Multiplex engineering using microRNA-mediated gene silencing in CAR T cells.

Background: Multiplex gene-edited chimeric antigen receptor (CAR) T-cell therapies face significant challenges, including potential oncogenic risks associated with double-strand DNA breaks. Targeted microRNAs (miRNAs) may provide a safer, functional, and tunable alternative for gene silencing without the need for DNA editing.

Methods: As a proof of concept for multiplex gene silencing, we employed an optimized miRNA backbone and gene architecture to silence T-cell receptor (TCR) and major histocompatibility complex class I (MHC-I) in mesothelin-directed CAR (M5CAR) T cells.

Engineering a Juxtamembrane-Targeting CAR T-Cell Against Mesothelin: A Novel Binder Resilient to Shed Antigen in Ovarian and Pancreatic Cancer.

Mesothelin is an attractive target for CAR-T therapy on a number of cancer types; however, the efficacy of this therapy is diminished because the bulk of the cell surface-expressed mesothelin is shed through naturally occurring proteolysis leaving behind a short juxtamembrane peptide 'stump'. The two problems this creates are (1) the bulk of the target protein is no longer on the tumor cell and (2), the free soluble shed mesothelin remains in the tumor microenvironment and becomes present in blood/other body fluids binding to the mesothelin-targeted CAR-T and interfering with their ability to target the mesothelin that remains on the surface of the tumor. These issues have likely contributed at least in part to the lack of desired efficacy of CAR-T cells that target membrane distal regions of mesothelin (i.

Integrated Physiotherapeutic Intervention for Rehabilitation of a Patient With Intellectual Disabilities: A Case Report.

Intellectual disabilities (ID) encompass a broad spectrum of neurodevelopmental disorders marked by impairments in cognitive functioning and adaptive behavior. Accessing and benefiting from rehabilitation services pose significant challenges for individuals within this population. In this case study, the rehabilitation journey of a 44-year-old man with ID, emphasizes the tailored approach to his rehabilitation program.