx} 2.7 - 5.7 nm in increments of{Delta} r = 0.05 nm and defined helical repeats ranging from h {approx} 10 - 13 base pairs per helical turn. Nuclease digest reveals that DNA can be bent to r {approx} 3.0 nm without kinking, but only when h < ~10.9 bp/turn, while underwound DNA kinks irrespective of curvature. Histone proteins overwind DNA and thereby mechanically stabilize it. The natural helical repeat h0 increases from 10.45 to >11 bp/turn due to twist-bend coupling, which is not caused by kinking before ligation. These findings require reassessing our models and the energetics of molecular mechanisms involving DNA under mechanical stress.

biophysics↗

bioRxiv2024

Capture and Release of Minke Whales Offers New Research Opportunities Including Measurements of Mysticete Hearing

Knowledge about species-specific hearing is vital to assessing how anthropogenic noise impacts marine mammals. Unfortunately, no empirical audiogram exists for any mysticete whale. We therefore developed a catch-and-release method to assess hearing in a small mysticete, the minke whale (Balaenoptera acutorostrata). Stationary lead nets were placed to intercept migratory routes and direct animals into an ocean basin enclosed by nets and islets, while another net was pulled across the entrance once a whale entered the basin. The whales were then slowly corralled into a modified aquaculture pen using a net suspended between two boats. Subsequently, the water volume available to the whales was gradually reduced by raising the pen net by hand until the whales were secured in a "hammock" between the floating pen ring and a raft. From the raft, researchers could access the whales to monitor their health, apply instruments for hearing tests, or other research objectives, and attach tags to monitor the movements and diving behavior of the whale post-release. The method is a slow and controlled procedure, allowing continuous monitoring, and quick release of the whales, if needed. In the first three field seasons employing the method, three animals were caught for research procedures. Initial hearing measurements using auditory evoked potentials were successfully completed. After release the animals resumed migration and dive behavior were considered normal. Our observations demonstrate that minke whales can be safely guided via moored net barriers, corralled into an aquaculture pen, and safely handled for research purposes, before being released back into the wild.

physiology↗