Originally published on August 28, 2013.

The Cure SMA Scientific Advisory Board (SAB) helps organize, select the content, and chair sessions at the Cure SMA Research Group Meeting. Our SAB has written a summary of the scientific findings from the 2013 meeting.   During the 2013 meeting, 110 research presentations were given, including 38 talks during five podium sessions, and 72 poster presentations. 225 researchers from 15 different countries, 70 distinct organizations, and 17 biotech and pharmaceutical companies attended the 2013 meeting.

Enhancing the Predictive Ability of Preclinical Drug Studies, Chaired by Charlotte Sumner, MD, Associate Professor of Neurology, Johns Hopkins University

The 2013 conference opened with a special session consisting of a series of invited talks. The goal of the session was to discuss the best strategy for testing SMA drugs in the preclinical setting in order to maximize the possibility of seeing  efficacy in subsequent human drug trials. The main focus  was on the endpoints used in drug testing in mouse models of SMA, how they parallel human disease, and which are most predictive of outcomes in human SMA. Dr. John Porter, Program Director, Neurogenetics Cluster started the session with a talk on “New NINDS Guidelines on Preclinical Rigor with Focus on SMA”, where he discussed the best procedures for designing preclinical drug testing studies in mice and other animal models.  A series of talks were given comparing human pathophysiology in mouse and humans, with an emphasis on comparing and contrasting the various endpoints currently used in drug testing in SMA mouse models to those used in humans.  For example, Dr. Richard Finkel, Chief of Neurology at Nemours Children’s Hospital gave a talk on “ The Overview of Type I SMA:  Description of Natural History, Pathology, and Current Clinical Trial Endpoints”. Dr. W. David Arnold of Ohio State University then discussed a new mouse model endpoint he has been testing that is designed to assess neuromuscular junction function in serve mouse models on of SMA.  Dr. Thomas Crawford of Johns Hopkins University spoke on the pathophysiology of SMA Type II and III, emphasizing the fact than collateral sprouting and remodeling of motor axons is key feature of human disease, which needs to be reflected in mouse models of intermediate and mild SMA. 

Dr. Cat Lutz of the Jackson Laboratory then gave an overview of all available SMA mouse models, including providing to all attendees a Reference Guide to Mouse Models of Spinal Muscular Atrophy. During her talk Dr. Lutz discussed that mice are not humans. Thus, it is critical to recognize and expect differences between mouse and human disease manifestations and to understand their impact when conducting and interpreting preclinical drug testing results.   In fact, whether a mouse model effectively reflects human disease depends on a few factors. These include considerations like:  1) the research questions being explored, 2) the specific model that is being utilized to answer that question, and 3) the scientific design of the experiment. She also stressed that the easiest endpoint is not always the best endpoint. As the previous speaker’s in the session who discussed characteristics of human disease stressed, it is critical to use clinically relevant endpoints, such as those assessing neuromuscular junction functionality. Moreover, it is typically best to use multiple endpoints in several different models of a particular disease when testing any drug candidate. 

Next Dr. Karen Chen of the SMA Foundation reviewed the data on a series of SMA biomarkers that could have predictive ability of disease progression in both humans and mouse models of SMA. Next Dr. Kathryn Swoboda of the University of Utah spoke about the potential importance of newborn screening in developing SMA therapeutics. She explained the scientific rational and design of clinical trials in presymptomatic patients. The session ended with Scott Clarke of Biomarin speaking on industry considerations in reducing risk in drug development. When selecting new drug programs, industry considers unmet medical need, the availability of good clinical trial design and endpoints, ease of patient recruitment, preclinical study results, intellectual property, and financial consideration to make decisions on the development of drug candidates.

SMN Expression and Function, Chaired and Written by Rashmi Kothary, PhD, Associate Director and Senior Scientist at the Ottawa Hospital Research Institute and Professor at the University of Ottawa

There were six talks in this session. Dr. Sandra Duque from the Burghes laboratory at OSU presented on allelic complementation studies using transgenic mice to help identify human SMN mutations that can correct each other to form a functional SMN complex. This was an exciting discovery since it now allows one to determine the key interacting proteins that are critical for SMN complex function and which may be contributory to SMA disease etiology. Dr. Nadia Litterman from the Rubin laboratory at Harvard discussed their work on a pathway that regulates SMN protein stability, and could therefore be important for motor neuron survival. In a similar direction, Dr. Judith Steen, also from Harvard, presented efforts in her laboratory to understand the mechanisms of SMN protein stability and turnover. Both of the latter presentations focused on the E3 ubiquitin ligase pathway, and suggested that inhibiting this pathway could be important for motor neuron survival, an important therapeutic end-point for SMA patients.  These finding could contribute to future therapy development. Dr. Barrington Burnett from NINDS and Dr. Justin Boyer from the Kothary laboratory gave a set of talks describing primary myoblast culture and in vivo mouse studies pointing to an important role played by SMN in skeletal muscle, in the context of SMA pathogenesis.  Dr. Burnett focused on SMN function in regulating cytoskeletal dynamics, which impacts myoblast migration and fusion. Similarly, Dr. Boyer talked about early defects in the myogenic program in mouse models of SMA, which could contribute to the overall SMA phenotype. Both talks highlighted the importance of including muscle as a target tissue for therapy of SMA.  Dr. Yimin Hua from the Krainer laboratory at CSHL described elegant studies using antisense oligonucleotides in SMA model mice to demonstrate that restoring SMN expression in peripheral tissues was sufficient to give a full phenotypic rescue in a particular mouse model of SMA.

Non-splicing Related Phenotypes and Function of SMN, Chaired and Written by Mark Rich, MD, PhD, Associate Professor in the Department of Neuroscience, Cell Biology, and Physiology at Wright State University

There were three presentations in this session.  Dr. Eric Garcia from the Matera lab at UNC presented work using a drosophila model of SMA to investigate whether loss of SMN disrupts pre-mRNA splicing.  His data suggested that SMN null animals have developmental delay rather than global changes in splicing.  He concluded that his findings argue against a splicing-dependent etiology for SMA.  Dr. Yong-Chao Ma for Northwestern University presented work on a novel signal transduction pathway that results in regulation of the enzyme HDAC5.  This pathway is disrupted in SMA.  He presented data suggesting HDAC5 is a novel regulator of tubulin deacetylase, which might control microtubule-based axonal transport in motor neurons.  Disrupting this process in SMA could result in defective axonal transport, which may contribute to neuronal degeneration. Dr. Sara Custer from the Androphy lab presented results that SMN and alpha-COP interact in the brain and spinal cords of mice.   This interaction appears to be crucial to supporting the ability of SMN protein to mediate neurite outgrowth in a cell culture model of SMA. 

SMN Targets and Modifiers, Chaired and Written by Arthur Burghes, PhD, Professor of Molecular and Cellular Biochemistry at The Ohio State University

This session addressed additional genes that can influence the severity of SMA.  SMA severity is to a large extent determined by the number of copies of SMN2, with more copies producing more SMN protein and therefore a milder condition.  There are also some SMN2 genes with a variant that results in the production of more SMN. There is also the ability of other genes or factors to act on the SMN2 gene to produce more SMN, as well as the possibility of genes acting independently of SMN induction. In the latter situation, the genes are either in the pathway affected by SMN deficiency or act in a general manner to enhance the properties of a motor neuron and thus alleviate the effects of SMN deficiency. In addition there are genes that act to protect against SMN deficiency, for instance not all motor neurons are affected equally by SMN deficiency the eye muscles for example do not appear to suffer from SMN deficiency. Indeed, an elegant talk was given by Justin Lee from the Henderson laboratory (The Motor Neuron Center of Columbia University in New York).  First he showed that the motor neurons that targeted specific muscle groups where similarly affected in both man and the delta7 SMA mouse. Secondly, the group demonstrated that SMA predominantly affected certain subclasses of motor neurons and that the motor neurons that are not as overtly affected expressed high levels of a particular gene.  This gene could perhaps be protective in SMA.  The question that now remains is whether re-introducing this gene to motor neurons that have low SMN will protect them and ameliorate the SMA mouse.

Plastin3 has been found to be over expressed in some female SMA patients with a milder form of SMA than expected and thus suggested to modify SMA severity. There were two talks on Plastin3 and SMA.  Dr. Melissa Walsh from the Hart Laboratory (Brown University, Rhode Island) looked at Plastin3 in C. elegans (nematode worm) models with reduced SMN (SMA), Amyotrophic lateral sclerosis (ALS) and Huntington’s.  In all cases expression of Plastin 3 modulated the severity of symptoms (phenotype).  Exactly how this works is currently unclear, but it does imply that plastin acts well downstream of the initial insult and can  enhance the function of damaged motor neurons in general.  Dr. Markus Riessland of the Wirth laboratory (Institute of Human Genetics, University of Cologn, Germany) examined proteins that interact with Plastin3. In particular this group identified Coronin which functions in a Calcium dependent manner and could be important in controlling how the neuromuscular synapse behaves and functions.

Dr. James Sleigh of the Talbot laboratory (University of Oxford, Oxford) had previously shown in the mouse that the chondrolectin gene differs in the way it is produced in SMA motor neurons as opposed to unaffected motor neurons. In particular, the particular exons (packets of information in the DNA) chondrolectin can be stitched together in different ways (splicing) to make several different messenger RNAs.  Messenger RNAs are then a blue print to make several different chondrolectin proteins, which can function in somewhat different ways. Altering this splicing process is fundamental to SMA since it is clear that the SMN protein itself functions in the splicing / mRNA processing  pathway.  Therefore, the question becomes is this alteration in chondrolectin critical to the development of SMA?  However, this is not completely clear yet. When SMN is reduced in zebrafish, introduction of the critical chondrolectin form corrects the defects, but this is not the case in a motor neuron like cell.  The ability of this chondrolection form to provide correction in SMA mice remains the critical question.

Lastly Dr. Umrao Monani (Motor neuron center, Columbia University New York) presented data using specific mouse crosses that clearly showed important aspects of SMA biology. Firstly there are genes in different strains of mice which modulate the SMA phenotype. Secondly these variants influence expression of SMN from SMN2 thus giving a very clear path to how they work. The next key will be to identifying what these genes influencing SMN expression are, which could open the avenue to new therapeutic targets in SMA.  In fact, the goal of all of these studies is to identify new genes that modulate SMN severity and can serve as therapeutic targets of SMA.  A critical aspect of all these studies is to determine whether these new targets will serve as new therapeutics targets and can be verified in SMA mice. 

SMA Therapy Development, Chaired by Douglas Kerr MD, PhD, Director of Neurology Research and Development Biogen Idec

Five talks were given during the session, which focused on SMA therapy development. The first talk was by Dr. Maureen Sherry Lynes from the Rubin lab at Harvard University.  She discussed novel drug screens in SMA patient-derived motor neurons that are being carried out in the Rubin lab.  She described several new hit compounds that elevate SMN expression across multiple backgrounds and SMA types.   Dr. Jon Cherry from the Androphy lab at Indiana University described studies to elucidate the mechanism of action of a novel series of compounds that increase SMN expression.  These appear to work by increasing the half-life of SMN protein.   Dr. Erik Osman from the Lorson lab at the University of Missouri described a novel ASO sequence called E1, which is located in exon 7.  When treating a severe mouse model of SMA with this ASO, survival was increased by 300%, and it increased by 600% in a new intermediate mouse model of SMA.   Dr. Brian Kaspar from Nationwide Children’s hospital provided an update on translating two gene therapy delivery routes for SMA, including both systemic and CSF delivery routes.   IND-enabling studies for the systemic methods have been completed and an IND will be submitted to the FDA in the coming months.  The CSF directed delivery is progressing in parallel.   Dosing finding experiments are underway to define the minimally effective dose for CSF delivery for survival in mice and for motor neuron transduction in mice and primates.  Finally in this session, Dr. Chien-Ping Ko presented data on the Roche / PTC drug program.   He showed animal model data using their small molecule compound that corrects SMN2 splicing defects.   Dosing resulted in long-term survival over 100 days and also corrected motor neuron defects.   Administration of a suboptimal dose  until day thirty results in partial rescue.  These mice can be used to mimic a mild model of SMA.  Increasing drug dosage on day thirty in these mice results in further recovery of the phenotype, suggesting later drug delivery can be beneficial in at least certain situations.

Clinical Research, Moderated by Thomas Crawford, MD, Chaired by Professor of Neurology, Johns Hopkins University

The clinical research session consisted of seven talks.  Dr.  Phillip Zaworski of PharmOptima described a new ECL immunoassay capable of detecting SMN protein in whole blood in both mice and humans.  It detected significant differences in protein levels between different SMA genotypes.   Dr.  Reske Wadman of University of Utrecht showed that SMN protein levels in blood cells correlate with SMN2 copy number, disease duration, and age.  However, they are not a biomarker in her study for SMA subtype of motor status, perhaps due to decreasing SMN levels with age in concert with increasing motor deficits. Dr. Louise Simard of the University of Manitoba presented on a case of SMN2 conversion to SMN1 in an at risk fetus, resulting in a healthy baby carrying a seemingly at risk-haplotypes.  Dr.  Adele D’Amico from Rome presented data from survey  of 38 questions to parents of children with type I SMA to collect further natural history data in this population. In the next talk, Dr. Jacqueline Montes showed data that ambulant SMA patients have reduced strength and cardio-respiratory fitness during exercise, due to de-conditioning.   Moreover, patients also showed fatigue during the six minute walk test, which is unique to SMA.  This represents a peripheral and central dysfunction of neurotransmission particular to SMA and not directly related to fitness.  Dr. Eugenio Mercuri from Rome reported on data to validate the six-minute walk test in ambulatory SMA patients.   The six-minute walk test appears to be a suitable clinical trial measure for ambulatory SMA patients.  Longitudinal data indicates the results are stable over a six-month period, although patients reaching puberty during the testing period had a higher risk of showing deterioration.  To closeout the session, Dr. Kathie Bishop from Isis Pharmaceuticals provided an update on the development of ISIS-SMNRX for SMA. the initial single-dose clinical study, ISIS-SMNRx was well tolerated at the dose levels evaluated in SMA patients; no safety concerns were identified.  Results from this study support continued development and further examination of ISIS-SMNRx in longer multiple-dose clinical studies that are currently ongoing.