|Suramin has a molecular weight of 1297 g/mol. This makes it 3-4 times larger than most drugs, which are usually around 250-500 g/mol. The large size and structure of suramin make it a challenge to synthesize large amounts that meet the highest standards for pharmaceutical grade quality.|
Suramin is not approved for any use in humans in the United States except to handle the few cases of African sleeping sickness (trypanosomiasis) that have recently traveled from Africa. It is illegal to import suramin for human use without FDA approval. It is illegal to use suramin in humans for any purpose in the US except in FDA-approved clinical trials. Quoting from our 2017 publication, “Like many intravenous drugs, when administered improperly by untrained personnel, at the wrong dose and schedule, without careful measurement of drug levels and monitoring for toxicity, suramin can cause harm. Careful clinical trials will be needed over several years at several sites to learn how to use low-dose suramin safely in autism, and to identify drug–drug interactions and rare side effects that cannot currently be predicted. We strongly caution against the unauthorized use of suramin.”1 Homeopathic use of suramin is also illegal and untested.
Suramin was first synthesized by Bayer chemists in Germany in 1916. Suramin is not a natural product found anywhere in Nature. The synthesis of suramin was an extension of Paul Ehrlich’s pioneering work that showed that certain chemical dyes were concentrated in microbial parasites like the trypanosomes that cause African sleeping sickness. By achieving high concentrations inside the parasite, these dyes acted like “silver bullets” that could kill the parasites inside a cell while leaving the infected cells unhurt. The building blocks for the first dyes used by Ehrlich were derived from the petroleum and coal tar industries. Suramin has been used to treat African sleeping sickness (trypanosomiasis) for 100 years. Millions of adults and children have been treated with suramin in Africa. Serious side-effects were rare at steady-state blood levels less than about 100 µM for 4 weeks used to treat sleeping sickness unless the patients were seriously debilitated by famine or other diseases before starting treatment for sleeping sickness.
Figure 1. The blood levels of suramin used to treat ASD are 10-times lower than the doses used to treat sleeping sickness and 25-times lower than the doses needed to treat cancer. Lower doses cause fewer side-effects.
In the 1990s, cancer researchers began casting a wide net to discover old drugs with anti-cancer properties. Suramin has anticancer activity, but only when used at very high doses that produced steady-state blood levels of up to 250 µM for periods up to 6 months. These doses are not only toxic for cancer cells, but also produce many side-effects that are not seen when suramin is used at lower doses. The therapeutic window for suramin is about the same as aspirin. When used at the correct low-dose, both suramin and aspirin are safe and effective. However, increasing either drug to even 3-4 times above the normal therapeutic dose can cause side effects. The blood levels used to treat cancer are 25-times higher than those that were found to be effective in ASD (Fig 1).
Geoff Burnstock and purinergic signaling
ATP is made and used inside of cells as the universal currency of energy. Geoff Burnstock discovered that ATP outside the cell, extracellular ATP (eATP), had signaling properties like neurotransmitters in a brilliant series of experiments that date to the early 1970s. Over the next 25 years, 19 “purinergic” receptors were cloned and characterized that are regulated by purines like eATP, ADP, AMP, adenosine, pyrimidines like UTP, and related molecules. Purinergic receptors are widely expressed in every cell type in the body. In 1988, suramin was shown to be a competitive antagonist (inhibitor) of ATP signaling. This made suramin the oldest antipurinergic drug. To this day, suramin remains the only drug with antipurinergic properties that is approved for human use.
Mitochondrial changes in response to stress, injury, regeneration, and DNA mutations
Dr. Naviaux has been caring for children and adults with primary genetic forms of mitochondrial disease for over 25 years. He was a cofounder and former President of the Mitochondrial Medicine Society (MMS). He has conducted seminal translational research, moving discoveries made in the lab to the bedside to help patients. His lab discovered the cause of the oldest Mendelian form of mitochondrial disease—Alpers syndrome2,3. Alpers syndrome was first described in 1931 by Bernard Alpers. Dr. Naviaux’s discovery of its cause brought to a close a 70-year medical mystery.
In 2000, Naviaux and his team helped discover the first mitochondrial DNA (mtDNA) mutation that caused ASD. That mtDNA study created a paradox that flew in the face of conventional wisdom. Instead of causing a decrease in mitochondrial function, the mtDNA mutation that caused autism caused a 250% increase in complex I activity in mitochondria in ASD4. This led Dr. Naviaux to throw out the prevailing wisdom and explore new ways of making sense of these apparently contradictory facts. This study showed that forces outside of mitochondrial DNA were having a more profound effect on mitochondrial function than the “primary” mtDNA mutation.
From 2001-2010, the convergence of several apparently unrelated rivers of research set the stage for the cell danger response hypothesis. These research initiatives ranged from near-infrared light therapy, mitochondrial challenges to long-term space flight faced by NASA, the biocavity laser5-7, and the remarkable healing properties of the MRL mouse8 in what was called the “Mighty Mouse Project”.
The birth of the Cell Danger Response (CDR) hypothesis
In 2008, Dan Wright, the chairman of the board of the United Mitochondrial Disease Foundation (UMDF), called Dr. Naviaux on the phone. He said, “Autism is an epidemic. This is a national tragedy. I think you might be able to help. I’d like to send you to a meeting at NIH so you can start thinking about autism.” Within one month, Dr. Naviaux had the germ of an idea. Within 6 months he conceived the “purinergic theory of autism” that hypothesized that abnormalities in ATP signaling could be at root of the problem. He searched through thousands of drugs in the world pharmacopeia to find any that could be used to inhibit ATP signaling. He found only one drug: that drug was suramin. The next stages of research started with a simple question, “Could the antipurinergic properties of suramin be used to treat the core symptoms of autism spectrum disorder?” In April of 2011, Dr. Naviaux was awarded one of just three international “Trailblazer” awards by Autism Speaks to test this idea. The results of this mouse study helped crystallize a unifying theory that had the potential to explain the biology behind many chronic disorders.
Dr. Naviaux reviewed 70 years of autism research papers and books on the neuroscience of ASD. He first accepted as true all the well-conducted scientific reports of hundreds of genetic and environmental “causes” or triggers of chronic disease. But how could so many different factors each be a cause of ASD? The behavioral outcome of ASD was the same no matter what the specific cause in an individual child was found to be. There must be a common denominator at the root of the diversity of causes
Dr. Naviaux’s research led him to call this common denominator the cell danger response (CDR). A helpful metaphor to understand the CDR is that it is final common bell that can be rung by many different mallets—by many kinds of stress, by many different triggers. You can see a video about mitochondria, the cell danger response and suramin in autism at this link: https://www.youtube.com/watch?v=zIdUufy8Lks. See Figure 2 for a timeline for the development of the CDR hypothesis and its application to treat autism spectrum disorder.
|Figure 2. Timeline of Discovery. The discovery of the role of mitochondria and purinergic signaling in ASD involved the confluence of several independent rivers of biomedical and biophysical research. The CDR hypothesis provides a single unifying theory that can explain 70 years of facts about the genetics and environmental factors in ASD.|
Putting it all together—stages of the CDR make up the Healing cycle
Could the symptoms of autism be caused by a treatable metabolic syndrome? Could these symptoms be caused by getting stuck in a repeating loop of metabolism that is part of a normal, but transient response that has become dysregulated and persistent? Is all or most chronic disease ultimately traceable to abnormalities in mitochondrial function and ATP-related signaling, at least at it beginning? Can anti-purinergic drugs be used to restore normal function of the healing cycle and help patients get back on the road to recovery? These were just some of the questions that needed to be answered. In the course of caring for children with primary mitochondrial disease, Dr. Naviaux noticed that once children suffer a neurometabolic setback, they then have to fight back over weeks or months to heal and to regain what they have lost.
Dr. Naviaux noticed that the classical stages of healing that have been studied for over 150 years would need a minimum of 3 different kinds of mitochondria to progress through each stage. The 5 classical stages of healing are: hemostasis, inflammation, proliferation, remodeling, and recovery. Healing is a process not a state. Healing is a circle with a beginning, middle, and end. Dr. Naviaux started by calling this circle the healing cycle that brings us back from injury to recovery and health.
After combining the basic research results about healing in the MRL mouse with clinical experience with children with primary mitochondrial disease it became clear that there were also 3 sequential stages of the CDR, and that each stage was defined by changes in specific mitochondrial functions. Healing was made possible by regulating the creation and transformation—the cytoecological succession—of 3 differently polarized types of mitochondria. CDR1 requires M1 mitochondria and supports hemostasis, innate immunity, and inflammation. CDR2 requires M0 mitochondrial and supports proliferation, adaptive immunity, and regeneration. CDR3 requires M2 mitochondria and supports remodeling, differentiation, and recovery. Finally, the return to full health after the healing cycle is completed requires choreographed changes in mitochondria to respond to circadian cues that are coordinated by the brain. Each of these biological facts was used to construct the healing cycle (Fig 3).
|Figure 3. The health, healing and aging cycles. eATP is released by every stressed cell. When the stress is enough to cause injury, enough eATP is released to trigger the cell danger response (CDR). Three different kinds of mitochondria are needed at different times in the healing cycle: M1 for innate immunity and inflammation, M0 for proliferation and adaptive immunity, M2 for differentiation and remodeling.|
A drug Renaissance on the horizon
Dr. Naviaux frequently says, “Our work is not about suramin, or any other single drug. Our research is aimed at discovering a completely new way to think about the cause and treatment of autism and dozens of other complex chronic disorders.” Suramin is just the first in a new class of drugs that will be synthesized to help regulate purinergic signaling. Unfortunately, the importance of ATP and related metabolites in regulating the symptoms of disease and the stages of the healing cycle has only recently been recognized. Each of the 19 different purinergic receptors have different functions, and new roles for specific P2Y, P2X and P1 receptors are still being discovered.
New antipurinergic drugs (antagonists) and propurinergic drugs (agonists) are now being synthesized and tested but few have yet completed Phase 3 clinical trials and been approved. The exceptions to this are the P2Y12 inhibitors like Plavix, which inhibit ADP-stimulated platelet aggregation. Several P2Y12 inhibitors are approved to treat heart disease, but other purinergic receptors are likely to be more important in ASD. We were lucky that suramin is a non-selective inhibitor of most of the known types of purinergic receptors. Now new drugs need to be made and studied individually that are selective for just one or two of the 19 purinergic receptors .
The goal will be to find specific therapies that can bring patients with chronic conditions through the stages of healing discussed above. We envision creating a shelf-full of related drugs that can be matched to each patient and each disease. It is our hope that each success will lay the groundwork for more successes, and soon there will be a drug Renaissance that will create dozens of new tools that doctors can use to regulate the cell danger response and help patients heal.
Systematic clinical trials
Prospectively randomized, double blind, placebo-controlled clinical trials are the gold standard for building medical knowledge. Dr. Naviaux believes that many different disorders share abnormalities in the CDR and the healing cycle. Diverse symptoms can be produced when the healing cycle is blocked by persistent activation of the CDR. As new antipurinergic drugs are developed, they will each need to be tested in rigorously designed clinical trials. Some disorders with symptoms caused or worsened by abnormalities in purinergic signaling may include:
- Autism spectrum disorder (ASD)
- Chronic Fatigue Syndrome (ME/CFS)
- Post-treatment Lyme disease syndrome (PTLDS)
- Fragile X syndrome
- Treatment-Resistant Major Depressive Disorder with suicidal ideation
- NARP, Leigh, and other Primary Mitochondrial Diseases
- Post-traumatic stress syndrome (PTSD)
- Chronic pain syndromes in children and adults
- Drug addiction recovery therapy, e.g., opioid addiction with hyperkatifeia
- Amyotrophic lateral sclerosis (ALS)
- Gulf War Illness (GWI)
- Treatment-resistant, post-COVID long-haulers with multisystem chronic fatigue syndrome
- Severe Obsessive-Compulsive Disorder (OCD)
- Lesch-Nyhan Syndrome (HPRT deficiency)
- Pediatric acute-onset neuropsychiatric syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS)
- Landau-Kleffner epilepsy
- Tourette’s syndrome
- As an additive in organ transplant media to improve organ survival, and decrease inflammation and rejection
- Generalized anxiety disorder (GAD)
- Subacute-chronic traumatic brain injury (TBI)
- Small fiber polyneuropathy (SFPN)
- Postural orthostatic tachycardia syndrome (POTS)/Dysautonomia
- Subacute spinal cord injury
- Early Parkinson disease
- Early Alzheimer dementia
Suramin was shown to be safe and effective in three preclinical models of ASD9-11 and a small human clinical trial1 in peer-reviewed papers published between 2013-2017. Further development of suramin was passed from Dr. Naviaux’s university research lab to the private sector. Dr. Naviaux no longer has any control over the next clinical studies or the priorities of different diseases for testing, although he is recommending ASD, ME/CFS, and post-treatment Lyme disease (PTLDS) as a few of the top candidates.
Two private companies are now developing the manufacturing pipeline to make suramin for future clinical trials. These are Kuzani (https://kuzani.com) and Paxmedica (https://www.paxmedica.com). Earlier this year, Paxmedica announced they were able to confirm in a larger scale trial the results of our SAT1 trial – that suramin was safe and effective in ASD (https://www.paxmedica.com/news). Suramin improved all the core symptoms of ASD in a Phase 2b clinical trial in 50 children with ASD in Africa. Follow-up studies are in active development. The next clinical trials in autism are scheduled for 2022, once the COVID risk is low again.
- Foundation papers for the CDR hypothesis from the past 50 years (PDF)
- The 1st mtDNA mutation to cause autism. PMID: 10868777
- Metabolic features of the cell danger response (CDR). PMID: 23981537
- Antipurinergic therapy in the MIA mouse model. PMID: 23516405, 24937094
- Antipurinergic therapy in the Fragile X mouse model. PMID: 25705365
- Purinergic coordination of synaptic networks. PMID: 16210541
- Purine-driven CDR in children with ASD PMID: 27904735
- The suramin autism treatment 1 (SAT1) trial. PMID: 28695149, 29253638
- Naviaux, R.K., et al. Low-dose suramin in autism spectrum disorder: a small, phase I/II, randomized clinical trial. Ann Clin Transl Neurol 4, 491-505 (2017).
- Naviaux, R.K. & Nguyen, K.V. POLG Mutations Associated with Alpers’ Syndrome and Mitochondrial DNA Depletion. Annals of neurology 55, 706-712 (2004).
- Naviaux, R.K., et al. Mitochondrial DNA polymerase gamma deficiency and mtDNA depletion in a child with Alpers’ syndrome. Annals of neurology 45, 54-58 (1999).
- Graf, W.D., et al. Autism associated with the mitochondrial DNA G8363A transfer RNA(Lys) mutation. Journal of child neurology 15, 357-361 (2000).
- Gourley, P.L., et al. Reactive biomolecular divergence in genetically altered yeast cells and isolated mitochondria as measured by biocavity laser spectroscopy: rapid diagnostic method for studying cellular responses to stress and disease. J Biomed Opt 12, 054003 (2007).
- Gourley, P.L. & Naviaux, R.K. Optical phenotyping of human mitochondria in a biocavity laser. IEEE J. Selected Topics Quantum Electronics 11, 818-826 (2005).
- Gourley, P.L., et al. Ultrafast nanolaser flow device for detecting cancer in single cells. Biomed Microdevices 7, 331-339 (2005).
- Naviaux, R.K., et al. Retained features of embryonic metabolism in the adult MRL mouse. Molecular genetics and metabolism 96, 133-144 (2009).
- Naviaux, J.C., et al. Antipurinergic therapy corrects the autism-like features in the Fragile X (Fmr1 knockout) mouse model. Molecular autism 6, 1 (2015).
- Naviaux, J.C., et al. Reversal of autism-like behaviors and metabolism in adult mice with single-dose antipurinergic therapy. Translational psychiatry 4, e400 (2014).
- Naviaux, R.K., et al. Antipurinergic Therapy Corrects the Autism-Like Features in the Poly(IC) Mouse Model. PloS one 8, e57380 (2013).