Cedars-sinai Medical Center

Joshua Breunig

Moise Danielpour

Clive N Svendsen

Vaithilingaraja Arumugaswami

Gi Bum Kim

Aslam Akhtar

Clive Svendsen

Delivery of glial cell line-derived neurotrophic factor (GDNF) has provided benefits to Parkinsonian patients and is currently being tested in a Phase 1/2a clinical trial for ALS patients. However, chronic trophic factor delivery prohibits dose adjustment or shut off in the event of side effects. To address this, the Inventors engineered a stably integrating, third-generation doxycycline-regulated vector, allowing inducible and reversible expression of a therapeutic molecule Human iPSC-derived neural progenitors were stably transfected with the vector, expanded and transplanted into the adult mouse brain. The Inventors observed that the addition and withdrawal of doxycycline led to GDNF expression that could be induced and reversed multiple times, demonstrating that doxycycline can penetrate the graft and regulate transgene expression in vivo. The Inventors' findings provide a proof of concept for combining gene and stem cell therapy for effective modulation of ectopic protein expression in transplanted cells.

Methods and compositions for inducible expression of neurotrophic factors

Described herein are donor vectors and systems for use in in vivo dual recombinase-mediated cassette exchange. Also described are animal models for consistent, rigorous, and facile investigation of transgene expression. Further described are methods of screening for therapeutic drugs using these animal models, and methods of treatment.

Systems and methods for in vivo dual recombinase-mediated cassette exchange (dRMCE) and disease models thereof

The present invention provide for methods of inducing an oncolytic effect on tumor cells using Zika virus. The invention also provides for inducing an oncolytic effect on brain tumors and treating brain tumors, and in particular, glioblastomas and neuroblastoma. The treatment involves the administration of Zika virus, which has an oncolytic effect on the tumor cells.

Method of inducing an oncolytic effect on tumor cells using Zika virus

Described herein are composition and methods related to targeting the Nf1-Ras-Ets axis, that when perturbed, is identified as playing a role in initiation and maintenance in glioma. A postnatal, mosaic, autochthonous, glioma model that captures the first hours and days of gliomagenesis in more resolution than conventional genetically engineered mouse models of cancer demonstrates that disruption of the Nf1-Ras pathway in the ventricular zone at multiple signaling nodes uniformly results in rapid neural stem cell depletion, progenitor hyperproliferation, and gliogenic lineage restriction. By abolishing Ets subfamily activity, which is upregulated downstream of Ras, there is block of glioma initiation, thereby providing new therapeutic avenues for targeting glioma.

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Los Angeles, CA, United States of America

Joshua Breunig