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NIH grant 1R41CA306619-01A1: Alphavirus vector-mediated expression of a connexin43 mimetic peptide in glioblastoma therapy
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: Samy Lamouille. Award: $400000.
Start: 2026-09-18T00:00:00.
Glioblastoma (GBM) is among the most aggressive and treatment-resistant brain tumors, with median survival
remaining ~14 months despite standard-of-care treatment. GBM recurrence is driven by a therapy-resistant
subpopulation of glioblastoma stem cells (GSCs), which evade chemo- and radiotherapy and regenerate tumor
mass. Currently, there are no FDA-approved therapies that specifically target GSCs. Thus, novel strategies
capable of safely and selectively eliminating GSCs are urgently needed to improve patient outcomes.
We identified a novel, channel-independent tumor-promoting role of connexin43 (Cx43) in GSCs, mediated by
its cytoplasmic interaction with microtubules. We developed JM2, a Cx43 mimetic peptide that disrupts this
interaction and specifically kills GSCs without affecting normal brain cells. Our preliminary data show that JM2
reduces GSC populations in vivo in patient-derived GBM xenografts and extends survival when combined with
temozolomide (TMZ), the current standard chemotherapeutic agent for GBM. To enable systemic delivery of
JM2 across the blood-brain barrier, we propose the use of a brain-tropic, non-integrating alphavirus vector.
This platform exhibits strong tumor selectivity and has shown no off-target toxicity in preclinical studies in mice
and dogs. Notably, we demonstrate that an alphavirus expressing Gaussia luciferase (gLuc) significantly
reduces tumor burden in an orthotopic syngeneic GBM model, providing critical proof-of-concept for this
approach.
In Aim 1, we will optimize alphavirus vectors encoding JM2 using single or multiple peptide copies. Expression
and viral fitness will be quantified in vitro, and biodistribution assessed in healthy and tumor-bearing mice. We
will evaluate the safety and tolerability of systemically administered alphavirus-JM2 in immunocompetent mice,
using clinical scoring, cytokine profiling, histopathology, and viral genome quantification to assess toxicity and
immune activation.
In Aim 2, we will assess therapeutic efficacy in both syngeneic and patient-derived orthotopic GBM models,
evaluating tumor burden, GSC depletion, and overall survival. We will also generate a research-grade, tag-free
version of the virus optimized for downstream clinical application. A regulatory affairs firm (subcontracted) will
provide guidance to ensure alignment with future IND-enabling studies.
In vivo mouse models are essential, as the tumor microenvironment, including immune cell interactions and the
blood-brain barrier, cannot be replicated in vitro. Immunocompetent models are required to evaluate virusimmune
system interactions, and animal testing remains a regulatory prerequisite for clinical translation.
This Phase I project will establish feasibility for a novel peptide-expressing alphavirus gene therapy targeting
both bulk GBM cells and GSCs. Successful completion will validate the safety and therapeutic potential of this
platform, positioning it for regulatory advancement and future clinical translation.document fetched 2026-09-27 02:45