2011 SMA Annual Conference

1. 2011 SMA Annual Conference Orlando June 23-25, 2011

2. 2011 Families of SMA conference June 23-26, 2011

3. Event information • Location: Walt Disney World Resort • Participants: 1500 people living with SMA and family, including around 45 Canadians.

4. Whatis SMA • Spinal muscular atrophy is the name given to a group of genetic muscle-wasting disorders. • SMA affects the nerve cells that control voluntary muscle. These nerve cells are called motor neurons and SMA causes them to die off. • The significant majority of cases of SMA are caused by the deletion or mutation of the SMN (survival motor neuron) gene located on chromosome 5. • Two versions of this gene exist: SMN1 and SMN2. These genes differ by only five basepairs, and these five basepairs are considered translationally silent. The SMN protein is ordinarily involved with the metabolism of a compound known as RNA. • The absence of SMA1 causes SMA, while the quantity of SMA2 modulates the severity of the disorder.

5. Type of SMA: SMA Type I, or infantile SMA Type II, or intermediate SMA Type III, or juvenile SMA Type IV, or adult

6. Research – Priorities for FSMA Drug Pipeline • Build existing drug pipeline with 2 new programs - TBA • Transition programs currently in the pipeline to government and industry leadership • $3m to be spent on research this year, over $50 million to date Biomarkers • Biomarkers study in conjunction with National Institute of Neurological Disorders and Stroke – application deadline Sept 1, 2011. Will provide early indications to trials ex. change in muscle size.

7. Drug companies are attracted to SMA because: - Cause in known - Back-up gene (SMN 2) - High unmet needs with no current therapies - Treatable - Orphan disease (less than 200,000 affected) - Profitable • Goal of the clinical trials: Find new treatment to cure, stop or reverse the progression of the disease. • Required evidence: - Drugs are safe, side effects understood - Correct dose - Proof that the drugs are effective The importance that clinical trials are not treatments…

8. Government incentives for companies to develop orphan diseases therapies (exclusivity, tax benefits, fee deductions, grants) • Difficulties and challenges with research and orphan diseases: - Small population - A lot of diseases and type of diseases - Testing on humans - Animal models are incomplete - New process

9. Rehabilitation • Dr. Brian Snyder, Harvard Medical School, believes given the promising treatments for SMA and since kids are living longer there is justification to do hip surgery in children • Stretching, stretching, stretching…daily • Studies show 7.5 hours week of weight bearing required for optimum bone density • Benefits of surgery: prevent dislocation for comfort, pelvic alignment, improved sitting balance • Surgery is less severe in a child patient, best approach is to mitigate with minor surgeries when children are young • He believes that hip dislocation is what causes scoliosis • NO BODY CASTS – 4x decrease in bone density • Dr. Snyder is willing to confer with your orthopaedic surgeon

10. Dr. John Grayhack, Children’s Memorial Hospital, Scoliosis presentation • TLSO braces for SMA kids need to be more lightweight and softer than most scoliosis patients, abdomen needs to be cut out due to ‘belly breathing’ otherwise will affect function • Pulmonary function, magnitude, and flexibility are factors to determine when to do surgery • Golden age – 10 if possible

11. Treatments for common colds in SMA kids (Dr. Richard Shell, Paediatric Pulmonologist) • Cough assist recommended for all kids – most effective when used regularly not just when sick (prevention tool). 1-2x day when healthy, as often as necessary when sick. - Good hydration to keep mucous thin - Suctioning - Avoid anti-histamines (thicken mucous) - Increase use of cough assist - Maintain oxygen levels above 95%, supplement with oxygen is needed - Judicious use of antibiotics - Head lower than feet

12. Education - Support Panel Several young adults shared experiences attending college away from home: • Managing personal support workers • Push schools to identify how they can support the student: - modifications to dorms such as swipe door locks, motion sensor sinks, - providing note takers or have professors provide notes, - provide second set of text books

13. Grandparents talk it out… • A lot of emotion and humor!!! •  Concerns of the grandparents: - Fair with all of the grandchildren when one has SMA - Effect on siblings - Live far, don’t know what to do - Conflict with the parents - Compensate with what the affected children can’t do - Advocate as a grandparent is important - Don’t know how to talk or what to say to the affected children about the disease

14. Becomingcollegeready • Discussion about getting prepared to go away to college • What to plan for each year of high school in order to make a good decision on which school to attend. • Where and how to access resources at the collegiate level and how they will differ from high school.

15. Tips: • Understand the requirement for your degree: do research • Go to class • Self motivation is the key • Visit school at all time, to see when its crowded or not. • Teacher in colleges are experts on a specific subject but not necessarily good educators. • Make sure to speak to them. Give your limitations • Being organized and asking help from people, not always asking the same person: make sure to create a network. • In college, your on your own!!!

16. Teen on wheels • It is hard to be a teenager in today’s society. The combination of rapidly changing hormones, peer pressure, and educational challenges are often too much for most young people to handle. • If asked to imagine all of these factors combined with a diagnosis of SMA, most would probably picture a disaster waiting to happen. But being a teen with SMA is not impossible and in fact it can produce some of the most influential and positive times in a young person’s life.

18. 15th Research Group MeetingJune 23-25, 2011

19. Special Session: Comparative SMA pathologyin Mice and Man with Therapeutic Implications • Keynote address: Lessons learned in Pompe Disease. Dr. Dwight Koeberl, Duke University Medical Centre • Invited talks on Comparative SMA Pathology in Mice and Men Neuronal and muscle phenotypes in SMA mice Dr. Gillingwater, U Edinburgh, Dr. Mentis, Columbia University Neuronal and muscle phenotypes in humans Dr. Sumner, John Hopkins School of Medicine Systemic extra-neuronal phenotypes in SMA mice Dr. DiDonato, Northwestern U; Melissa Bowerman, U of Ottawa, Brian Kaspar, Nationwide Children’s Hospital Systemic extra-neuronal phenotypes in humans Dr. Sabine Rudnik-Shooneborn, U of Acchen, Dr. Swoboda, U of Utah

20. Heterogeneity among SMA models • Heterogeneity among humans • Neuromuscular junction formed normally but rapidly broken down • In humans, NMJ is connected but structurally abnormal • Synaptic transmission defects – precedes motor neuron death • Defects also seen in skeletal muscle • In humans, different muscles are affected differently (eg. Diaphragm significantly spared) • Defects observed in heart, pancreas (glucose metabolism) • No heart defects observed in humans

21. Q’s: How relevant are mouse models? Which model is best for pre-clinical trials? What cells need to be corrected? Will CNS drugs correct non-CNS cells? Do Pompe clinical trials inform SMA trials?

22. Clinical Research Session • Congenital Heart disease in SMA Dr. Holuba et al. Columbia U • Electrical impedance myography as a biomarker in SMA Dr. Rutkove, Boston, MA • Pilot study of in-home monitoring of pulmonary function in SMA type 2 Dr. Constantinescu et al., Columbia U • SMN transcripts: potential biomarker? Dr. Simard, U Manitoba • Phase II trial of salbutamol in SMA type 3 patients Dr. Morandi, Milano, Italy

23. No evidence of congenital heart disease in SMA • Electrical impedance & muscle strength stable (over 1.5 years, mean 9.8 yrs old) • In-home, overnight recordings (LifeShirt system) are safe, convenient, useful to detect sleep disordered breathing/outcome measure • Increased SMN transcripts in 1/3 of VPA treated patients suggests that measuring SMN transcripts may provide an informative clinical trial outcome • Significant relationship between muscle function/BMI/SMN2-fl transcript levels in ambulant patients, no correlation in wheelchair-bound patients; no relationship with clinical outcome

24. SMA Models and Observed Phenotypes • Disruption of SMN in pigs Monique Lorson, U Missouri • Plastin 3 – SMA modifier? Christine Beattie, The Ohio State U; Bastian Ackerman, Inst of Human Genetics, Cologne, Germany • SMN in NMJ, muscle, and during early human development Tara Martinez, Johns Hopkins U; Rebeca Martinez-Hernandez, Barcelona, Spain; Karen Ling, U Southern California; Simon Parson, U Edinburgh

25. Creation of pig model a challenge but SMA carrier piglets expected in July, crosses will be required to produce pigs with SMA phenotype • Smn stabilizes or affects production of plastin3 protein and this contributes to NMJ changes and movement defects. Over-expression of plastin3 results in positive effects on MNs and NMJs of SMA mice (severe) • Increasing Smn in muscle has a positive effect on SMA mic • Can detect abnormal NMJs in early second trimester of foetal life in SMA foetuses • Do measures muscle microvasculature correlate with disease phenotype

26. Therapy Development Session • Stem cells derived therapies for SMA StefaniaCorti, UMilan, Italy ; Hans Kierstead, U California at Irvine • Pre-clinical trials of antisense or small molecules affecting SMN2 splicing Paul Porensky, The Ohio State U & U Western Australia; YiminHua,Isis Pharmaceuticals & Cold Spring Harbour; Frank Rigo, Isis Pharmaceuticals & Cold Spring Harbour; Nikolai Naryshkin, PTC & SMA Foundation • Gene therapy: AAV9 in young Cynomolgus Macaques Kevin Foust et al., Nationwide Children’s Hospital

27. Reprogrammed patient fibroblasts into stem cells and differentiated iPS cells into MNs (defects = cell number, size, axon length). Normal iPS cells graft into SMA mice spinal cord • Human motor neuron progenitor cells from hESC provide neuroprotective factors in SMA mice and improve functional outcomes • Correcting splicing inside and outside the CNS is very promising with effects lasing for extended periods following a single introduction • demonstrate bioavailability, brain-penetration etc. • AAV9 can enter monkey CNS (found in both neurons and glia)

28. and much more.......... • SMN Molecular Functions & SMN regulation • Posters