Person:

Sharma, Jitendra

Background: Patients with relapsing–remitting multiple sclerosis (RRMS) may experience breakthrough disease despite effective interferon beta (IFNβ) therapy. Fludarabine (FLU) is a chemotherapeutic agent used in lymphoproliferative disorders that may be synergistic when combined with immunomodulatory therapy to control active multiple sclerosis (MS). Objective: The objective of this study was to explore the safety and tolerability of FLU versus monthly methylprednisolone (MP) in IFNβ-treated RRMS patients with breakthrough disease. Clinical and MRI effects of IFNβ-1a plus FLU were evaluated. Methods: Eighteen patients with breakthrough disease [⩾2 relapses over the prior year and ⩾1.0-point increase in Expanded Disability Status Scale (EDSS) score sustained for ⩾3 months] after >1 year of IFNβ therapy were enrolled in this prospective, open-label, randomized, proof-of-concept, pilot study. Patients received intravenous (IV) MP 1 g daily for 3 days and then were randomized to receive 3 monthly IV infusions of FLU 25 mg/m2 daily for 5 consecutive days (n = 10) or MP 1 g (n = 8). All patients maintained their intramuscular IFNβ-1a treatment throughout the study. Analyses explored safety signals and directional trends; this preliminary study was not powered to detect clinically meaningful differences. Results: Both combination treatments were safe and well tolerated, with all adverse events mild. Patients treated with IFNβ-1a plus FLU had similar relapse rates, EDSS scores, and MS Functional Composite scores, but significantly less acute corticosteroid use for on-study relapses and better responses on some MRI outcomes, versus patients treated with IFNβ-1a plus MP. Conclusions: Further study of FLU for breakthrough disease in patients with RRMS is warranted.

Mutation or disruption of the SHANK3 (SH3 domain and ankyrin repeat) gene represents a highly penetrant, monogenic risk-factor for Autism Spectrum Disorder (ASD) and is a cause of Phelan–McDermid syndrome (PMS). Recent advances in gene editing have enabled the creation of genetically engineered non-human primate (NHPs) models, which might better approximate the behavioral and neural abnormalities of ASD than rodent models and lead to more effective treatments. Here, we report CRISPR/Cas9-mediated generation of germline transmissible cynomolgus macaques and their F1 offspring carrying SHANK3 mutations. Genotyping of somatic cells and brain biopsies confirmed mutations in the SHANK3 gene and reduced SHANK3 proteins. Analysis of fMRI data revealed altered local and global connectivity patterns indicative of circuit abnormalities. The founder mutants exhibited sleep disturbances, motor deficits, and increased repetitive behaviors, as well as social and learning impairments. Together, these results parallel some aspects of the gene-circuit-behavior dysfunction in human ASD and PMS.