Publications

A MEK1/2 inhibitor trametinib for the treatment of amyotrophic lateral sclerosis - Interim analysis of a Phase 1/2a clinical trial

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with a huge unmet need for disease-modifying therapies. As the pathogenesis and pathophysiology of ALS is largely unknown, various therapies with unique mechanisms are under development to find clues for ALS treatment. By utilizing a neural stem cell screening platform (ATRIVIEW®), trametinib (SNR1611, Mekinist®) was identified as the most neuroprotective and neurogenerative drug from an FDA-approved drug library. As older age at onset is related to faster progression, trametinib may show significant efficacy in age-stratified, well-powered clinical trials, warranting its further development for ALS.

Combined treatment with trametinib and riluzole improves motor function by enhancing autophagy in the SOD1-G93A mouse model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurological disease characterized by selective degeneration of motor neurons that causes muscle paralysis and eventual death. However, current treatments are far from providing a fundamental cure for the disease, and the need for more effective disease-modifying treatment is still strong. We found that low dose trametinib+riluzole combination therapy is pharmacologically superior to monotherapy in the ALS mouse model and could serve as a promising clinical combination for the improvement of current neuroprotective treatment strategies of ALS.

High content phenotypic screening platform ATRIVIEW® for compounds that induce neurogenesis and neuroprotection mechanisms in the neurodegenerative environment.

ATRIVIEW®-HCS is a phenotypic and biomarker-based drug screening system using neural stem cells derived from neurodegenerative disease model mice. It analyzes changes in morphology and neurogenesis/neuroprotection biomarker expression simultaneously.

GNUV205, a bifunctional protein of engineered IL-2 fused with a novel anti-PD1 antibody, exhibits superior tumor suppressing efficacy in vivo.

We found that GNUV205 is a candidate-stage bifunctional immuno-cytokine for solid cancer therapy expected to overcome the limitations of current standard-of-care therapies, such as IL-2 or anti-PD-(L)1s.

Trametinib activates endogenous neurogenesis and recovers neuropathology in a model of Alzheimer’s disease.

Enhancing adult neurogenesis in the brain has been suggested as a potential therapeutic strategy for AD. We developed a screening platform, ATRIVIEW®, for molecules that activate neuronal differentiation of adult mouse NSCs. The most potent hit from an FDA-approved drug library was SNR1611 (trametinib), a selective MEK1/2 inhibitor. From our result, we suggest that restoration of endogenous adult neurogenesis by trametinib may be a promising therapeutic approach to AD.

MEK1/2 inhibition rescues neurodegeneration by TFEB-mediated activation of autophagic lysosomal function in a model of Alzheimer’s Disease

Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder, which is characterized by cognitive deficit due to synaptic loss and neuronal death. Extracellular amyloid β plaques are one of the pathological hallmarks of AD. The autophagic lysosomal pathway is the essential mechanism to maintain cellular homeostasis by driving clearance of protein aggregates and is dysfunctional in AD. Here, we showed that inhibiting MEK/ERK signaling using a clinically available MEK1/2 inhibitor, trametinib (GSK1120212, SNR1611), induces the protection of neurons through autophagic lysosomal activation mediated by transcription factor EB (TFEB) in a model of AD.

GNUV205, an Engineered IL-2 Variant Fused with a Novel Anti-PD-1, Potently Regresses Tumor Growth without Toxicity via Selective Targeting to PD-1+ Teff Cells in Tumor Microenvironments

GNUV205 was designed to overcome these limitations by fusion of the TME-selective anti-PD-1 and eIL-2 selective for IL-2Rβγ-expressing Teff cells via our proprietary heterodimeric Fc platform technology.

2021 SfN_MEK1/2 inhibition rescues neurodegeneration by activation of autophagic lysosomal function in Alzheimer’s Disease

We report that administration of trametinib, a MEK1/2 specific inhibitor, ameliorates memory deficits and synaptic dysfunction and reduces Aβ deposition in various Alzheimer’s disease models. The mechanism of neuroprotection by trametinib is achieved through an enhancement of protective autophagy, a conserved cellular process for clearing dysfunctional organelles and protein aggregates. Thus, we demonstrate that trametinib contributes to the recovery of damaged neuronal functions, representing a potential treatment for Alzheimer’s disease. .