NEWSLETTER—The UCSD Suramin Autism Study From the UCSD Mitochondrial and Metabolic Disease Centerand the desk of Dr. Robert K. Naviaux, MD, PhD - April 14, 2016, Newsletter #2.Suramin Study Director, and Professor of Medicine, Pediatrics, Pathology, and Genetics

BeginningsThe UCSD Suramin Autism Study began with a new idea about the origins and treatment of autism in 2008. This new idea emerged from 20 years of clinical experience caring for children with genetic forms of mitochondrial disease, combined with new observations of a different kind of mitochondrial dysfunction in autism, and Dr. Naviaux’s long-standing interest in the connection between genes, environment, and metabolism in human health and disease. Dr. Naviaux published the first descriptions of these new ideas in 20121-3. Research in the lab led to the discovery that a drug called suramin, used for 100 years to treat African sleeping

sickness, corrected the symptoms of autism in two classical mouse models. The mouse models have many of the same troubles with social behavior, learning, attention, fear of novelty, anxiety, brain circuits and connections, muscle coordination, GI motility, gut microbiome, immune system, and metabolism as children with ASD. Dr. Naviaux’s team published these results in 2013-20154-6.

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Many children with autism are trapped behind a glass wall that inhibits normal development. If Dr. Naviaux’s theory is correct, this wall is created by the cell danger response (CDR)3—a normal response that defends the cell from harm in the short term, but can persist abnormally in autism. The UCSD clinical trial was the first test of suramin in children with ASD.

Mitochondria were the lighthouses that guided the way to new discoveries in autism research.

Children with Mitochondrial Disease provided the first clues that revolutionized how we think about autism spectrum disorders (ASDs).

What is suramin?Suramin is unique in all of medicine. It is the oldest man-made drug still in active medical use. It was first synthesized by Bayer scientists in 1916, and has been used for nearly 100 years for the treatment of African sleeping sickness in both children and adults. Because of this long history, we have extensive information about its risks and how to use the drug safely. In addition to its long-known anti-parasitic properties, in 1988, suramin was discovered to bind to cellular receptors that sense and respond to danger. Working in this way, suramin calms the cell danger response (CDR) and reverses the metabolic syndrome that is ultimately caused by the special kind of mitochondrial dysfunction seen in autism. Suramin is the first of a new class of medicines called antipurinergic drugs. These new medicines work by inhibiting the cell danger signals sent by extracellular ATP. Dr. Naviaux’s pioneering work was honored with a Trailblazer award in 2011.

What is the cell danger response (CDR) and how is it related to autism?When cells are threatened, they activate an ancient and deeply embedded code—a subroutine in our genetics—that protects us from danger3. Like nations at war, one of the first responses of cells to environmental danger is to harden their borders, and to limit communication with neighboring cells. Dr. Naviaux calls this the Cell Danger Response (CDR)3. It is is a natural

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The UCSD Suramin Study Team. Front row (left to right): Deyna Arellano, RN; Suzanne Goh, MD; Cindy Adams, PharmD; Jeanne Townsend, PhD; Brooke Curtis, PsyD; Lee Vowinkel, RN; Cindy Knott, RD; Cindy Ewing. Back row (left to right): Dennis Perpetua; Marissa Westerfield, PhD; Thane Ross, Pharm; Gail Reiner, DNP; Robert Naviaux, MD, PhD; Maeve Taaffe, RN; Alan Lincoln, PhD. Other team members (not pictured): Leanne Chukoskie, PhD; Sonia Jain, PhD; Suzanne Parlett; Qamdhyn Hale; Ji Sun, PharmD; Richard Haas, MD; Rema Reman, PhD; Juan Leon; Lisa Marvin; Sue Husband; Diana Rodriguez, PhD, RN; Kefeng Li, PhD; Jane Naviaux, MD, PhD; Lin Wang, MD, PhD. Study Advisors: Geraldine Dawson, PhD; Doris Trauner, MD; Steve Edelson, PhD; Stephen Porges, PhD; Elizabeth Mumper, MD.

and universal cellular response to any kind of acute injury, toxin, or infection. Even certain DNA mutations like Fragile X and copy number variations (CNVs) like the one that causes Angelman syndrome can activate the CDR. Healing normally shuts down the CDR after the threat is gone in a few days or weeks. This allows cellular resources spent for defense, to be redirected back toward normal growth and development. But sometimes the CDR persists abnormally—gets stuck. Because the CDR is a normal and universal response to injury or threat, the question relevant to autism treatment is not “Why does the CDR turn on?” Instead, the important question is “Why doesn’t the CDR turn off when it should?” And for treatment, the the most important question is, “How can we turn off the CDR when it persists too long?” Dr. Naviaux’s research has shown that the CDR is maintained by abnormal purinergic signaling. When the CDR persists during times of rapid brain growth, it usurps cellular resources for defense, and creates roadblocks to normal developmental progress. This can lead to autism spectrum disorders1-6, and many other disorders3. Suramin helps to normalize purinergic signaling, removes the roadblocks, and allows cells to return to normal metabolism and development.

The Clinical Trial—The First Study of Suramin in AutismThe UCSD Suramin Autism Treatment trial opened in May 2015 and clinical studies were completed in March 2016. This first study was small. We studied 10 subjects divided into 5 pairs, and matched for age and autism severity. Half of the children received a single intravenous infusion of suramin, and the other half received a single dose of saline as a placebo. The results were very promising. All of the children who pre-enrolled will have first preference for the follow-up studies. The researchers plan to submit their results for publication in this summer. If accepted for publication, the research results could be published in the scientific literature before the end of 2016. The next studies (studies #2, 3 and 4) are now being planned.

Locations and Contact Information The infusions and routine blood and urine tests took place at the UCSD Clinical Translational Research Institute (CTRI) in La Jolla, California. All the behavioral studies took place at the UCSD RAD (Research on Autism and Development) Lab, La Jolla. For more information about the trial you can click on the link at clinicaltrials.gov: https://www.clinicaltrials.gov/ct2/show/NCT02508259.

FundingFunding for this trial was entirely supported by private donors and foundations. If you would like to help support this trial and future autism treatment studies, please feel free to contact Dr. Naviaux by email (naviaux@ucsd.edu) or cell phone (619-993-2904).

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References (Available upon request as PDF files from: naviaux@ucsd.edu)

1. Naviaux RK: Mitochondria and Autism. In The Neuroscience of Autism Spectrum Disorders. Edited by Buxbaum JD, Hof PR. Waltham, MA: Academic Press, Elsevier; 2012: 179-193

2. Naviaux RK: Oxidative shielding or oxidative stress? J Pharmacol Exp Ther 2012, 342:608-618.3. Naviaux RK: Metabolic features of the cell danger response. Mitochondrion 2013.4. Naviaux RK, Zolkipli-Cunningham Z, Nakayama T, Naviaux JC, Le T, Wang L, Schuchbauer M,

Rogac M, Li Q, Dugan LL, Powell S: Antipurinergic Therapy Corrects the Autism-Like Features in the Poly(IC) Mouse Model. PloS One 2013.

5. Naviaux JC, Schuchbauer MA, Li K, Wang L, Risbrough VB, Powell SB, Naviaux RK: Reversal of autism-like behaviors and metabolism in adult mice with single-dose antipurinergic therapy. Translational Psychiatry 2014, 4:e400.

6. Naviaux JC, Wang L, Li K, Bright AT, Alaynick WA, Williams KR, Powell SB, Naviaux RK: Antipurinergic therapy corrects the autism-like features in the Fragile X (Fmr1 knockout) mouse model. Molecular Autism 2015, 6:1.

AcknowledgmentsAll the research that led to these discoveries was supported by gifts from private citizens and foundations. Dr. Naviaux thanks the following people and foundations who have helped to support the UCSD Suramin Autism Study:

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UCSD Trailblazers—The 2011 Team that started this work. Front row (left to right): Lin Wang, MD, PhD; Zuela Zolkipli, MD; Laura Dugan, MD; Jane Naviaux, MD, PhD; Susan Powell, PhD; Tomohiro Nakayama, MD, PhD; Thuy Le, PhD; Back row (left to right): Mihael Rogac, MD, PhD; Michael Schuchbauer; Robert K. Naviaux, MD, PhD; Other team members (not pictured): Qingbo Tang, PhD.

• The UCSD Christini Fund• The Jane Botsford Johnson Foundation• The UCSD Mito 5k Walk and Roll• The Wright Family Foundation• The Lennox Foundation

• Autism Research Institute (ARI)• It Takes Guts Foundation• The Gupta Family and Satya Fund• The Rodakis Family