Two Mass General Brigham Scientists Honored for Work on Neurodegenerative and Cancer Therapies
Pictured left to right: Miceal Chamberlain, Paul Anderson, MD, PhD, Clotilde Lagier-Tourenne, MD, PhD, Li Chai, MD, Roger Kitterman, and Chris Coburn
Investigators earn $10,000 awards to promote early-stage innovations presented at the 2023 World Medical Innovation Forum.
At the 2023 World Medical Innovation Forum, 16 Mass General Brigham investigators presented their discoveries and insights aimed at disrupting the fields of central nervous system/brain health, oncology, and inflammation & immunology as part of the forum’s “First Look” session. Two of these presentations received additional recognition for addressing an unmet need as well as having clinical impact, scientific strength, and collaboration opportunities.
Mass General Brigham presented $10,000 awards to Clotilde Lagier-Tourenne, MD, PhD, associate professor of Neurology and the Araminta Broch-Healey Endowed Chair in ALS at Massachusetts General Hospital, and to Li Chai, MD, associate director of Adult Transfusion Medicine and associate professor of Pathology at Brigham and Women’s Hospital. Lagier-Tourenne and her team discovered a new approach to aid nerve regeneration among patients with neurodegenerative diseases. Chai led a team that identified a new therapy targeting a specific protein in cancer patients.
A New Therapeutic Strategy for Patients with Neurodegenerative Diseases
Many neurodegenerative diseases have one thing in common: the alteration of RNA metabolism. Mutations and disruptions that prevent RNA-binding proteins from binding properly and regulating their RNA targets have been identified in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer’s disease.
Lagier-Tourenne and her team investigate the molecular mechanisms driving neurodegeneration in ALS and FTD. They recently identified TDP-43 as a crucial RNA-binding protein that regulates the expression and splicing of stathmin-2, a neuronal growth-associated factor. Experiments show that stathmin-2 loss results in diminished nerve regeneration. Remarkably, although TDP-43 broadly affects many RNAs, they discovered that the restoration of stathmin-2 can support the regeneration of motor neurons.
The team tested two approaches to block splicing of stathmin-2. One approach entailed using the CRISPR effector dCasRx and another using small pieces of RNA that bind to stathmin-2. In preclinical models, they demonstrated that RNA injection could rescue stathmin-2 levels. They also used pharmacological and genetic screens to identify potential novel targets for translational drug development in neurological diseases.
“The restoration of stathmin-2 has shown remarkable potential in maintaining the connection between motor neurons and muscles, making it an attractive therapeutic strategy for patients,” said Lagier-Tourenne.
Lagier-Tourenne and her team have started a program that is supported by Mass General Brigham Innovation to develop lead compounds that restore stathmin-2 in neurodegenerative diseases. They are also seeking partners for co-funding to accelerate clinical development.
Protein-Targeting Therapy Offers New Approach in Cancer
Cancer accounts for nearly 10 million deaths every year, highlighting the need for new approaches. Transcription factors (TFs) drive many cancer processes but have largely been underexplored as therapeutics. However, recent breakthroughs and successes have highlighted TF degradation as one of the most exciting new frontiers in the development of novel cancer drugs.
Over the past 20 years, Chai has led a team studying an oncogenic TF protein, SALL4, which is typically found in fetal tissues. However, it is also re-activated in approximately one-third of cancer patients across almost every human cancer type.
To uncover SALL4’s role in cancer, Chai and her team used mice that expressed SALL4 and developed leukemia and/or liver tumors. Through loss-of-function studies, they reduced SALL4 using sequences of RNA known as shRNA. They found cell growth inhibition and cell death in leukemias as well as SALL4-expressing solid tumors in both cell culture and in vivo xenotransplants.
“These findings demonstrate the significant potential of SALL4 as a cancer target. We also expect that SALL4 can be targeted with limited toxicity due to its limited expression in normal tissues,” said Chai.
Moving forward, the team is seeking funding to form a startup. They hope to complete pre-clinical and IND-enabling studies for a lead compound to treat hepatocellular carcinoma, develop companion diagnostics, and expand to lung cancer.
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