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GSX2 is a homeobox transcription factor (TF) controlling the specification of the ventral lateral ganglionic eminence and its major derivative, the corpus striatum. Medium spiny neurons (MSNs) represent the largest cell component of the striatum and they are primarily affected in Huntington disease (HD). Here, we used CRISPR technology to generate a pluripotent GSX2-reporter human embryonic stem cell (hESC) line that can be leveraged to monitor striatal differentiation in real-time and to enrich for MSN-committed progenitors.

GSX2 is a homeobox transcription factor (TF) controlling the specification of the ventral lateral ganglionic eminence and its major derivative, the corpus striatum. Medium spiny neurons (MSNs) represent the largest cell component of the striatum and they are primarily affected in Huntington disease (HD). Here, we used CRISPR technology to generate a pluripotent GSX2-reporter human embryonic stem cell (hESC) line that can be leveraged to monitor striatal differentiation in real-time and to enrich for MSN-committed progenitors., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase (BTK) and has shown single-agent activity in recurrent/refractory central nervous system (CNS) lymphoma. Clinical responses are often transient or incomplete, suggesting a need for a combination therapy approach. We conducted a phase 1b clinical trial to explore the sequential combination of ibrutinib (560 or 840 mg daily dosing) with high-dose methotrexate (HD-MTX) and rituximab in patients with CNS lymphoma (CNSL). HD-MTX was given at 3.5 g/m 2 every 2 weeks for a total of 8 doses (4 cycles; 1 cycle = 28 days). Ibrutinib was held on days of HD-MTX infusion and resumed 5 days after HD-MTX infusion or after HD-MTX clearance. Single-agent daily ibrutinib was administered continuously after completion of induction therapy until disease progression, intolerable toxicity, or death. We also explored next-generation sequencing of circulating tumor DNA (ctDNA) in cerebrospinal fluid (CSF) before and during treatment. The combination of ibrutinib, HD-MTX, and rituximab was tolerated with an acceptable safety profile (no grade 5 events, 3 grade 4 events). No dose-limiting toxicity was observed. Eleven of 15 patients proceeded to maintenance ibrutinib after completing 4 cycles of the ibrutinib/HD-MTX/rituximab combination. Clinical responses occurred in 12 of 15 patients (80%). Sustained tumor responses were associated with clearance of ctDNA from the CSF. This trial was registered at www.clinicaltrials.gov as #NCT02315326., (© 2019 by The American Society of Hematology.)