Fight SMA Annual Conference 2007
The Good Fight
| Researchers' Conference | Families' and Friends' Conference |
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| Oxford BioMedica | PTC Therapeutics |
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| Biogen Idec | Genzyme |
 DavisMade |
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When: April 22-24, 2007
Where: L'Enfant Plaza Hotel, Washington, D.C.
What: As in years before, these are informal day meetings in which we plan to share the latest scientific results as well as have plenty of time for discussion. This year's conference will have a special emphasis on gene therapy and its importance to spinal muscular atrophy. With the participation of the attending and presenting researchers, we will have an open, interactive, and exciting meeting.
Schedule of Events
- Sunday, April 22, 2007
- 3:00 PM Check-in for Researchers Begins
- 7:00 PM Cocktail Reception
- Monday, April 23, 2007
- 8:00 AM Breakfast and Introduction by Chris Lorson
- 8:30 AM Basic and Translational SMA Investigation Presentations and Discussion
- Axonal activity by Michael Sendtner
- SMN: centrist, peripheralist, or other? by Arthur Burghes
- HDAC inhibition and SMA mice by Charlotte Sumner
- Characterizing SMN protein stability/turnover by Barrington Burnett
- 10:15 AM Break
- 10:30 AM Basic and Translational SMA Investigation Presentations and Discussion Continues
- Novel SMN interacting proteins - potential roles in axonal transport by Elliot Androphy
- Surgical delivery of therapeutics in SMA by Nick Boulis
- ES-Stem cell therapies in SMA by Doug Kerr
- 12:30 PM Lunch
- 1:00 PM Basic and Translational SMA Investigation Presentations and Discussion Continues
- An innovative and integrated approach to identify compounds that modulate SMN protein expression at the post-transcriptional level by Sergey Paushkin
- SMN inducers: a novel pathway for SMN induction by Alex MacKenzie
- SFHR-mediated modification of SMA mouse embryonic stem cells by Federica Sangiuolo
- Novel AAV approaches in motor neuron disease by Jude Samulski
- An innovative and integrated approach to identify compounds that modulate SMN protein expression at the post-transcriptional level by Sergey Paushkin
- 3:00 PM Break
- 3:15 PM Gene Therapy Presentations and Discussion
- Neurofilaments and axon protection by Michael Garcia
- 7:00 PM Dinner
- Tuesday, April 24, 2007
- 8:00 AM Breakfast
- 8:30 AM Gene Therapy Presentations and Discussion Continues
- Modulating SMN2 splicing through gene therapy by Chris Lorson
- Gene therapy in motor neuron disease by Brian Kaspar
- Perspectives from AAV/ALS by Marco Passini
- 10:30 AM Break
- 10:45 AM Clinical SMA Investigation Presentations and Discussion
- Common sense observations by Robert Leshner
- Genomic analysis through nanotechnology by Han Cao
- Update on SMA Foundation drug discovery program by Meg Winberg
- Update on Families of SMA research program by Jill Jarecki
- 12:30 PM Lunch and Discussion
- 1:00 PM Clinical SMA Investigation Presentations and Discussion Continues
- AmSMArt Update; the challenge of too few patients by Susan Iannacone
- Update on valproate, pre-symptomatoc treatment, and associated topics by Kathy Swoboda
- SMN induction by novel indoprofen analogs by Jill Heemskerk
- 3:00 PM Researcher Conference Closes
Presentation Summaries
Prepared by FightSMA Science Director, Dr. Chris Lorson.
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Dr. Chris Lorson |
Michael Sendtner, M.D.
Dr. Sendtner elegantly described the possibility that the SMN defect associated with SMA is related to an axonal-specific function. The SMN function(s) responsible for SMA development are currently unknown, however, two primary theories exist: SMN is involved in snRNP assembly and motor neurons require more snRNP assembly than other cell types at a particular stage in development; SMN performs an axonal-specific activity that may involve RNA or protein transport. Dr. Sendtner has previously published work that identified several SMN interacting factors that support a role in axonal transport and his current work further emphasized this possibility.
Arthur Burghes, Ph.D.
Dr. Burghes presented work that addressed the possibility that SMA results from a lack of snRNP assembly in motor neurons. In a detailed analysis of specific snRNP activity, a unique SMA-associated defect was observed in a rare snRNP pathway. Several types of snRNP pathways exist and use similar cellular components, but the exact building blocks can vary slightly - this in turn, leads to different types of genes being regulated by different snRNP complexes. This provides intriguing insight into SMN's best described cellular function, snRNP assembly, and may help to delineate between axonal transport and snRNP assembly. However, a rigorous analysis has yet to be completed, and a definitive answer can likely only come once transgenic animals are generated that harbor SMN missense mutations that separate SMN function (snRNP assembly vs axonal transport).
Charlotte Sumner, M.D.
Dr. Sumner has recently shown that an HDAC inhibitor, TSA, can prolong life in the SMA mouse model. Not only was life extended significantly, but several "quality of life" factors seemed to be elevated in TSA treated animals, including grip strength. So not only did TSA improve survival, but muscle strength and functionality was at least partially rescued and disease onset was delayed. Dr. Sumner is currently pursuing TSA treatment regimens to determine whether earlier drug treatments impact disease onset and disease progression. Interestingly, a new feeding regimen was developed that effectively supplemented the animals' daily caloric intake. The increase in calories AND the drug treatments had synergistic effects and in several mice, dramatically lengthened the time of survival.
Barrington Burnett, Ph.D. (from Dr. Kurt Fischbeck's laboratory)
Dr. Burnett is actively studying a poorly understood area of SMN protein biochemistry: SMN protein stability. While it is well-established that SMN is relatively stable and the SMN Δ7 protein is relatively unstable, surprisingly little information is known regarding actual turn-over rates or protein domains that are important for SMN turnover. Dr. Burnett has provided the first rigorous comparison of SMN protein stability and determined that the SMN protein half life is measured in days, rather than hours. Additionally, SMN within a SMN/Gemin complex is likely even more stable. Currently, proteosome inhibitors such as MG132 are rather toxic and, while MG132 extends SMN stability, the toxicity is too high to be considered a viable therapeutic avenue. However, newer, more specific inhibitors are currently being developed and may provide an additional platform for drug discovery in SMA.
Elliott Androphy, M.D.
Dr. Androphy is recently identified two novel SMN interacting proteins from a neuronal-specific two-hybrid screen. He discussed one if these SMN interacting clones, referred to as C160. Interestingly, this factor is involved in vesicle formation and transport of RNA and protein cargos. While a functional interaction has not been established yet, SMN and C160 interaction domains have been specifically identified and the two factors co-localized in cultured cells and in hippocampul neurons. The second project that Dr. Androphy addressed was the development of a novel platform for high-throughput screening. Dr. Androphy developed the first SMN reporter assay which was subsequently modified by many groups, however, this new platform is more representative of the endogenous SMN2 gene and is therefore believed to be able to identify a broader range of SMN-inducing compounds. The reliability and reproducibility of this assay are robust - two factors which are critical in assay development. Dr. Androphy has established collaborations with LDDN to screen ~15,000 compounds and original hits are being confirmed and developed through medicinal chemistry for analysis in a 12-point dose-response curve.
Nick Boulis, M.D.
Dr. Boulis is a neurosurgeon who has been developing a surgical device to allow the specific delivery of spinal cord therapeutics (e.g. drugs, viral vectors, stem cells). This is currently being modeled on pigs since their organ systems and size closely mimic humans. The system includes a special canula that can identify specific CNS regions which can aid in the guidance and identification of the appropriate target tissue. This is a monumental step forward, however, spinal cords represent special hurdles and the complete surgical procedure has yet to be optimized. Dr. Boulis discussed a second project which focused upon developing a neuronal-specific AAV capsid. The initial concept was made possible from a phage-display strategy that identified a very small peptide that had remarkably high affinity for motor neurons. This small peptide has subsequently been cloned into a flexible region within the AAV capsid which is expressed on the outer part of the viral capsid. Work is underway to deliver genes to motor neurons and identify the most appropriate vector and promoter for maximal efficacy.
Sergey Paushkin, Ph.D.
Dr. Paushkin discussed PTC Therapeutics ongoing SMA research program. One of the platforms for drug discovery that is being employed by PTC is "read-through." In this process, disease-associated termination codons are specifically targeted and compounds such as PTC 124 and 144 are capable of suppressing recognition of these abnormal stop codons. PTC has had great success in diseases such as CF and DMD, and clinical trials are ongoing for both of these indications. An additional platform is being implemented termed GEMS, in which the non-coding portions of RNAs are targeted to induce higher levels of expression by altering RNA degradation or translation regulation. A third approach involves modifying SMN2 splicing to induce the inclusion of SMN exon 7. All three programs are still in the early stages, however, there is considerable excitement about these projects in light of the recent Nature manuscript demonstrating effectiveness for PTC 124 in a model of DMD.
Doug Kerr, M.D., Ph.D.
Dr. Kerr has developed a procedure that generates a highly enriched population of motor neurons from embryonic stem cells from SMA mice. This is an outstanding tool for therapeutic analysis from a stem cell therapy perspective, but also as a means to test potential SMA compounds in a more complex cellular system that faithfully represents the in vivo target for the SMA compounds. Dr. Kerr has been able to demonstrate that ES-derived motor neurons generated from normal mice can make contact with muscle, send an appropriate signal, and subsequently stimulate the muscle target. SMA motor neurons can still grow relatively well and they appear to have relatively minor defects regarding their ability to find a target, however, once stimulated SMA motor neurons undergo massive cell death and growth abnormalities. Chemical inductions that mimic an axonal impulse also induce similar massive levels of cell death. This work furthers our understanding of the cellular signals that lead to motor neuron loss in SMA patients and suggest mechanisms that may be useful to prevent or slow motor neuron loss.
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Dr. Alex MacKenzie |
Alex MacKenzie, M.D., Ph.D.
Dr. MacKenzie has used an in silico analysis to identify compounds that target SMN induction. This approach yielded a novel class of activators that are well studied signal transduction components. While still in the early stages, Dr. MacKenzie's group has demonstrated that SMN expression can be induced in SMA patient cells when this signal transduction cascade is activated. This is a powerful approach to identifying SMN inducing compounds and additional analysis is likely to identify alternative pathways that activate SMN.
Federica Sangiuolo, Ph.D.
Dr. Sangiuolo is implementing a technique referred to as small fragment homologous replacement. In this strategy, a relatively small segment of DNA is inserted into SMA ES stem cells to replace the dysfunctional SMN2 exon 7 sequence. After the procedure, the genomic DNA of the recipient cells now contains a fully functional copy of the SMN1 gene. In culture cell models, this system was shown to dramatically alter SMN splicing ratios and resulted in an increase in SMN protein as measured by western and immunofluorescence (gems). This strategy has been applied to other genetic disorders such as CF and has application to a variety of genetic disorders that are due to relatively small genetic lesions.
Richard Jude Samulski, Ph.D.
Dr. Samulski is an esteemed virologist and long-standing investigator in the development of gene therapy vectors. Dr. Samulski discussed the evolution of a viral vector and how scientists can "force" the evolution of AAV vectors to identify novel viruses that exhibit novel functions such as enhanced motor neuron expression or tropism. Naturally, viruses are restricted to specific hosts and cell types, however, Dr. Samulski has developed techniques that can modify flexible regions within the viral genome which can confer novel properties that allows the virus to gain and thrive in new cellular environments. AAV2 is a serotype that has been used extensively for gene therapy vectors and its role in ongoing clinical trials was discussed, including Canavan's disease and DMD.
Brian Kaspar, Ph.D.
Dr. Kaspar has a long standing interest in gene therapy and discussed grounding breaking work in amyotrophic lateral sclerosis (ALS) which demonstrated the retrograde delivery of AAV2-IGF which extended survival in a murine model of ALS. Dr. Kaspar discussion strategies to increase the efficiency of viral gene delivery, including EMG guided delivery for retrograde delivery, enhancing the transgene promoter, self-complementary AAV (scAAV) vectors, and performing unbiased screens to identify novel AAV serotypes. This screen is based upon generated novel, random AAV serotype by introducing small random mutations into a flexible domain within the capsid. This is a powerful technique that could lead to the identification of a novel class of highly efficient viral vectors that can specifically target motor neurons.
Marco Passini, Ph.D.
Dr. Passini discussed the hurdles in bringing AAV to the clinic for diseases such as ALS and SMA, and an important step in his work demonstrated that AAV expressing IGF can be retrogradely transported in non-human primates at levels approaching 3/5%. Relatively small neurons were examined in the brain and it is clear that additional evidence will be required for larger neuronal populations. Dr. Passini also presented work on IGF-1 delivery in an ALS and demonstrated that both AAV1 and AAV2 can be retrogradely transported. IGF-1 expression resulted in an increase in survival from 121 vs 133 days.
Han Cao, Ph.D.
Dr. Cao presented state-of-the-art work that is currently being conducted at a start-up company within a tech-incubator at Princeton University. Dr. Cao's technology allows genomic analysis to be performed using nanotechnology. Currently, technologies exist that are very efficient at identifying very small DNA differences (sequencing individual bases) and very large genomic regions (FISH). However, the intermediate differences, at the level of 100's or 1000's of basepairs is relatively inefficient. Dr. Cao has developed small nanochannel arrays. A small slit of laser light is focused upon the DNA entering the slits, longer DNA can be stretched with a "hook" that elongates and unwinds the DNA. Different dyes, stains, and markers can be used to identify a pattern within the DNA which can then be scanned by the laser sensor and analyzed to find the appropriate patterns. This technology has the potential to dramatically alter the way genomes are screened, making it affordable and rapid.
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Dr. Kathy Swoboda |
Meg Winberg, Ph.D.
Dr. Winberg discussed the ongoing research programs at The SMA Foundation. Multiple drug screens have been initiated including animals studies (CominatorRx), gem analysis (Curis), and PTC Therapeutics. Lexicon Genetics is screening knock-out mouse collections to identify SMN-inducing compounds. Drosophila and C. elegans modifier screens are underway to identify additional genes that may serve as secondary drug targets for SMA therapeutics. PGI is systematically examining compounds in the SMA mouse model by several parameters including weigh, behavior and survival.
Jill Jarecki, Ph.D.
Dr. Jarecki discussed the ongoing research program at Families of SMA, detailing the active 24 grants, including two drug discovery projects: deCODE and Paratek Pharmaceuticals. deCODE has developed a platform to characterize a class of compounds called quinazolones. Medicinal chemistry has led to the identification of compounds that are excellent drug-like molecules, with good PK activity and blood brain barrier penetration. The Paratek collaboration is with Cold Spring Harbor and Dr. Adrian Krainer and is designed to stimulate SMN2 splicing. Additionally, Project Cure SMA has initiated a Phase II Carni-Val trial at 6 sites.
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- Attending Researchers
Elliott Androphy, M.D.
Nick Boulis, M.D.
Arthur Burghes, Ph.D.
Barrington Burnett, Ph.D.
Han Cao, Ph.D.
Seng Cheng, Ph.D.
Kurt Fischbeck, M.D.
Michael Garcia, Ph.D.
Jill Heemskerk, Ph.D.
Susan Iannacone, M.D.
Jill Jarecki, Ph.D.
Brian Kaspar, Ph.D.
Doug Kerr, M.D., Ph.D.
Robert Leshner, M.D.
Chris Lorson, Ph.D.
Alex MacKenzie, M.D., Ph.D.
Marco Passini, Ph.D.
Sergey Paushkin, Ph.D.
Jeff Rothstein, M.D., Ph.D.
Richard Jude Samulski, Ph.D.
Federica Sangiuolo, Ph.D.
Michael Sendtner, M.D.
Charlotte Sumner, M.D.
Kathy Swoboda, M.D.
Meg Winberg, Ph.D.
University of Massachusetts Medical School
The Cleveland Clinic
Ohio State University
National Institutes of Health
BioNanomatrix, Inc.
Genzyme Corporation
National Institute of Neurological Disorders and Stroke
University of Missouri-Columbia
National Institute of Neurological Disorders and Stroke
University of Texas at Southwestern Medical Center
Families of SMA
Columbus Children's Research Institute Center for Gene Therapy
Johns Hopkins Hospital
Children's National Medical Center
University of Missouri-Columbia
Children's Hospital of Eastern Ontario
Genzyme Corporation
PTC Therapeutics, Inc.
Johns Hopkins Hospital
University of North Carolina, Chapel Hill
Tor Vergata University School of Medicine, Italy
Universität Würzburg Institut für Klinische Neurobiologie, Germany
Johns Hopkins University/National Institutes of Health
University of Utah School of Medicine
Spinal Muscular Atrophy Foundation
Senate Briefing
"Spinal Muscular Atrophy (SMA): Legislation for a Vanguard Genetic Disease"
A Senate Briefing sponsored by the Honorable John Warner (VA)
Tuesday, April 24th, 2007
4:00 - 6:00 p.m.
Dirksen Senate Office Building, Room 562
The briefing will include:
- Introduction by Martha Slay, President of FightSMA
- Briefing Panel
- Chris Lorson, Ph.D., University of Missouri-Columbia
- Alex MacKenzie, M.D., Ph.D., Children's Hospital of Eastern Ontario
- Robert Leshner, M.D., Children's National Medical Center
When: April 24-27, 2007
Where: L'Enfant Plaza Hotel, Washington, D.C.
What: Our time together will focus on presentations from scientists about basic and translational SMA research, on a terrific panel that will address the day to day needs of an SMA child, and on raising SMA awareness and support on Capitol Hill.
Schedule of Events
- Tuesday, April 24, 2007
- 3:00 PM Check-in
- 7:00 PM Drop-In Dinner
- Wednesday, April 25, 2007
- 8:00 AM Breakfast and Scientific Update Presentation by Drs. Alex MacKenzie and Chris Lorson
- 10:00 AM Break
- 10:15 AM "Thriving with SMA" Panel Presentation and Q&A
- 12:00 PM Lunch
- 12:30 PM "Thriving with SMA" Panel Presentation and Q&A Continues
- 2:15 PM Break
- 2:30 PM Consultations with Panelists
- 5:30 PM SMA Coalition Meeting **Closed Meeting**
- 5:30 PM Fundraising and Development Seminar by Alan Hutson of The Monument Group, Inc.
- 7:00 PM Dinner and Presentations
- Thursday, April 26, 2007
- 8:00 AM Breakfast and Briefing for Capitol Hill Visits
- 9:00 AM Congressional Visits According to Individual Schedules
- 5:00 PM Reception hosted by Congressman Patrick Kennedy
- Friday, April 27, 2007
- 8:00 AM Breakfast
- 11:00 AM Check-out
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Scheduled Panelists for Thriving with SMA: Optimal Integrated Care
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Brian Weaver, MS RRT-NPS RPFT |
Meg Bradbury, MS - Genetic Counselor. Ms. Bradbury is the genetic counselor at Children's National Medical Center, Washington D.C. and she specializes in neuromuscular diseases. She works with families and patients who attend the neuromuscular clinics and also works in the Research Center for Genetic Medicine which specializes in neuromuscular research and diagnostics.
Tina Duong, MPT - Physical Therapist. Ms. Duong is a Clinical Evaluator Coordinator for the Cooperative International Neuromuscular Research Group, working in clinical research for Duchenne Muscular Dystrophy. She specializes in pediatric physical therapy and has a special interest in integrating functional exercise/activities with medical treatment of children with neuromuscular disorders.
Sally Evans, MD - Physiatrist. Dr. Sally Evans is the Children's Division Chief of Physical Medicine and Rehabilitation at Children's National Medical Center and Administrative Director of the inpatient unit at the National Center for Childhood Rehabilitation at the National Rehabilitation Hospital.
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Richard Finkel, MD and Jill FitzGerald, LCSW |
Jill FitzGerald, LCSW - Licensed Clinical Social Worker. Ms. FitzGerald has been in private practice for 16 years and 10 years ago, established the Grief Resource Center of Richmond, specializing in individual, group, and family counseling for those in need facing issues related to grief, loss, and bereavement. She offers consultation and training to the community, provides crisis de-briefing to community agencies following tragic loss, and provides monthly support groups for the staff of a local hospice. In addition, Ms. FitzGerald is a founding board member and current volunteer for ComfortZone Camp, a national bereavement camp for children and teens.
Richard Finkel, MD - Pediatric Neurologist. Dr. Richard Finkel is the director of the Neuromuscular Program at The Children's Hospital of Philadelphia. Recently, Dr. Finkel directed a survey to assist the SMA ICC Standard of Care and Clinical Trials committees guide future SMA care and research.
Robert Leshner, MD - Pediatric Neurologist. Dr. Robert Leshner is professor of neurology and pediatrics at Children's National Medical Center with a focus on neuromuscular diseases and muscular dystrophy. Dr. Leshner will serve as the moderator for the panel.
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Mary Schroth, MD |
Mary Schroth, MD - Pediatric Pulmonologist. Dr. Schroth has been on the faculty of the University of Wisconsin since 1993. She has been instrumental in the development of the respiratory care program for children with neuromuscular disorders at UW. She also developed a pediatric multidisciplinary clinic for patients with neuromuscular disease with colleagues from pediatric rehabilitation medicine and pediatric orthopedic surgery.
Kathy Swoboda, MD - Pediatric Neurologist, University of Utah. Dr. Swoboda leads Project Cure and is currently conducting a trial for SMA children with Valproic Acid. Dr. Swoboda has extensive experience with SMA children both as a clinician and as an investigator. She will be speaking to nutrition needs as a panelist.
Brian Weaver, MS RRT-NPS RPFT - Respiratory Therapist. Mr. Weaver is on staff at the University of Medicine and Dentistry of New Jersey. He is a Perinatal/Pediatric Clinical Specialist and Senior Registered Respiratory Therapist. Mr. Weaver is published and has lectured in therapy for Type I and Type II SMA patients.
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Congressional Visits
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Patrick Higgins speaks with New Jersey Congressman Mike Ferguson |
The SMA Day on Capitol Hill was highly successful. SMA families and others from across the country visited more than 65 congressional offices, meeting with Congressmen and women and their staff to advocate on behalf of spinal muscular atrophy (SMA) and urging them to recognize the opportunity of the SMA Treatment Acceleration Act to open doors for SMA and countless other diseases. The proposed Act would establish a national clinical trials network to develop treatments that are safe and effective for SMA patients. The efforts were effective in enlisting the support of a number of legislators on both sides of the aisle.
These very important visits were also a source of energy for the SMA Community. One SMA mom said, "It means a great deal to our family that our elected representatives are willing to listen and, hopefully, take action on this true life and death issue." The one-on-one meetings helped to put a face on this horrible disease. The conference attendees were able to explain better than anyone why the fight against spinal muscular atrophy is so critical. One Congresswoman's aide told a visiting family that they had "come as parents" because the Congresswoman "really likes to hear personal stories." Another family was told that "it makes an impression when families attend and come to the Hill to share personal experiences."
Some of the attendees were kind enough to provide additional feedback to their visits:
- "He was surprised and impressed at the knowledge that NINDS had singled out SMA as closest to a treatment/cure."
- "They are going to do due diligence but are very seriously considering sponsorship of our bill!"
- "She was very receptive to our visit, was attentive and asked questions."
- "We have met...on other Capitol Hill meetings. As usual he was fully briefed and even attended Tuesday's meeting. He is always willing to support SMA issues and promised to lookout for the Bill."
- "Great meeting -- She was new to SMA but very empathetic and committed to talking to their Leg. Director about co-sponsoring."
- "He was amazing! He knows so much about SMA and seemed really interested. He was excited that he was able to attend the researchers meeting, and wished he could have met more SMA families."
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Reception on Capitol Hill
April 26, 2007
5:00-7:00 p.m.
Rayburn House Office Building
Room B339
Congressman Patrick Kennedy of Rhode Island addressed the reception attendees about spinal muscular atrophy research funding and the SMA Treatment Acceleration Act. The proposed legislation, developed through a collaborative effort between Fight SMA, the SMA Foundation, and Families of SMA, would establish a national clinical trials network to develop treatments that are safe and effective for SMA patients.
Conference attendee Karin Vallo captured the speech on video. Karin is a leader in the Desiree's Buddies/FightSMA Southwest chapter in Albuquerque, New Mexico, and is the grandmother of Desiree. A big "thank you" goes out to Karin for helping us make this video available!
The Good Fight 2007
SMA Support is dedicated to providing information, equipment, supplies and support to families affected by Spinal Muscular Atrophy. It is our goal to improve the quality of life for those families dealing with SMA to the best of our ability.
FightSMA is dedicated to accelerating the search for a treatment and cure for spinal muscular atrophy (SMA), the number-one inherited cause of infant death. We pursue this objective by raising awareness and funding for SMA research.