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Cure SMA Awards 10 New Grants in Basic Research BASIC RESEARCH DRUG DISCOVERY CLINICAL TRIALS CLINICAL CARE RESEARCHER MEETING LATEST ADVANCES COMPASS A Publication Dedicated to Research Updates | SUMMER 2017 Cure SMA Awards 10 New Grants in Basic Research In this issue of Compass, we are proud to Our hope is that Spinraza is just the leading edge of a robust drug pipeline, with a breadth and depth that reflects our goal announce over $1.03 million in new funding. of treatments for all ages, stages, and types of SMA. We’ve seen many advances in recent years, from new techniques Basic Research Grants in gene therapy, which Cure SMA is funding with an award Basic research is the first step in our comprehensive research to Nationwide Children’s Hospital through our transla- model. We fund basic research to investigate the biology and tional grant program, to drugs that affect muscle and nerve cause of SMA, in order to identify the most effective strategies function that could be used in combination with drugs like for drug discovery. We also use this funding to develop tools Spinraza that target the underlying genetics of SMA. We’re that facilitate SMA research. actively working on additional treatments that target the underlying genetics of SMA as well as therapies that target Without basic research, the SMA drug pipeline would not other systems, pathways, and processes affected by SMA. Our continue to grow and diversify. We need both a breadth and goal is a combination of therapeutic approaches that can be a depth of options in our quest for a maximally effective SMA tailored to each individual SMA patient. therapies for all types and stages of the disease. Basic research is our investment in future drug development for SMA. Broadening the Drug Pipeline and Developing Combination Therapies Continuing Need for Basic Research Because of a genetic mutation in the survival motor neuron The FDA approval of Spinraza has ushered in a new stage in gene 1 (SMN1), individuals with SMA don’t produce survival the SMA community. As we enter this new era, Cure SMA motor neuron protein (SMN protein) at high enough levels, remains committed to the needs of the SMA community. causing motor neurons to shrink and eventually die. This While we celebrate the long awaited approval of Spinraza, results in muscle weakness that impacts daily activities as well there remains much to be done and many questions to be as the basic functions of life, such as breathing and eating. answered as we continue to work to most effectively treat Prior basic research projects uncovered the SMN1 gene and SMA. While Spinraza will offer tremendous benefit to those the link to SMN protein. However, there are many unan- with SMA, there is also a need for continued research and swered questions about the SMN protein. development investment. It will likely take a combination of therapies to achieve the greatest possible effect for each and every SMA patient at every age and stage of disease. For more information on these grants, our research model, and the latest research news visit www.cureSMA.org SUMMER 2017 BASIC RESEARCH DRUG DISCOVERY CLINICAL TRIALS CLINICAL CARE RESEARCHER MEETING LATEST ADVANCES These questions include: • What are the functions of the SMN protein and how does Our grant to Dr. Alberto Kornblihtt seeks to identify drugs which SMN perform those functions? use epigenetic, strategies to enhance the production of functional • What other cells, tissues, and processes are affected by the SMN protein from the SMN2 gene. Epigenetics refers to changes loss of SMN protein? that affect how much protein is made from a gene without alter- ing that gene’s sequence. • How, where, and when do we need to restore SMN protein in order to benefit those with SMA? Our grant to Dr. Jean Giacomotto will allow for the optimization of his previously developed zebrafish model to make it compat- • How can we use this knowledge to develop new combination ible with drug discovery. After optimization, a pilot screen will treatments for SMA, or to evaluate if treatments are effective? be performed to identify drug candidates which improve SMA symptoms in the fish. By funding research into these unanswered questions, we can develop new treatment strategies that will add to the breadth of Dr. Yongchao Charles Ma has found that the activity of Cdk5, the SMA drug pipeline, as well as develop combination therapies. A cyclin-dependent kinase 5, is significantly increased in SMA motor broad pipeline is particularly important as we seek to develop treat- neurons. The grant investigates the underlying reasons for this hy- ments for all ages, types, and stages of SMA. peractivity and if its inhibition can be used as a therapeutic strategy. New Grants to Learn More About the When and Where of SMN ONGOING BASIC RESEARCH PROJECTS Our grant to Dr. Jocelyn Cote will fund research into CURRENTLY BEING FUNDED BY CURE SMA understanding the function of the SMN protein, focusing on the role SMN plays in protein production. • Identification of SMN:HuD • A pilot, open-label, dose re- bound RNAs critical for motor sponse study investigating the Our grant to Drs. Oliver Gruss and Utz Fischer will analyze the im- neuron development effect of low-dose Celecoxib pact of SMN on cellular signaling networks in an effort to under- Christine Beattie, PhD, Ohio on SMN2 in patients with stand the role SMN plays in the overall activity of the cell. State University Spinal Muscular Atrophy Hugh McMillan, PhD, and Alex • Defining the contribution of Dr. Christian Lorson has found that some types of neurons get McKenzie, PhD, Children’s RNP assembly pathways to the Hospital of Eastern Ontario “sick” when SMN levels are low, while others do not. Our grant will SMA phenotype Research Institute focus on how astrocytes, another cell type present in the central Arthur Burghes, PhD, Ohio nervous system, protect some neurons while leaving others vulner- State University • The Development of a Clinically Relevant Outcome Measure for able to low levels of SMN. • Assessing mediators of muscle SMA Therapeutic Trials weakness in SMA mice Chad Heatwole, MD, University Our grant to Dr. Christine DiDonato focuses on skeletal muscle Christine DiDonato, PhD, Lurie of Rochester proteins and their sensitivity to calcium, which impacts their ability Children’s Hospital of Chicago • Preclinical development of a to contract and generate force. Our grant to Dr. Stephen Kolb will • Muscle satellite cell biology JNK drug candidate to alter look at when SMN is needed to clarify the critical issue of timing and muscle regeneration in disease progression in SMA for SMN increasing therapies. Smn- depleted mice Charlotte Sumner, MD, Johns Rashmi Kothary, PhD, Ottawa Hopkins Hospital and Imago Our grant to Dr. Stephen Kolb will look at when SMN is needed to Hospital Research Institute Pharmaceuticals clarify the critical issue of timing for SMN increasing therapies. • Novel approaches against • Slowing SMN degradation to spinal muscular atrophy by treat SMA New Grants to Study SMA Modifiers and targeting splicing regulators Barrington Burnett, PhD, Antoine Clery, PhD, ETH Identify New Drug Targets Uniformed Services University Zurich • Pharmacological inhibition In our grant to Dr. Arthur Burghes genes that vary between these • Assessing the reversibility of p38αMAPK as a candidate discordant siblings, siblings with the same copy number of SMN2 of proximal axon abnormali- therapeutic approach for SMA but presenting with different disease severity, will be compared. ties in SMA mice, Charlotte Livio Pellizzoni, PhD, Sumner, MD, Johns Hopkins This will give insights as to what genes may be able to modify SMA Columbia University disease severity. Hospital • Development of a drug to • Novel Strategies to Increase increase SMN2 transcription In SMA, actin, which is a protein that helps muscles to contract SMN2 RNA Kevin Hodgetts, PhD, Brigham doesn’t work properly Our grant to Dr. Remy Bordonne will sup- Megerditch Kiledjian, PhD, and Women’s Hospital port the discovery of genes, called SMN-modifier genes, that rescue Rutgers, The State University defects in actin functioning, in cells with low SMN protein levels. of New Jersey SUMMER 2017 BASIC RESEARCH DRUG DISCOVERY CLINICAL TRIALS CLINICAL CARE RESEARCHER MEETING LATEST ADVANCES More About Our New Basic Research Grants Investigating the Mechanism by Which SMN Examining the Role of Astrocytes and the Regulates Translation: Identification of Novel Influence upon Lower Motor Neuron Therapeutic Targets Susceptibility in SMA Jocelyn Cote, PhD, at the Ottawa Hospital Research Insti- Christian Lorson, PhD, at the University of Missouri for $75,000 tute for $140,000 Objective: Despite the lack of SMN in every cell in the body Objective: We have been the first to describe a new func- in SMA, not all cell types, or even neurons, become “sick” tion for SMN in the regulation of protein production and when SMN levels are very low. The goal of this project is to we propose to perform experiments to gain a better under- understand why some neurons get sick while other neurons standing of how SMN goes about doing this new function- do not get sick. and to determine the consequences of losing this function in cells from SMA patients. Research Strategy: By examining the differences between astrocytes from different regions within the central nervous Research Strategy: We propose to use a series of biochemi- system, we hope to identify new factors that help “protect” cal, molecular and cellular approaches that will allow us to some neurons while understanding why other neurons are learn about a new function for SMN in the regulation of not “protected.” protein production. Significance:This proposal is designed to investigate why Significance:The current proposal will provide crucial lower motor neurons are specifically impacted in SMA. This insights into a novel function for SMN in spinal cord motor understanding is important from a biological perspective as neurons.
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