2018-2019 progress report

For Salla disease research, treatments, awareness, and family networks. 2018-2019 REPORT

ABOUT The Salla Treatment and Research Foundation was established in 2018 as the first-ever organization dedicated to promoting Salla disease research, treatments, awareness, and family networks. The Foundation supports collaborative scientific research in order to accelerate the prospects for effective medical treatments for those affected with Salla. The Salla Treatment and Research Foundation is driven by an unwavering belief that no disease is too rare to fight, and that with sufficient support, hope, and faith, a small team of committed researchers, families, supporters, and advocates can create meaningful solutions for those impacted by this disease.

Contents 4 Letter from STAR President 6 Letter from STAR Researchers 8 What is Salla? 7 STAR Across the Globe 10 Salla Research Progress Report 11 Selected 2018-2019 Activities 18 Your Support 19 Financial Overview 20 Special Thanks

Letter from STAR President Jessica Klein Foglio On behalf of the entire Board of Directors of the Salla Treatment and Research (“STAR”) Foundation, I am delighted to present our 2018-2019 report. This document has been carefully prepared by the Board to inform our researchers, friends, and families of the remarkable progress and status of our fledgling organization, and what remains for us to accomplish. We want to share with you our mission, our goals, and the Hundreds of hours of time and effort have been donated significant impact that all of our stakeholders have had on to this organization and cause, many by families with no our organization - every dollar has resulted in direct direct ties to the disease. We personally thank you all for impacts to our progress in establishing more baseline your generosity and empathy to those of us who face this research regarding Salla. Our foundation is the direct disease daily. "STAR families" - those represented on our result of passion - the passion of mothers and fathers who Board and all who have dealt with Salla - have felt the chose not to accept a diagnosis of an orphan disease for hopelessness and loneliness of this diagnosis; we have which there is minimal research, little outlook, and no cried tears from frustration over the seeming unfairness of treatment or cure. We are families that have pooled our our circumstances and have also wept in joy in seeing our resources and our talents to start something from nothing; children progress, meet, and exceed seemingly impossible we endeavor to sponsor the research and effort that yields milestones. It is from these moments and memories that Letter from STAR President treatments and cures for any person in the world that is drive us - to make the change we want that no one should affected by Salla. Despite the challenges and tribulations have to experience those moments again. We hope you many of our families have faced, we remain optimistic and share in our optimism that the journey to a world without humbled - this foundation has been supported by an Salla has begun and we thank you for every person’s part outpouring of moral and financial support by families and in beginning - and completing - this journey. friends. 4

Our Strategy: Collaboration Build Awareness Initiate and Support Scientific Research Identify Effective and Viable Treatments Letter from STAR President 5

Report from STAR Researchers Dr. Steven U. Walkley, DVM, PhD Dr. Melissa Wasserstein, MD Just over 2 years ago on November 9, 2017, the Foglio family came to the Rose F. Kennedy Intellectual and Developmental Disabilities Research Center (IDDRC) at the Albert Einstein College of Medicine in New York and met with a team of scientists led by Dr. Steven Walkley and their son’s Montefiore physician, Dr. Melissa Wasserstein. This was a new program at Einstein-Montefiore, Operation IDD Gene Team, whose goal was to help parents more fully understand the nature of the genetic diagnosis underlying their child’s intellectual disability and to let them know they were not alone in their quest for answers. Here the Foglio’s heard a lay tutorial addressing the science Since that fateful decision, a S.T.A.R. was born, and was buoyed behind their son’s diagnosis. They learned that Salla disease is by numerous collaborations with other affected families in the an ultrarare type of lysosomal storage disorder – genetic U.S. and Europe, by successful fundraisers and by a first “think diseases which themselves are uncommon – and one for which tank” meeting held in Tarrytown, New York in the fall of 2018. little research was underway in the U.S. or Europe. There was Organized by Drs. Walkley and Wasserstein, this intense one- even a lack of knowledge as to whether any other families in the day meeting represented a “first” for Salla disease, where a US might be affected. They also learned that while there was no dozen top notch scientists from the U.S. and Europe came treatment known for Salla disease, a closely related lysosomal together with an equal number of families affected by this Report from STAR Researchers disease (cystinosis) did have a treatment, developed at the condition. As a result, a Sialic Acid Storage Disease (SASD) National Institutes of Health (NIH) some years earlier. More Research Collaborative was established and projects initiated in research might lead to a therapy for Salla as well. As a result, labs at Einstein and the NIH. within 6 weeks of the tutorial the Foglio’s announced that they A summary of current work and their advances is provided on would create a foundation dedicated to Salla disease families the following page. and to finding a treatment for this disease. 6

Salla Research Progress Report A summary of current research being conducted as a result of the support from the Salla Treatment and Research Foundation A knockout mouse model of Salla disease has been established at Einstein. -The CNS disease in this mouse model is being fully characterized. -A therapy examining substrate reduction directed at glycosphingolipid storage is being tested. A new Salla disease knockin mouse model is being generated at NIH. -A CRISPR SLC17A5 knock-in Finnish mutation (Arg39Cys) mouse is being created, with efforts currently in progress focused on a targeted mutation screen. -This new model, which is anticipated to show a more chronic disease progression than the rapidly fatal KO model (and thus better reflect human disease), will be used in future phenotyping/drug treatment studies. SLC17A5/Sialin mutation analysis allowing for research confirmation of diagnosis has been established at NIH. -Genetic screening for SLC17A5 gene defects on gDNA has been set up (research base). -Optimized sequencing of mRNA to show effects of specific mutations on gene expression has been established. -All currently published SLC17A5 mutations are being compiled for a publication. Salla disease cell lines are being established at NIH for research/sharing purpose (fibroblasts + lymphoblastoid cells). -Fibroblasts (skin cells) and Lymphoblastoid (blood) cells now being established will allow us to look at the disease state in a controllable cell model. -Coriell repository cell lines: Mutations in these commercially available SALLA cell lines are being determined, informative for other research groups that purchase these lines. -NIH SALLA patient cell lines are being characterized. The Salla disease intracellular phenotype is being characterized at NIH for use in drug screening/testing + purpose. -Immunofluorescent (IF) lysosomal staining on SALLA fibroblast cultures were started to establish lysosomal size, cellular distribution and intracellular movement - not previously described for SALLA. - Other cellular markers will be tested by IF + confocal microscopy imaging. NIH investigators are establishing/characterizing SIALIN antibodies for use by all research groups. -Testing commercially available Sialin/SLC17A5 antibodies for Western Blotting and immunofluorescence on human cells is underway. Efforts toward collecting Natural History data for Salla disease are in place. -Knowledge of the natural history of a disorder is valuable to the FDA when comparing the results of treated and untreated patients. Dr. Wasserstein at Montefiore has experience with Free Sialic Acid Storage Diseases (FSASDs) and other lysosomal storage diseases. In addition, a limited natural history study of FSASD can be conducted under a clinical protocol that already exists at the NIH. Up to 6 affected individuals would be evaluated with medical consultations, imaging, and SLC17A5 mutation analysis, and a skin biopsy would be obtained to grow fibroblasts for laboratory investigations. Those can include studies of what drugs might reduce the sialic acid content of the cells’ lysosomes, in a screen for candidate therapies. Outreach/awareness of SALLA research has been expanded. -An abstract and poster entitled “Collaborative Development of Therapeutics for Sialic Acid Storage Disease” authored by NIH and Einstein scientists will be presented by Mary Hackbarth at the following meetings. {American Society of Human Genetics annual meeting (Oct 15-19, 2019; Houston, TX); 2019 NHGRI Symposium (Nov 25-26, 2019, NIH Campus, Bethesda, MD); ASCB/EMBO annual meeting (Dec 7-11, 2019, Washington, DC). -A second Salla disease Think Tank meeting is being scheduled for September, 2020, to be held at the NIH. Like the first think tank, scientists and clinicians with focus on Salla disease from the US and Europe will be invited to attend.

What is Salla? An ultra-orphan rare lysosomal storage diserase Salla disease, intermediate severe Salla disease, and infantile free sialic acid storage disease (ISSD) are neurodegenerative disorders resulting from increased lysosomal storage of free sialic acid. The mildest phenotype is Salla disease, which is characterized by normal appearance and neurologic findings at birth followed by slowly progressive neurologic deterioration resulting in mild to moderate psychomotor retardation, spasticity, athetosis, and epileptic seizures. The most severe phenotype is ISSD, characterized by severe developmental delay, coarse facial features, hepatosplenomegaly, and cardiomegaly; death usually occurs in early childhood. Free sialic acid storage disorders result from defective free sialic There are no consensus clinical diagnostic criteria for Salla acid transport out of lysosomes caused by pathogenic variants disease. The diagnosis of Salla disease is suspected in in SLC17A5, encoding the lysosomal transport protein sialin. The individuals who manifest truncal ataxia and hypotonia at age diagnosis of a free sialic acid storage disorder is suggested by approximately one year, developmental delays and growth significantly elevated free (i.e., unconjugated) sialic acid retardation in early childhood, and severe cognitive and motor (referred to as N- acetylneuraminic acid, a negatively charged impairment or intellectual disability in adulthood. The sugar) in urine and/or cerebrospinal fluid using the fluorimetric association of intellectual disability, spasticity, ataxia, thiobarbituric acid assay, thin-layer chromatography, or mass myelination defects, and facial coarsening in adulthood is spectrometry. The diagnosis is established either by suggestive of Salla disease. The diagnosis of infantile free sialic demonstrating lysosomal (rather than cytoplasmic) localization acid storage disease (ISSD) is suspected in individuals with of elevated free sialic acid or by identifying pathogenic variants early multisystemic involvement including: hydrops fetalis, in SLC17A5. hepatosplenomegaly, failure to thrive, increasingly coarse facial features, neurologic deterioration typical of a lysosomal What is Salla? storage disease, dysostosis, and early death. 8

Salla disease is the mildest phenotype, characterized by a ISSD, the most severe phenotype, is characterized by normal appearance and normal neurologic findings at severe developmental delays, coarse facial features, birth followed by slowly progressive neurologic hepatosplenomegaly, and cardiomegaly. ISSD can present deterioration resulting in mild-to- moderate psychomotor prenatally and in the neonatal period with nonimmune retardation. Muscular hypotonia is often first recognized hydrops fetalis [Lemyre et al 1999, Stone & Sidransky 1999, at approximately age six months. One third of affected Froissart et al 2005]. Some affected infants are born children learn to walk. Speech can be limited to single prematurely. Other affected infants appear normal at birth words but understanding of speech is good. Slow but deteriorate and lose milestones during infancy [Kleta developmental progress often continues until the third et al 2003, Kleta et al 2004]. Seizures are common. Some decade, after which regression can occur. Some infants with ISSD develop proteinuria and nephrotic individuals with Salla disease present later in life with syndrome [Lemyre et al 1999, Ishiwari et al 2004]. Skeletal spasticity, athetosis, and epileptic seizures, becoming changes may include irregular metaphyses, diffuse nonambulatory and nonverbal. Affected individuals are hypomineralization, club feet, short femurs, enlarged characterized as good-humored and sociable. Abnormal metaphyses, fractures, hip dysplasia, anterior beaking of myelination of the basal ganglia and hypoplasia of the the dorsal vertebrae, and hypoplasia of the distal corpus callosum are constant and early findings. MRI phalanges [Froissart et al 2005]. Death usually occurs in reveals these predominant white matter changes. early childhood, typically from respiratory infections. Cerebellar white matter changes are also present and can Salla disease is believed to have been reported in explain the ataxia. In addition to the central approximately 150 individuals, mainly from Finland and dysmyelination, a peripheral dysmyelination with the Sweden. Individuals with molecularly proven Salla disease clinical picture of a polyneuropathy occurs with variable have been identified outside of Finland and Sweden. neurologic presentations. Affected individuals do not have organomegaly, skeletal dysostosis, or abnormal eye findings. In a single individual, growth hormone and gonadotropin deficiencies were observed. Life expectancy Letter from STAR President From "Free Sialic Acid Storage Disorders" (2013) by David Adams, MD, PhD and William A Gahl, MD, PhD appears to be shortened, although affected individuals up to age 72 years have been observed. 9

STAR Foundation has connected with Salla families in 7 U.S. states and 12 countries.

SEPTEMBER 2018 THINK TANK & FAMILY CAMP Organized by Drs. Walkley and Wasserstein, this intense one-day meeting represented a “first” for Salla disease, where a dozen top notch scientists from the U.S. and Europe came together with an equal number of families affected by this condition. As a result, a Sialic Acid Storage Disease (SASD) Among the participating researchers: Research Collaborative was established and Dr. David Adams, M.D., Ph.D. projects initiated in labs at Einstein and the NIH. Dr. Kostantin Dobrenis, Ph.D. Dr. William A. Gahl, M.D., Ph.D. Dr. Bruno Gasnier, Ph.D. Dr. Marjan Huizing, Ph.D. Dr. Marc C. Patterson, M.D. Dr. Richard J. Reimer, M.D. Dr. Steven U. Walkley, DVM, Ph.D. Dr. Melissa Wasserstein, M.D. Dr. Roberto Zoncu, Ph.D.

DECEMBER 2018 NEW YORK HOLIDAY AUCTION The first-ever community-wide fundraiser for the Salla Treatment and Research Foundation took place in Riverdale, NY, attracting local television and print media coverage and raising awareness of Salla disease and the new effort to fund dedicated research at the National Institutes of Health.

DECEMBER 2018 NOVEMBER 2019 JERSEYS FOR JACKSON For two years in a row, the community in Sioux Falls, South Dakota has come together for the "Jerseys for Jackson" event. Organized by the Horsted family, the event has been covered by local media, expanding awareness of Salla and raising funds for Salla research.

FEBRUARY 2019 A STAR FOR JADA CONCERT Organized by Shawn Merriman, the "Star for Jada" concert in Manitoba, Canada was the first international event for Salla disease, gaining local media attention and raising thousands of dollars for Salla research.

AUGUST 2019 GEORGIA STAR GALA The LeBlanc family brought together family, friends and local businesses for a remarkable gala event near Atlanta, Georgia, in what was the most successful fundraiser yet in support of the Salla Treatment and Research Foundation.

INTERNATIONAL STAR WALK SEPTEMBER 2019 $39,000 5 raised countries In our most ambitious event since the creation of the Salla Treatment and Research Foundation, the first annual "International STAR Walk" took place in 5 countries worldwide with numerous communities coming together to support family and friends, raising significant awareness and support for the Foundation and the research ahead.

A WORLDWIDE EFFORT Feature news articles and chocalate sales in Switzerland, lemonade stands in New York, wine events in Georgia, bake sales in California, speaking opportunities at scientific conferences, and more... in two short years, efforts to raise awareness and resources has been taking place across the world, led by a network of Salla families and friends who together are building momentum to advance Salla treatment and research.

SUPPORT STAR Dear friend, It has been so inspiring to see our communities come together in support of Salla families since the founding of the Salla Treatment and Research Foundation. We are eternally grateful to you, our friends, family, and all our supporters. The hope and progress that has been generated in the past two years is just the beginning. Together, we can make an enormous impact. Advancements in Salla research and treatments is within our reach. And we know it will happen with your help. With all our gratitude, Jessica Klein-Foglio Jessica Klein-Foglio, President, Salla Treatment And Research Foundation (Mikey's and Ben's mom) SUPPORT STAR 18

Financial Overview Growing Resources Per Year 2018-2019 200,000 150,000 100,000 50,000 0 2018 2019 Financial Efficiency 2018 - 2019 Administrative: 2% Marketing / Awareness: 5% Fundraising: 16% Research: 76% 19

SPECIAL THANKS There are too many individuals, families, and businesses across the world for all of the Salla families to thank. Below is just a partial list of the many who have helped us to generate hope and progress. Thank you. City of Odessa EY 2 Square Feet Landscaping Club Pilates (East Cobb) Family PowerSports of Odessa A-1 Broadcasting, Chuck Edmundson Cora Housewares Hardware Fifth Group ABC Prooerties Costco (Alpharetta) Gina’s Happy Faces Addeos Pizzeria Crystal Barbee Photography Goldfish Swim School (Johns Creek) Albert Einstein College of Medicine/ Darlene Glenn Hal’s Montefiore Medical Center. David and Shanit Halperin Hannah’s Food Truck All Around Gymnastics Delta, Melissa Murphy HB Liquors American Haircuts (Roswell) Dr. Bruno Gasnier, Ph.D. Hinzman Holdings Amy Coggeshall Dr. David Adams, M.D., Ph.D. Hollywood Feed (Cumming) Amy Stone Dr. Kostantin Dobrenis, Ph.D. Houcks Andretti Dr. Marc C. Patterson, M.D. I Canita Cake Ann Taylor Dr. Marjan Huizing, Ph.D. Imperial Fez Dr. Melissa Wasserstein, M.D. Ivy Lane Anne & Randy Ward Dr. Michael Papciak Jake's Steakhouse Borgattis Dr. Richard J. Reimer, M.D. Jennifer Klein Botanical Gardens Dr. Roberto Zoncu, Ph.D. Jeremy Jutkowitz Brad Buffington Dr. Stephanie Grogan John Patitucci Cabernet Steakhouse Dr. Steven U. Walkley, DVM, Ph.D. Joy Beider Café Intermezzo Dr. William A. Gahl, M.D., Ph.D. Joy Langer Cakes by Darcy Dry Bar Just in Time Consign, Reggie Martin Special Thanks El Felix JWO Jewelers Catch Air Enchant a Party Cherokee Drone Services Ennerations Children’s Hospital at Montefiore Chireen Hall & Latelier Hair Co. Chris Morman 20

Kaiser family and friends Sams Club (Roswell) The Roaden Family Katie Lester Scott Tarter The Seersucker Peach Kilwins Seth Deitchman The Shane Show Kimball House Shine Speech The Shaw Family L’atelier Hair Co, Chireen Hall Skyview wine and liquors The Solid Bow La Vida Massage Sno King The University of Georgia Athletics Department Laura Gill Sonya Chamberlain Therapy Stars & Strikes Lee Chadwick Sukari Spirits Tom and Dawn McGee New Generation Leek Fire & Safety Supplies Sunbelt Rentals Realty of Georgia Leigha Perkins Sweets by Sauer Top Golf Lloyd’s carrot cake Trader Joe’s (Roswell) Trader Joe’s (Roswell) Madison’s Trish Anderson Trish Anderson Magic by Harlin Truffles Chocolate Factory Truffles Chocolate Factory Magnolia Moon Twin Lakes Farm Twin Lakes Farm Mandy’s Hair Salon T-Mobile Riverdale Unique Nails Marcel The Alliance Theater Unleashed McCarty Equipment Co The Atlanta Hawks Vancortlandt Park House Museum Mekhal Anvaripour The Atlanta Zoo Vickie Jordan Michelle Badour The Beaufort Bonnet Company West Elm Morgan Stanley The Center for Puppetry Arts Whitney Panetta National Society of Colonial Dames In The Cheese Guy Wild Birds Unlimited (Dawsonville) the State of New York The Davis Book Club William David Salon & Spa (Alpharetta) Noca The Garner Family Zach & Allie Pridgen Novogrow LLC-Azriel Novogroder The Georgia Aquarium Zeke Moya, Car Freshies by Zeke’s Peeps Odessa Camera RC & Armory The Metropolitan Club Zulu Nyala Grop Osteria Mattone The Pink Valise Pike Nurseries Polo Golf and Country Club Rebecca Huffman, Origami Owl Special Thanks Rick and Mary Johnson Riverdale Stables Riverdale Yacht Club Ruffle Butts 21

BOARD Jessica Klein-Foglio, President Michael Foglio David A. Halperin Kenneth Klein Adam LeBlanc John Patitucci CONTACT Salla Treatment And Research Foundation PO Box 1051 Riverdale Station Bronx, NY 10471 Web: www.SallaResearch.org Email: [email protected] Facebook.com/SallaResearch Salla Treatment And Research Foundation is a 501 (c) 3 not-for-profit organization. All contributions are tax-deductible.