The Sean M. Healey Center for ALS at Massachusetts General Hospital is pleased to announce three new fellowships that will advance its work to find a cure for ALS.
With the help of donors including the Byrne Family, the Judith and Jean Pape Adams Charitable Foundation and the Cullen Education and Research Fund, these new young investigators will have the opportunity to play a central role in breaking down current barriers, accelerating the translation of research findings into care, and expanding treatment access to innovative and personalized therapeutic trials.
Byrne Family Endowed Fellowship in ALS Research and the Judith and Jean Pape Adams Charitable Foundation Early Career Research Award
The Byrne Family Endowed Fellowship, with matching support from the Judith and Jean Pape Adams Charitable Foundation, have generously provided endowments to fund an early career ALS researcher at Mass General.
Our inaugural fellow is Dr. Tiziana Petrozziello, a neuroscientist and a post-doctoral fellow in the Sadri-Vakili NeuroEpigenetics Laboratory. Her research is focused on understanding the molecular mechanisms that lead to pathogenesis in amyotrophic lateral sclerosis (ALS). She received her PhD in Neuroscience at the University of Naples Federico II, in Italy, where she studied a novel neuromodulatory role of SOD1 in ALS. It was during this time that she became committed to understanding the disease mechanisms that underlie ALS, given the lack of cures and the devastation that it causes for families.
Following completion of her PhD, Dr. Petrozziello began her post- doctoral training in Dr. Annunziato’s lab, in the Department of Neuroscience at the University of Naples Federico II, where she studied dysregulation of calcium homeostasis in ALS. During this time, she received the Best Poster award from the Italian Society of Neuroscience (SINS, XVII National Congress) for her work on ALS. In January 2019 she joined the Sadri-Vakili lab, knowing that she would be able to use human post-mortem ALS samples and biofluids to identify targets for the development of novel therapies and biomarkers for ALS.
Dr. Petrozziello is highly motivated, dedicated, and extremely productive. She is also a fast learner and technically skillful. Therefore, it was no surprise that she published her first paper from the Sadri-Vakli lab within the first year of arriving at Massachusetts General Hospital. This paper focuses on the role of inflammation in ALS using post-mortem human samples (Petrozziello et al., 2020). In addition, she was also a co-author on a methods paper demonstrating how to successfully extract the innate central nervous system immune cells, microglia, from post-mortem human samples (Bordt et al., 2020). Currently, her studies in the Sadri-Vakili lab are focused on elucidating how alterations in mitochondrial function and dynamics lead to motor neuron loss in ALS. Specifically, she is using post-mortem brain and spinal cord samples from a large cohort of ALS patients and controls to investigate changes in bioenergetics using the most current technology. Dr. Petrozziello has identified two specific targets that lead to fragmentation of mitochondria and thereby a decrease in the neuron’s energy production. Importantly, she has in hand genetic and pharmacological tools to target these proteins and mitigate deficits in mitochondrial function.
Cullen Education and Research Fund Young Investigator Awards
The Cullen Education and Research Fund for ALS research provides financial support for two outstanding post- doctoral fellows and/or junior faculty who are undertaking or conducting high risk-high reward scientific initiatives in ALS innovative basic and/or clinical research projects with a focus on improving outcomes and treatments for patients with ALS. Aaron Held, PhD and Matthew Nolan, PhD are inaugural recipients of the Cullen Education and Research Fund Young Investigator Awards.
Dr. Held is a postdoctoral fellow in the Wainger Lab who has demonstrated a deep commitment to ALS work and has established himself as a creative and promising scientist, bringing critical quantitative insight and rigor to biological disease models. As a graduate student at Brown University, he developed drosophila knock-in ALS models and built from scratch unbiased analytical tools that identified and quantified disease phenotypes in the flies. His desire to focus on human stem cell models in a translational environment, led him to Mass General, and he joined the Wainger group soon after the lab received an NIH New Innovator award to develop models of the neuromuscular junction in ALS. The timing was outstanding, as Aaron has since leveraged the high-content image capacity of the instrument to build tools the group now uses to phenotype ALS patient-derived motor neurons at large scale.
Using custom-written analysis scripts, Dr. Held has enabled large-scale, unbiased analyses of neuronal outgrowth and firing patterns of hundreds of individual neurons imaged simultaneously. He has demonstrated increased calcium signals in ALS compared to CRISPR gene-edited controls consistently across several ALS genetic subtypes and is currently correlating the neuronal activity with the outgrowth analysis. These analytical tools have allowed the group to perform several new areas of research. With support from Sanofi, we have established a high-quality phenotypic screen assay to identify potential compounds that could be rapidly repurposed to clinical trials, as we have done previously with retigabine in ALS – showing that a drug identified in iPSC motor neurons may yield a successful pharmacodynamic effect in ALS patients.
In a separate project, Aaron is using the tools he created to dissect and understand multiple facets of ALS pathology, focusing specifically on how different ALS mutations converge on TDP-43 phosphorylation and mislocalization in ALS. The hypothesis is that understanding this genetic convergence will lead to the identification of targets for sporadic ALS. Aaron’s insight and software have improved the quantification of muscle contraction in our stem cell-based model of the neuromuscular junction, for which the first manuscript is currently under review at Nature Neuroscience.
Dr. Nolan is a postdoctoral researcher in the Lagier-Tourenne Laboratory, studying cellular mislocalization and aggregation of proteins, a common feature in neurodegenerative diseases and a central disease mechanism in ALS. Despite tremendous progress in our understanding of the mechanisms underlying neurodegeneration, therapeutically targeting protein mislocalization remains challenging. Dr. Nolan proposes to optimize a method recently developed in cancer biology to identify factors that trigger or prevent abnormal aggregation of proteins in ALS. Using the CRISPR/cas9 genome editing, he will systematically inactivate each 20,000 genes of the genome in ALS patient cells (cultured skin cells and iPSC-derived neurons) in order to identify which genes rescue abnormal protein aggregation in patient cells and may represent novel therapeutic targets for ALS.
While the efficiency of CRISPR/Cas9 system has provided unprecedented opportunities to identify modifiers of disease-related phenotypes in human cells, its use in human neurons has so far been very limited. The Blainey Laboratory at the Broad Institute has recently developed a microscopy-based platform called “Optical Genetic Screen” that is amenable to human neurons but has not yet been used in neurodegenerative diseases. Dr. Nolan proposes an ambitious program to apply ALS to this innovative screening method recently developed in cancer cells. By leveraging complementary expertise from the Blainey and Lagier-Tourenne groups, Dr. Nolan will optimize the method to identify modulators for protein mislocalization in ALS neurons. We believe this project will not only advance our understanding of ALS disease mechanisms, but also serve as the foundation for development of therapeutic approaches.
Dr. Nolan received a PhD in Clinical Neuroscience from the University of Oxford in the United Kingdom under the supervision of Dr. Ansorge and Pr. Talbot. He investigated the mechanisms of selective vulnerability of the primary motor cortex in ALS. In 2019, he joined the Lagier-Tourenne laboratory at Mass General for his postdoctoral training to widen his expertise in molecular and cellular mechanisms leading to neurodegeneration in ALS. His goal is to become an independent academic investigator and continue his research efforts to better understand disease mechanisms in ALS and to develop novel therapeutic strategies for this disease.
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