RESEARCH GRANTS 1 HDF RESEARCH GRANTS We like the philosophy of the Hereditary Disease Foundation that monies raised go directly to support research and that scientists from around the world “are encouraged to collaborate and share their work. “ We’ve devoted ourselves to being supporters and research partners, and we have not been disappointed. The research is vibrant with possibilities. Sandy Fox Member, Board of Directors Hereditary Disease Foundation 1 HDF RESEARCH GRANTS Osama Al-Dalahmah, MD, DPhil Anna Pluciennik, PhD Columbia University, New York, NY Thomas Jefferson University, Philadelphia, PA Cheryl Arrowsmith, PhD Paul Ranum, PhD University of Toronto, Canada Children’s Hospital of Philadelphia, PA Anne Ast, PhD Piere Rodriguez-Aliaga, PhD Max Delbrück Center for Molecular Medicine Stanford University, Palo Alto, CA Berlin, Germany Jennie C. L. Roy, PhD Kristina Becanovic, PhD Massachusetts General Hospital Karolinska Institutet, Stockholm, Sweden Harvard Medical School, Boston, MA Abdellatif Benraiss, PhD David M. Sabatini, MD, PhD University of Rochester, Rochester, NY Whitehead Institute for Biomedical Research Massachusetts Institute of Technology, Cambridge, MA Veronica Ines Brito, PhD University of Barcelona Charlene Smith-Geater, PhD Instituto de Neurosciencias, Spain University of California, Irvine, CA Lauren Byrne, PhD Joan Steffan, PhD University College London (UCL), England University of California, Irvine, CA Amit Laxmikant Deshmukh, PhD Xiao Sun, PhD The Hospital for Sick Children, Toronto, Canada Southwestern Medical Center, Dallas, TX Steven Finkbeiner, MD, PhD Leslie Thompson, PhD Gladstone Institutes University of California, Irvine, CA University of California, San Francisco, CA Nicholas Todd, PhD Brent Fitzwalter, PhD Brigham and Women’s Hospital Broad Institute of MIT and Harvard, Cambridge, MA Harvard Medical School, Boston, MA Ali Khoshnan, PhD Ray Truant, PhD California Institute of Technology, Pasadena, CA McMaster University, Ontario, Canada Ryan Lim, PhD Jean Paul G. Vonsattel, MD, with University of California, Irvine, CA Richard A. Hickman, MD Columbia University, New York, NY Roy Maimon, PhD University of California, San Diego, CA Gong-Her Wu, PhD Stanford University, Palo Alto, CA A. Jenny Morton, PhD University of Cambridge, England Ai Yamamoto, PhD Columbia University, New York, NY Christopher Ng, PhD Massachusetts Institute of Technology, Cambridge, MA X. William Yang, MD, PhD University of California, Los Angeles, CA Daniel O’Reilly, PhD University of Massachusetts Medical School Michael Zody, PhD Worcester, MA New York Genome Center, New York, NY Ellen Penney, MD, PhD Massachusetts General Hospital Harvard Medical School, Boston, MA HDF RESEARCH GRANTS T he Hereditary Disease Foundation provides funding for research that advances the discovery and development of treatments for Huntington’s disease and other brain disorders. We are passionate about finding and funding the most promising, creative and paradigm-changing research possible. Data generated with HDF grants allows researchers to apply successfully for major long-term funding from other sources, including the National Institutes of Health. OSAMA AL-DALAHMAH, MD, DPHIL Institution: Columbia University Medical Center New York, NY Project Title: Studying Huntington’s disease astrocytes in different parts of the brain: A regional study of the landscape of gene expression at the single cell level r. Al-Dalahmah aims to discover ways to increase the brain’s ability to protect itself from damage in DHuntington’s disease by studying the differences in gene expression between vulnerable brain areas that are severely affected in HD and more resilient regions. His emphasis is on astrocytes – the major support cells in the brain that nurture neurons and ensure their functioning. HD changes astrocytes in several ways - some may be beneficial and some deleterious. By looking at gene expression from thousands of cells in both vulnerable and resilient brain regions from the post-mortem brains of individuals who had adult onset and juvenile onset HD, Dr. Al-Dalahmah seeks to determine how astrocytes respond to damage caused by HD. This knowledge will provide insight into the earliest gene expression changes in HD. Knowing how to adapt the brain’s capacity to protect itself from the damage dealt to it by HD is critical for the development of new therapies. Dr. Al-Dalahmah is the 2020 recipient of the Nancy S. Wexler Young Investigator Prize. 3 HDF RESEARCH GRANTS CHERYL ARROWSMITH, PHD Institution: University of Toronto, Canada Project Title: Unravelling the connections between the Huntington’s disease protein and our genetic material here is still a lot we don’t know about the huntingtin protein which is mutated in Huntington’s disease Tpatients. Increasing evidence suggests that this protein plays a role in various processes involving genetic material in our cells. Dr. Arrowsmith’s lab has been able to show that huntingtin protein interacts with genetic messages called RNA. She aims to characterize the interaction of huntingtin with different types of genetic material and use cutting-edge microscopes to visualize how this interaction occurs. Her results will provide insight into how the huntingtin protein functions in our cells and how this might be altered in HD patients. ANNE AST, PHD Mentor: Erich E. Wanker, PhD Institution: Max Delbrück Center for Molecular Medicine Berlin, Germany Project Title: Manipulating seeding activity and proteotoxicity of amyloidogenic HTT aggregates by targeted amino acid exchanges n Huntington’s disease, the disease-causing huntingtin protein has lost its original folding instruction and Iforms stable protein clumps. These clumps operate as templates and pass on their corrupted folding pattern to other normally folded huntingtin molecules. Dr. Ast suspects that this process could be a driving force in HD development and progression. She wants to understand the connection between templated protein misfolding and toxicity and find a way to manipulate this process as a therapeutic approach. 4 HDF RESEARCH GRANTS KRISTINA BECANOVIC, PHD Institution: Karolinska Institutet, Stockholm, Sweden Project Title: Towards the discovery of genetic modifiers and targets for future Huntington’s disease treatments e all have the same genes with only minor differences on individual sites that affect the activity of genes Wand how much we have of a particular gene product in the body. These small genetic differences make us unique and different from one another and they are also the reason HD manifests itself differently in different people. In this research study, Dr. Becanovic wants to understand why people with the same number of CAG repeats sometimes have very different ages of symptom onset. The goal of this study is to identify the genetic variants that affect disease onset, so called “genetic modifiers”. If we succeed in identifying these genetic modifiers, we will be able to use this knowledge to develop better drugs. These would, unlike today’s medicines, not just treat symptoms but primarily protect the brain and slow down the development of the disease. ABDELLatIF BENRAISS, PHD Institution: University of Rochester, NY Project Title: White matter role in the pathology of Huntington’s disease untington’s disease has primarily been studied in neurons. Its impact on glial cells, the support cells in the Hbrain, has been less explored. Using genetic analyses, Dr. Benraiss has identified differences that indicate impaired glial cell function in HD. His work now focuses on how the correction of these differences in glial cells may better support neuronal function and improve HD symptoms. 5 HDF RESEARCH GRANTS VERONICA INES BRITO, PHD Institution: University of Barcelona Instituto de Neurosciencias, Spain Project Title: Exploring the role of RNA editing on the generation of pathogenic huntingtin fragments ecent advances in RNA biology have focused on a new layer of gene expression regulation coined as REpitranscriptomics: the study of chemical modifications decorating RNA that can move around and change, affecting the fate of messenger RNAs (mRNAs). In the case of Huntington’s disease, the mRNA in charge of translating mutant Huntingtin (mHTT) into protein can be differentially processed resulting in the generation of diverse mHTT fragments leading to alterations in both neuronal function and survival. Given that the most abundant RNA modification in the brain is the methylation m6A, Dr. Brito aims to investigate its possible role in HTT’s altered processing and consequent generation of one of the smallest yet most toxic HTT fragments: the exon 1 toxic protein. Her research might have important implications for therapeutic strategies targeting mHTT mRNA. The Hereditary Disease Foundation stands out in the “ high level of expertise it brings to bear on funding the best research to bring about a deeper understanding of Huntington’s “ disease and approaches to safe and effective treatment. Kenneth H. Fischbeck, MD, National Institutes of Health 6 HDF RESEARCH GRANTS LAUREN BYRNE, PHD Mentor: Edward Wild, MD, PhD Institution: University College London (UCL), England Project Title: Advancing biofluid biomarkers for disease-modifying trials in Huntington’s disease eurofilament light protein (NfL) is a protein found in brain cells and can be measured in blood as a Nbiomarker of neuronal health. Dr. Byrne and her colleagues previously showed that NfL increases with Huntington’s disease progression. Her current work aims