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Highlights from the 15th Annual Spinal Muscular Atrophy Research Group Meeting.

August 4, 2011.

The conference, the only open venue for annual communication between SMA researchers, has tangible benefits for the entire SMA community:
-Enables open communication of early, unpublished scientific data among researchers - a key component in accelerating the pace of research.
-Creates a vital sense of community among SMA researchers that generates a collaborative spirit, resulting in many productive research partnerships.
-Allows cross-disciplinary dialog among basic researchers, clinicians, and industry representatives, which is vital in creating effective therapies.
-Allows young researchers to interact with leaders in the field, which helps build the future of the SMA research community.
-Motivates SMA researchers by providing interaction with SMA families and patients.

In our latest conference survey, 95% of the researchers attending in 2011 indicated having an open and comprehensive SMA meeting is extremely important to the SMA research community, and specific feedback supports this statistic.  Researchers indicated that: "This is THE big meeting that brings everyone together and I cannot stress enough the value of this meeting. The meeting is the starting point for many collaborations and a place for researchers of all stripes to learn and place their work into the context of the broader field. Seeing the children with SMA alone is a huge value from this meeting, to always ground us in our goals for doing the work we do" and; "This is my first FSMA meeting, and it was by far the most valuable and relevant meeting I have been to over the last three years. I had been regularly going to Neuroscience, but would choose this meeting over that meeting because of the focus on SMA and the unique experience to meet the families. This meeting does a great job of focusing various groups of researchers towards common goals."    Also, one researcher said: "This meeting is a huge service to the community and is critical for the exchange of basic and clinical information on the disease and the basic biology of SMA. The meeting clearly is having a positive influence on therapeutic development for SMA. As a drug discovery researcher I have found the meeting to be the most focused and effective way of interacting with the research community in SMA and the most effective way to gain a perspective on the state of the field."

The conference is organized into sessions focusing on major unanswered topics in the field.  This year there were five distinct sessions with an expert moderator leading the discussion of each. Additionally, two poster sessions occurred, allowing for presentation of very current and still under investigation research.   

Over 100 abstracts were presented, including 36 as talks and 77 as posters.   The conference started off with a Special Session organized by FSMA with invited speakers entitled, "Comparative SMA Pathology in Mice and Man with Therapeutic Implications", designed to help inform therapy develop.  The other podium talks were selected from submitted abstracts and included the following topics:  Human Clinical Research, SMA Models and Neuronal Phenotypes, SMN Molecular Functions & SMN Expression Regulation, and SMA Drug Development.

Please click here to see the conference sponsors.

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Please click here to see the research meeting agenda.

Summary of Research Findings Presented at the 2011 Conference:

1.  Special Session: Comparative SMA Pathology in Mice and Man with Therapeutic Implications.  Moderated by Dr. Thomas, Crawford.  The goal of this session was to compare and contrast SMA pathology observed in animal models of SMA and in humans to inform effective drug development.   It started with a keynote address by Dr. Dwight Koeberl, MD, PhD, who discussed the successful drug development of Myozyme for the neuromuscular disease Pompe Disease.  He emphasized the overall development plan for Myozyme, how animal models were used to advance the drug, how well the animal models predicted efficacy in humans, and strategies for newer second generation drugs. 

The keynote address was followed by nine invited talks on comparative SMA pathology in humans versus mouse models.   These talks reviewed the facts regarding the known defects in SMA animal models and in humans in a variety of tissues.  Discussion focused on how changes compare among the different species.  This included discussion on the relevance of non-neuronal defects in humans versus mice and what these tell us about which tissues to target for drug activity.  Finally, the best use of SMA animal models in therapy development was discussed, including whether there are currently adequate animals models or more need to be generated.

Talks on Comparative SMA pathology in Mice and Man:
- Review of Peripheral Motor Neuron and Muscle Phenotypes in SMA Mice - Thomas Gillingwater, BSc, MBA, PhD, MCMI, FRMS, Professor of Neuroanatomy, University of Edinburgh.
- Review of Motor Neuronal Circuitry Phenotypes in the Spinal Cord of SMA Mice. - George Mentis, PhD, Assistant Professor, Columbia University.
- Review of Neuronal and Muscle Phenotypes in Humans, Including Recent Autopsy Studies - Charlotte Sumner, MD,  Assistant Professor of Neurology, Johns Hopkins School of Medicine.
- Overview of Systemic / Extra-Neuronal Defects in SMA Mice (heart, GI, necrosis, bone,  etc.) – Christine DiDonato, PhD, Assistant Professor, Department of Pediatrics, Northwestern University
-A novel role for SMN in pancreatic development, Melissa Bowerman, Ottawa Hospital Research Institute, Department of Cellular and Molecular Medicine, University of Ottawa.
- Overview of Evidence Indicating Possible Autonomic Nervous System Deficits in SMA Mice - Brian Kaspar, PhD, Associate Professor, Nationwide Children’s Hospital.
- Review of Heart and Vascular Defects in Humans   - Sabine Rudnik-Schöneborn, MD, PhD, Professor, Institute of Human Genetics, University of Acchen.
- Review of Systemic / Extra-Neuronal Phenotypes in Humans, Including Recent Autopsy Findings (adrenal insufficiency, GI issues, bone, etc.) - Kathy Swoboda , MD, Associate Professor of Neurology, University of Utah.
-Session Synopsis and Panel Discussion - Moderator, Thomas Crawford MD , Associate Professor of Neurology and Pediatrics, Johns Hopkins University School of Medicine.

2. Human SMA Studies.  Moderated by Dr. Kathryn Swoboda.   This session included discussion of new outcome measures and biomarkers for use in SMA clinical trials.   Nicole Holuba from Columbia University gave a talk on a retrospective chart review of type I, II, III SMA patients.  She showed that none of the SMA patients (n=102) had clinical evidence of congenital heart disease or dilated cardiomyopathy.   Of the 22 who underwent cardiac evaluations, two had CHD compared to the frequency of 75/1000 in general population.  Dr. Rutkove from Harvard discussed the use of electrical impedance myography as a clinical biomaker for SMA. It measures electrical current through the muscle and as such can indicate muscle health.  Dr. Simard of the Project Cure SMA group presented the levels of SMN mRNA transcripts in whole blood from control, carriers, SMA patients, and subjects in the CARNI-VAL Type I Infant Trial. About one third of type I patients showed an increase in full-length SMN mRNA levels after VPA treatment. Dr. Morandi of Catholic University in Rome discussed an ongoing Phase II placebo controlled clinical trial of Salbutamol in 44 SMA patients.  This group assessed baseline SMN transcript levels versus clinical severity and showed that transcript levels are related to muscle strength across the study population, but are not predicative for clinical outcome in individual patients.

3. SMA Models and Observed Phenotypes.   Moderated by Dr. Rashmi Kothary. The first talks of this session focused on the development of new animal models of SMA.  Dr. Monique discussed progress in making a pig model for SMA, which will aid in therapy development due to the species similarities to humans.  Dr. Sahashi from the Krainer lab talked on developing mild models of SMA, using antisense technology.  His approach could readily be extended to large animal models of SMA too.

The majority of this session focused on the role of SMN in motor neurons, including in the spinal cord, in motor axons, and at the neuromuscular junction.  Generally, these talks focused on results generated in a number of SMA animal models, including in mice, zebra fish, and drosophila (fruit flies).  These studies help address how specific SMA is to motor neurons and to determine what function of the SMN protein (being that there are several proposed) leads to SMA disease pathology.  

Two talks were given on whether plastin3 can overcome motor neuron defects caused by lowered SMN levels.  Dr. Beattie of OSU showed plastin3 expression rescues axon outgrowth, alterations at the neuromuscular junction (NMJ), and movement defects in SMA zebrafish.  Dr. Ackermann from the Wirth Lab in Germany reported that plastin over expression in SMA mice rescues NMJ defects but does not prolong survival. 

Dr. Martínez-Hernandez from the laboratory of Dr. Tizzano in Spain presented on early neuropathology in human SMA. She showed the presence of NMJ defects in early development in muscles from fetuses with severe SMA.

Two presentations were given characterizing NMJ defects in SMA mice.  Results from the Sumner lab at Johns Hopkins University suggested that increasing SMN in just muscle enhances survival, weight, motor function, and NMJ functionality, although expression in neurons has a larger impact. They authors suggest that healthier muscle may release a factor that improves motor neuron function.  Dr. Ling from the Ko lab at USC presented a thorough study showing that NMJ defects are muscle type specific, rather than general across all muscles. Understanding what causes vulnerability will have important implications to therapeutic strategies.  Finally, Dr. McCabe from Columbia University described motor synapse defects in the central nervous system in a fly model of SMA. He showed that inter-neurons are affected in the central nervous system. Also true in mice, SMA motor neuron pathology is not isolated to the periphery or neuromuscular junctions, but also to central synapses.  In flies, rescuing genes have been found, perhaps identifying new therapeutic avenues.

4. Regulation of SMN Expression and Function with Therapeutic Implications.  Moderated by Dr. Adrian Krainer.  This session addressed the regulation of SMN expression and function with particular focus on how the SMN2 gene can be modulated for therapeutic benefit.  Dr. Akten from the Steen lab in Harvard, reported that the E3 ubiquitin ligase is involved in SMN protein degradation. Inhibiting the E3 ligase in motor neurons leads to increased SMN levels and thus could provide a new therapeutic strategy for SMA.  Faraz Farooq from the McKenzie lab showed that the p38 and STAT5 molecular pathways regulate SMN levels.  For instance, activation of the STAT5 pathway by the molecule prolactin increases SMN levels substantially in SMA mice and prolongs survival by 60%.  Finally, Dr. Tiziano from Rome showed that the PI3 Kinase / Akt pathway leads to SMN enhancement after salbutamol treatment, leading to SMN2 splicing correction in patient fibroblasts.

5. SMA Therapeutic Development.  Moderated by Dr. Douglas Kerr. Platform presentations updating many of the ongoing drug programs in SMA were given, including talks on small molecules to enhance SMN levels, gene therapy to replace the SMN1 gene, cellular therapy to provide beneficial motor neuronal progenitors cells to the spinal cord, and antisense oligonucleotides (ASOs) to correct SMN2 splicing.  Leading companies working on SMA drug development, including ISIS Pharmaceuticals, PTC Therapeutics, and California Stem Cell, Inc gave talks.

The session included the following talks on ongoing drug programs:
- Stefania Corti PhD, University of Milan, Motor neurons from human spinal muscular atrophy induced pluripotent stem cells free of vector and transgenic sequences as a model and cell source for transplantation.
-Hans Kierstead PhD, California Stem Cell Inc., University of CA, Irvine, Stem cell derived therapeutic for Spinal Muscular Atrophy type I
- Paul Porensky MD, OSU,  Antisense morpholino against ISS-N1 corrects SMA mice
- Yimin Hua PhD, Cold Spring Harbor Lab, Robust rescue of severe SMA mice by systemic neonatal administration of antisense oligonucleotide that corrects transgenic SMN2 splicing 
- Frank Rigo PhD. ISIS Pharmaceuticals, Pre-clinical studies in mice and non-human primates support the development of an antisense oligonucleotide for the treatment of Spinal Muscular Atrophy
- Nikolai Naryshkin PhD, PTC Therapeutics, Small molecule compounds that correct alternative splicing of the SMN2 gene and restore SMN protein expression and function
- Kevin Foust PhD, Kaspar Laboratory, Nationwide Children’s Hospital, Biodistribution of IV injected AAV9 in young Cynomolgus Macaques

Most of the programs discussed in the drug session were represented during the final session at the SMA Families and Professionals Conference.  Here the leading experts in the SMA Research Community answered questions from SMA families. 

Three expert panels were held on:  Basic Research, Therapy Development, and Clinical Research. 
A video of this session can be found at SMA Community Connections.


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