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. Identification of the targets that are misregulated well as for designing optimized drugs. due to loss of this novel SMN function in SMA should lead to a more complete understanding of disease mechanism and has the potential to identify new therapeutic targets. This international grant is supported by funding from Families of SMA Canada. Staining of astrocytes (green) and motor neurons (red) from mouse spinal cord. Image courtesy of Dr. Lorson Regulatory Cues Modulating the Activity of originally appeared in Rindt SMN in Human Cells et al HMG 2015. Oliver Gruss, PhD, at the Rheinische Friedrich-Wilhelms-Univer- sitat Bonn in Germany and Utz Fischer, PhD, at the Julius-Maxi- milians-Universitat Wurzburg in Germany for $140,000 Skeletal Muscle Activators as Potential Objective: Our projects aims at understanding the details Modulators of Muscular Weakness in SMA of how SMN protein works in the cell. We will analyze the Christine DiDonato, at the Ann & Robert H. Lurie impact of SMN on cellular signaling networks to try to un- Children’s Hospital of Chicago for $140,000 derstand the role SMN plays the overall activity of the cell.

Objective: This proposal focuses on skeletal muscle proteins Research Strategy: We will use biochemical and biological and their sensitivity to calcium, which impacts their ability to assays to perform experiments on function and regula- contract and generate force. Skeletal muscles activators could tion of the SMN protein and the other proteins with which foreseeably be used alone or in combination with SMN-induc- SMN associates. ing drugs to provide enhanced benefit to SMA patients. Significance: Our study will provide new understanding Research Strategy: We will first investigate how proteins into how SMN functions and its role within cells. These known to modulate muscle activity in SMA skeletal muscle are insights will deepen our knowledge on the role of SMN in mis-regulated. Normal versions of these mis-regulated pro- things such as motor neuron degeneration and therefore, teins will be expressed in a mouse model of SMA to determine will aid in therapy development. their effect on the ability of SMA muscle to contract properly.

SUMMER 2017 BASIC RESEARCH DRUG DISCOVERY CLINICAL TRIALS CLINICAL CARE RESEARCHER MEETING LATEST ADVANCES

Identification of the Protective Mechanism Significance: These studies will allow us to gain insight into of a SMN Modifier Gene using S. pombe as a the potential mis-regulation of proteins that may contribute to reduced force production and endurance in SMA muscle and Model Organism how one might benefit from enhancing calcium sensitivity to Remy Bordonne, PhD, at CNRS-Centre National de Recherche improve muscle contraction. This work will have important Scientifique in France for $30,000 parallels to the Cytokinetics drug compound, tirasemtiv or CK-107, which works by sensitizing the muscle to calcium to Objective: In SMA, actin, which is a protein that helps mus- improve contraction and force generation. cles to contract doesn’t work properly. The goal of this project is to discover genes that rescue defects in actin functioning, in cells with low SMN protein levels.

Research Strategy: We will use S. pombe, a yeast, to try to un- derstand how a SMN-modifier gene protects the formation and function of actin networks, which are critical for muscle contraction. Significance:Understanding how this protective SMN-mod- ifier gene protects actin networks could potentially lead to the development of therapeutics which improve muscle contrac- tion in SMA. The junction between motor neurons and muscle in healthy (control) and SMA mice. Image courtesy of Dr. DiDonato.

Identification of SMA Modifiers and Deletion/Duplication Junctions in the SMA Region Arthur Burghes, PhD, at the Ohio State University for $140,000

Objective: The project objective is twofold. First, we want to identify the genes in humans that cause a milder or no phenotype in siblings despite having the loss of SMN1 Actin filaments in healthy (wt) and SMA cells. Image courtesy of and the same copy number of SMN2. The second objec- Dr. Bordonne tive is to identify parts of the SMN1 gene which may be deleted or duplicated without the absence of the whole gene. Doing so would improve carrier screening. Epigenetics in SMN2 E7 Alternative Splicing Alberto Kornblihtt, PhD, at the Universidad de Buenos Research Strategy: We will determine all variants that dif- Aires in Argentina for $140,000 fer between discordant siblings and concordant siblings. These will then be compared and all variants that differ in Objective: Epigenetics refers to changes, which without alter- concordants will be eliminated from the discordant file. ing the DNA sequence, affect how much protein is produced The remaining variants can mark the modifying gene(s) in from each gene. We will use epigenetic strategies to enhance the SMA. Novel genome sequencing techniques will be used production of SMN protein from the SMN2 gene, with the goal to look for deleted and duplicated parts of SMN1. of compensating for the missing SMN1 gene in SMA patients. Research Strategy: We will use epigenetic strategies developed in The identification of modifiers of SMA Significance: our lab to investigate how to promote functional SMN protein allows for accurate DNA testing that can predict severity production from the SMN2 gene. of disease as well as targets for therapeutic intervention in SMA. The identification of parts of the SMN1 gene Significance:This research may result in therapies that work which may be deleted or duplicated will aid carrier test- by epigenetic mechanisms. These therapies could potentially ing by identifying when this is the case. be used in combination with SMN-enhancing drugs, such as Spinraza, to improve effectiveness in patients. This international grant is supported by funding from Families of SMA Argentina.

SUMMER 2017 BASIC RESEARCH DRUG DISCOVERY CLINICAL TRIALS CLINICAL CARE RESEARCHER MEETING LATEST ADVANCES

Zebrafish Models of Spinal Muscular Atro- Research Strategy: We plan to use a combination of genetic, phy Optimized for Chemical Genetics and biological, and biochemical approaches to investigate how increased Cdk5 activity leads to motor neuron degeneration. Drug Discovery: From Proof-of-Principle to We will test reducing the activation of Cdk5 as a therapeutic New Insights and Treatments strategy in SMA mouse models. Jean Giacomotto, PhD, at the University of Queensland in Australia for $75,000 Significance:Our study will help us understand more about motor neuron degeneration in SMA. The findings Objective: In SMA, the lack of additional “druggable” tar- could potentially lead to the development of new thera- gets, beyond SMN, creates a gap in the traditional drug peutic strategies which could be used in combination with discovery pipeline. In order to address this issue, we have SMN-enhancing therapeutics, such as Spinraza, to achieve created a zebrafish model of SMA designed to be suit- maximal therapeutic benefit. able for large-scale drug screening.

Research Strategy: We will optimize our zebrafish model to make it compatible with drug discovery and run a pilot screening study using a pool of pharmacologically active compounds to potentially find beneficial drugs for SMA.

Significance: This research will generate the first animal model of SMA compatible with large-scale drug discov- ery experiments. This model can then be used to screen drugs and identify those which may warrant further drug SMA motor neuron cultures. Image courtesy of Dr. Ma development for SMA.

Arrested Development or Neurodegeneration? An approach to understand developmental motor neuron pathology in SMA Stephen J Kolb MD PhD, at The Ohio State University for $75,000

Objective: We will create a large animal pig model of newborn infants with SMA. We will use this model to un- derstand the pathological findings that are seen in motor Zebrafish model of SMA. Image courtesy of Dr. Giacomotto. neurons in infants with SMA.

Research Strategy: We will create the model by delivery of Regulation of Motor Neuron Defects by a virus that will knockdown the expression of SMN in fetal Cdk5 Signaling in SMA piglets in utero. Once these piglets are born, we will study Yongchao Charles Ma, PhD, at the Ann & Robert H. Lurie the motor neurons and determine if the pathological find- Children’s Hospital of Chicago for $75,000 ings are the same as in infants with SMA.

Objective: We have found that the activity of a protein Significance: This project will address the urgent ques- called Cdk5, cyclin-dependent kinase 5, is significantly tion of timing to optimize delivery of SMN increasing increased in motor neurons affected by SMA. In this project therapies in infants with SMA, and allow us to predict the we hope to find out why this protein displays increased long-term success of these therapies by modeling the con- activity and to test whether inhibiting hyperactive Cdk5 sequences of low SMN during fetal development. activity can be used as a therapeutic strategy.

SUMMER 2017 COMPASS Summer 2016 BASIC RESEARCH DRUG DISCOVERY CLINICAL TRIALS CLINICAL CARE RESEARCHER MEETING LATEST ADVANCES

Cure SMA Announces $2.5 Million in RUSPNew Planned Nomination Research Funding for SMA Accepted into Evidence Review As the SMA research landscape has developed and the drug The RUSP application for SMA now moves into evidence review, pipeline has grown, we recently undertook a systematic which is a six to nine month process. Once the evidence review review of our research funding priorities. Through is completed, the committee will make a recommendation to the conversations with independent SMA experts, our scientific Secretary of Health and Human Services, who will determine whether SMA will be added to the RUSP. The review by the HHS advisory groups, and the newly formed Medicine and Secretary can also take several months, meaning a final decision Science Committee in our Board of Directors, Cure SMA on the RUSP application could come in mid-2018. has created a strategic research plan to guide us into this “We are pleased that the committee has taken this significant first next phase of SMA research. This strategic research plan Many of the projects in this area will be carried out as part step toward recommending SMA for inclusion on the RUSP,” said identifies the areas of greatest need and where we are best Jill Jarecki,of a PhD, new Curea collaborative SMA’s chief industry scientific consortium. officer. “AddingThrough SMAthis positioned to make a significant difference: to the federalgroup, guidelines seven companies would help working ensure in that SMA all drugbabies development born with SMAwill receive share information,the best change ideas, for prompt,and data, effective working treatment. together to • Funding for Continued funding for basic research. As the committeebenefit our continues community. their review, we will continue our Left tobasic Right: research,Representative which Becky Ruth, investigates Grace Grutter, theand Lesliecauses Derrington and at advocacy for SMA screening implementation. Thank you again to a newbornbiology screening of hearingSMA, in will Missouri. encourage Grace and Lesliefurther testified development in support of of our working• Greater group funding for their for hardpatient work care on initiatives.the nomination.” Cure SMA newborn screening legislation sponsored by Rep. Ruth. has been working to collect data and information on the combination therapies. Basic research is the critical first At the meeting, the committee heard testimony from the SMA The Secretary’sstep to identifying Advisory Committee these non-SMN on Heritable systems, Disorders pathways in and communityexperiences in support of ofliving the application. with SMA. Dr.Funding Jarecki fortestified, the coming along Newbornsprocesses and Children that can (SACHDNC) be targeted announced for drug development. that they have with Debrayear Schaefer, will be used who tohas create had two a database granddaughters that will affected demonstrate by accepted spinal muscular atrophy into the review process for the SMA: onethe who impact passed of SMAaway inover 2012, time. and This one informationwho was diagnosed will help in • As RecommendedGreater funding Uniform for Screening clinical Paneland regulatory (RUSP). The research. RUSP is a utero andthe has scientific benefited and from research early treatment communities with Spinraza.create answers that more SMA drug programs progress through clinical trials, list of conditions that all newborns in the US are recommended address these real-world concerns, and accelerate therapy to be screenedthere is for.a need for us to address clinical and regulatory development for SMA. The increased funding will also be issues and bring the patient voice into the process. used to help develop centers of excellence for SMA care.

For more information on these grants, our research model, and the latest research news visit www.cureSMA.org

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