DAVIS—A 16-member team of international researchers is targeting autism spectrum disorder (ASD) to see if a drug discovered in the Bruce Hammock lab at the University of California, Davis, can support efforts to control or block the neurodevelopmental disorder.

ASD, which impacts the nervous system, affects 1 percent of the U.S. population or 62.2 million globally. An estimated 64 percent and 91 percent of the population are at risk genetically.

The researchers' latest paper, “Maternal Glyphosate Exposure Causes Autism-Like Behaviors in Offspring through Increased Expression of Soluble Epoxide Hydrolase,” appears in the current edition of the Proceedings of the National Academy of Sciences (PNAS). Glyphosate is a broad-spectrum systemic herbicide and crop desiccant used to kill broadleaf weeds and grasses that compete with agricultural crops. 

“In the research of autism, brain-gut-microbiota axis plays a key role in ASD from human studies,” said lead researcher and neurobiologist Kenji Hashimoto of the Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan. “Accumulating evidence suggests abnormal composition of gut microbiota in subjects with autism. In this study, we found abnormal composition of gut microbiota in offspring after maternal glyphosate exposure. Thus, exposure of glyphosate during pregnancy may cause abnormal composition of gut microbiota in offspring, resulting in the risk for autism.' 

The drug discovered in the Hammock lab inhibits sEH, a natural enzyme that regulates epoxy fatty acids, “which control blood pressure, fibrosis, immunity, tissue growth, depression, pain and inflammation to name a few processes,” said co-author Hammock, a distinguished professor with a joint appointment in the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center. Human clinical trials underway to see if the non-addictive drug relieves chronic pain. 

“It is critical to appreciate that mouse models are not absolutely predictive of the human situation,” Hammock said.“Similarly, maternal immune stress is simply a model that gives behavioral changes in the offspring.  That said, it is a relevant model of abnormalities in mental development in the offspring.   This is a widely used model of the effect of maternal stress on the next generation that has been established in many species, including nonhuman primates. Sadly, maternal stress was shown tightly associated with the mental state of human children as well.” 

“Our paper implies no human health risk,” Hammock pointed out. “This was a very high dose of glyphosate, actually close to acute toxicity. This is stress, and the bioassay is the effect of stress in the dam on the pups. The paper shows that with massive doses of glyphosate to the dams for long periods in the maternal stress model that glyphosate causes behavioral abnormalities in the pups.”

“Such studies are important to generate hypotheses of environmental risk,” said Hammock, who meshes his expertise in chemistry, toxicology, biochemistry and entomology, in his 50-year research to find a non-addictive drug to control chronic pain. “Because we only saw maternal immune stress at exceptionally high doses of glyphosate, our data fail to support the hypothesis that glyphosate exposure causes autism with expected dietary, environmental or even occupational exposure.”

The research drew financial support from the Japan Society for the Promotion of Science (to Hashimoto); and the National Institute of Environmental Health Sciences (NIEHS) River Award (to Hammock), and NIEHS Superfund Program (to Hammock). Hammock has directed the UC Davis Superfund Program for nearly four decades.

The Hashimoto-directed Chiba group has shown that these drug candidates prevent and even reverse a variety of chronic diseases of the central nervous system in mice and human cells including ASD like behaviors.   

The 16 co-authors include Hammock lab researchers Jun Yang, Sung Hee Hwang and Debin Wan. 

Yang said that the researchers “hypothesized that the role of the sEH is important in the pathogenesis of ASD in offspring after maternal glyphosate exposure based on our previous finding that sEH plays a key role in the development of ASD-like behavioral abnormalities in juvenile offspring after maternal immune activation (MIA), a prenatal environmental factor.”

Said Hwang: “Some epidemiological studies suggest an association between glyphosate use in agriculture and increases in autism like disorders. The doses we used in mice were so high that we fail to support glyphosate epidemiological associations between the herbicide use and the cause ASD-like behaviors. 

The PNAS abstract:

“Epidemiological studies suggest that exposure to herbicides during pregnancy might increase risk for autism spectrum disorder (ASD) in offspring. However, the mechanisms underlying the risk of ASD by herbicides such as glyphosate remain unclear. Soluble epoxide hydrolase (sEH) in the metabolism of polyunsaturated fatty acids is shown to play a key role in the development of ASD in offspring after maternal immune activation. Here, we found ASD-like behavioral abnormalities in juvenile offspring after maternal exposure to high levels of formulated glyphosate. 

“Furthermore, we found increases in sEH in the prefrontal cortex (PFC), hippocampus, and striatum of juvenile offspring and oxylipin analysis showed decreased levels of epoxy-fatty acids such as 8(9)-EpETrE in the blood, PFC, hippocampus, and striatum of offspring after maternal glyphosate exposure, supporting increased activity of sEH in the offspring. Moreover, we report abnormal composition of gut microbiota and short chain fatty acids in fecal samples of juvenile offspring after maternal glyphosate exposure. Interestingly, oral administration of TPPU (an sEH inhibitor) to pregnant mothers from E5 to P21 prevented ASD-like behaviors such as social interaction deficits and increased grooming time in the juvenile offspring. These findings suggest that maternal exposure to high levels of glyphosate causes ASD-like behavioral abnormalities and abnormal composition of gut microbiota in juvenile offspring, and that increased activity of sEH might play a role in ASD-like behaviors in offspring after maternal glyphosate exposure. Therefore, sEH may represent a target for ASD in offspring after maternal stress from occupational exposure to contaminants.  

“Maternal exposure to high levels of the herbicide glyphosate may increase the risk for autism spectrum disorder (ASD) in offspring; however, the underlying mechanisms remain largely unknown. Maternal glyphosate exposure during pregnancy and lactation caused ASD-like behavioral abnormalities and abnormal composition of gut microbiota in murine male offspring. Soluble epoxide hydrolase (sEH) in the brain of offspring after maternal glyphosate exposure was higher than controls. Treatment with an sEH inhibitor from pregnancy to weaning prevented the onset of ASD-like behavioral abnormalities in offspring after maternal glyphosate exposure. The glyphosate exposures used here exceed any reasonable dietary, environmental or occupational exposure, but they indicate that increased sEH plays a role in ASD-like behaviors in offspring.”

 

(See commentary published in journal Cancer Metastasic and Reviews at https://rdcu.be/b33IN)

A drug discovered in the Bruce Hammock laboratory at the University of California, Davis may control the body's inflammatory response to COVID-10 and could help patients recover, according to a nine-member research team's newly published commentary in the journal Cancer Metastasis and Reviews, Springer Nature publishing group.  

“COVID-19 results in excessive inflammation and a cytokine storm caused by the human body's reaction to the SARS-CoV-2 virus,” said lead author Dipak Panigrahy, a Harvard University physician and researcher who collaborates with the Hammock laboratory.

“Controlling the body's inflammatory response to COVID-19 will likely be as important as anti-viral therapies or a vaccine,” Panigraphy said. “Stimulation of inflammation resolutions via pro-resolution lipid mediators that are currently in clinical trials for other inflammatory diseases is a novel approach to turning off the inflammation and preventing the cytokine storm caused by COVID-19.”

 “We propose that this drug will alleviate the cytokine storms that occur when the immune system is overwhelmed, when the patient is battling for survival,” Panigrahy said.

The drug is an inhibitor to the soluble epoxide hydrolase (sEH) enzyme, a key regulatory enzyme involved in the metabolism of fatty acids.   

Editor-in-Chief and Professor Kenneth Honn selected their commentary, “Inflammation Resolution: a Dual-Pronged Approach to Averting Cytokine Storms in COVID-19?,” as the top paper of the month. The work is based on more than 40 years of eicosanoid research from the Hammock lab and more than 40 years of eicosanoid research from the Charles Serhan lab at Harvard Medical School.

Pioneering research from the Panigrahy and Hammock labs shows that cell debris from surgery, chemotherapy, toxin exposure and other causes lead to production of high levels of pro-inflammatory mediators commonly called cytokines.

 “The tremendous cell destruction caused by COVID in the lungs leads to cell debris, activating a series of events leading to the cytokine storm and mortality,” Panigrahy said. “Controlling inflammation is key to resolving any intense infection, and thus, desired treatments should modulate and particularly resolve inflammation.”

“A rapid immune response is critical to controlling this virus,” Panigrahy emphasized.

 “We believe it holds promise to combat the inflammation involved with this disease,” said co-author Hammock, a UC Davis distinguished professor who holds a joint appointment with the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center.  “It hit me in March that what we really need to do is not so much block cytokines as to move upstream to modulate them and resolve them rather than block inflammation.”

 “We can increase the concentration of natural pro-resolving mediators termed EETs which act on a biological system to produce other pro-resolution mediators which modulate inflammation and actively resolve the process,” explained Hammock, who founded the Davis-based company EicOsis Human Health LLC, to bring the inhibitor to human clinical trials, which are underway in Texas.

Physician-researcher Irene Cortés-Puch of UC Davis and EicOsis

Co-authors include three physician-researchers: Charles Serhan, Patricia Sime of the Division of Pulmonary and Critical Care Medicine, Virginia Commonwealth University, Richmond, and Irene Cortés-Puch of the Division of Pulmonary, Critical Care and Sleep Medicine, UC Davis Medical Center, and an EicOsis project scientist.

 “It is this resolution of inflammation and the subsequent repair that is critical to restore patient health,” said Serhan, whose studies with collaborator Sime show that immune resolution and repair are active processes in the lungs and other tissues. What drives the process, Serhan said, is the production of specific pro-resolving agents (SPMs). 

Puch, who did research at the National Institutes of Health (NIH) on acute respiratory distress syndrome (ARDS) and sepsis, said the drug should be effective in treating ARDS, which she defined as “a respiratory failure characterized by rapid onset of widespread inflammation in the lungs and common among seriously ill COVID-19 patients.”

“We think there are a series of control systems that fail to modulate the patient's response in COVID,” Cortés-Puch said. “The severe outcomes in some patients from the virus infection often are attributed to the cytokine storm, and blocking these cytokines represents a major therapeutic effort, which so far has failed.  Our view is that we can move several steps upstream and control the cytokine storm not just at the level of individual cytokines and in doing so, we can  encourage resolution of inflammation. In doing so, we can encourage resolution of inflammation.” 

Said William Schmidt, EicOsis vice president of clinical development: “Our drug candidate has not caused any adverse effects at high doses in diabetic-hypertensive patients.  Since this soluble epoxide hydrolase inhibitor acts upstream to down-regulate the eicosanoid and the cytokine storm, we are optimistic that it can help patients.”  The Federal Drug Administration recently granted another EicOsis drug candidate a “fast track” status.

 “In the meantime, we are looking at blood markers through time that are helping us to see the order of events leading from the original virus infection to the severe organ damage and cytokine storm that occurs in the most severe cases,” said Cindy McReynolds, a UC Davis doctoral student in pharmacology/toxicology, and EicOsis project manager.

Hammock said the UC Davis team began researching cytokine storms 16 years ago in projects based on the thesis of former doctoral student Kara Schmelzer. Now the UC Davis and Harvard scientists are targeting COVID-19.

Said Hammock: “In March, Cindy, Irene and I worked on a grant proposal with a group of scientists from the European Union to combine an anti-viral agent with an anti-inflammatory agent.”

“It hit me at that time,” Hammock reiterated, “that what we really need to do is not so much block cytokines as to move upstream to modulate them and resolve rather than block inflammation.  We are lucky to have been working on such a resolving agent at UC Davis for decades.”

Other co-authors of the paper are Molly Gilligan and Allison Gartung of the Panigrahy lab; Sui Huang of the Institute for Systems Biology, Seattle; and Richard Phipps, independent scholar, Richmond, Va.

Much of the research was funded by NIH grants, including a National Institute of Environmental Health Science (River Award) to Hammock. The Panigrahy laboratory is generously supported by the Credit Unions Kids at Heart Team; the C.J. Buckley Pediatric Brain Tumor Fund; and the Joe Andruzzi Foundation.

The abstract:

Severe coronavirus disease (COVID-19) is characterized by pulmonary hyper-inflammation and potentially life-threatening “cytokine storms”. Controlling the local and systemic inflammatory response in COVID-19 may be as important as anti-viral therapies. Endogenous lipid autacoid mediators, referred to as eicosanoids, play a critical role in the induction of inflammation and pro-inflammatory cytokine production. SARS-CoV-2 may trigger a cell death (“debris”)-induced “eicosanoid storm”, including prostaglandins and leukotrienes, which in turn initiates a robust inflammatory response. A paradigm shift is emerging in our understanding of the resolution of inflammation as an active biochemical process with the discovery of novel endogenous specialized pro-resolving lipid autacoid mediators (SPMs), such as resolvins. Resolvins and other SPMs stimulate macrophage-mediated clearance of debris and counter pro-inflammatory cytokine production, a process called inflammation resolution. SPMs and their lipid precursors exhibit anti-viral activity at nanogram doses in the setting of influenza without being immunosuppressive. SPMs also promote anti-viral B cell antibodies and lymphocyte activity, highlighting their potential use in the treatment of COVID-19. Soluble epoxide hydrolase (sEH) inhibitors stabilize arachidonic acid-derived epoxyeicosatrienoic acids (EETs), which also stimulate inflammation resolution by promoting the production of pro-resolution mediators, activating anti-inflammatory processes, and preventing the cytokine storm. Both resolvins and EETs also attenuate pathological thrombosis and promote clot removal, which is emerging as a key pathology of COVID-19 infection. Thus, both SPMs and sEH inhibitors may promote the resolution of inflammation in COVID-19, thereby reducing acute respiratory distress syndrome (ARDS) and other life-threatening complications associated with robust viral-induced inflammation. While most COVID-19 clinical trials focus on “anti-viral” and “anti-inflammatory” strategies, stimulating inflammation resolution is a novel host-centric therapeutic avenue. Importantly, SPMs and sEH inhibitors are currently in clinical trials for other inflammatory diseases and could be rapidly translated for the management of COVID-19 via debris clearance and inflammatory cytokine suppression. Here, we discuss using pro-resolution mediators as a potential complement to current anti-viral strategies for COVID-19.

The Food and Drug Administration has granted a fast-track designation to a non-narcotic drug candidate being developed by EicOsis LLC, a pharmaceutical company founded by UC Davis distinguished professor Bruce Hammock to treat chronic pain in humans and companion animals.

“The fast-track process is designed to facilitate the development and expedite the review of new therapies to treat an unmet medical need in the treatment of a serious condition,” said EicOsis founder and CEO Hammock, who holds a joint appointment with the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center.

“This designation will enable us to have early and frequent communication with the FDA throughout the drug development and review process,” Hammock said, “and this often leads to faster drug approval and patient access.”

The drug candidate, known as EC5026, targets a novel pathway to block the underlying cause of certain types of pain. Described by EicOsis, a Davis-based company, as a “novel, non-opioid and oral therapy for neuropathic and inflammatory pain,” it inhibits the soluble epoxide hydrolase (sEH) enzyme, a key regulatory enzyme involved in the metabolism of fatty acids. UC Davis recently licensed certain patents supporting the underlying technology exclusively to EicOsis.

The FDA granted EC5026, an investigational new drug (IND) clearance in October 2019. It is currently the subject of a Phase 1a clinical trial in healthy human volunteers. Phase 1b clinical trials are scheduled to begin this fall.

Earlier studies showed that the EicOsis-developed inhibitors reduce inflammatory and neuropathic pain in rodents, horses, dogs and cats, and without the addictive effects associated with opioids or multiple side effects of nonsteroidal anti-inflammatory drugs (NSAIDS).

Hammock said the successful fast-track application is the work of three EicOsis team members: clinical scientist Irene Cortés-Puch, a critical care medicine physician and researcher; project manager Cindy McReynolds, a UC Davis doctoral student in pharmacology and toxicology; and vice president of clinical development William Schmidt, who has focused his entire professional career on developing novel pain medicines.

“Without them, we would not have had the fast track,” Hammock said. “They did a superb job.”

Cortés-Puch worked in Spain in intensive care and emergency units, where she treated patients with acute respiratory distress syndrome (ARDS), and then accepted a position at the National Institutes of Health to study sepsis and ARDS, now targeted as the killer of COVID-19 patients. ARDS is respiratory failure characterized by rapid onset of widespread inflammation in the lungs.

“Listening to patient stories and working with pain management specialists has given me an understanding of the urgent need for new pain medications,” said McReynolds. “It's inspiring to work with such an amazing team in addressing this critical problem and the Fast Track status will allow us to advance this potential treatment as quickly as possible.”

Said Schmidt: “FDA's decision to grant the fast track designation to EC5026 is an important milestone in our ongoing efforts to develop a safe and effective new approach for pain management. We look forward to working closely with the FDA to optimize the development of this novel, non-opioid drug candidate for neuropathic pain.”

Dr. Scott Fishman, vice chair of the UC Davis School of Medicine's Department of Anesthesiology and Pain Medicine, who is not involved with EicOsis, commented: “It is not a coincidence that this FDA fast-track designation comes as the United States is addressing the enormous problem of opioid abuse and is seeking safer and more effective treatment for pain. This FDA designation reflects the substantial promise of this new and novel analgesic drug.”

Nearly 16 million Americans suffer from neuropathic pain, according to the National Institutes of Health (NIH). Physicians often prescribe opioids, which can lead to misuse, addiction and intolerance. Alternatively, the EicOsis drug is an effective, non-addictive drug for pain management, Hammock said.

Every day more than 130 Americans die from opioid overdose, according to the National Institute of Drug Abuse. The total economic burden of prescription opioid misuse alone in the United States is estimated at $78.5 billion a year. That includes the costs of health care, lost productivity, addiction treatment, and criminal justice involvement.

“I know my patient is suffering and sadly I know I've gone through everything available to help,” said rheumatologist Laura Carbone, professor and division chief of rheumatology in the Department of Medicine, Medical College of Georgia, Augusta University. “I struggle, we both struggle, to find a way to make today better as we both hope for something better to come that will really help. That is the daily reality of pain.” She is not involved with EicOsis.

NIH has financially supported the discovery and development of EC5026 and its advancement into clinical trials through the Blueprint Neurotherapeutics Network (BPN) of the NIH Blueprint for Neuroscience Research and the NIH's Helping to End Addiction Long-term (HEAL) Initiative.

Hammock, a member of the UC Davis faculty since 1980, received his doctorate in entomology and toxicology from UC Berkeley. Nationally recognized for his achievements, he is a fellow of the National Academy of Inventors, which honors academic invention and encourages translations of inventions to benefit society. He is a member of the U.S. National Academy of Sciences, a fellow of the Entomological Society of America, and the recipient of scores of awards, including the first McGiff Memorial Awardee in Lipid Biochemistry; and the Bernard B. Brodie Award in Drug Metabolism, sponsored by the America Society for Pharmacology and Experimental Therapeutics.

The UC Davis professor traces the history of his enzyme research to 1969 during his graduate student days in the John Casida laboratory, UC Berkeley.  Hammock was researching insect developmental biology and green insecticides when he and colleague Sarjeet Gill, now a distinguished professor at UC Riverside, discovered the target enzyme in mammals that regulates epoxy fatty acids.

“My research led to the discovery that many regulatory molecules are controlled as much by degradation and biosynthesis,” Hammock said. “The epoxy fatty acids control blood pressure, fibrosis, immunity, tissue growth, depression, pain and inflammation to name a few processes.”

Bruce Hammock today

The legendary Bruce Hammock, UC Davis distinguished professor who holds a joint appointment with the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center--is featured in the current edition of American Entomologist.

Entomologist Marlin Rice, a past president of the Entomological Society of America (ESA), penned the piece, titled "Bruce D. Hammock: Science Should Be Fun!"

Wrote Rice: "Bruce D. Hammock is widely known for his groundbreaking research in insect physiology, toxicology, pharmacology, and experimental therapeutics. Early contributions were in fundamental regulatory biology, development of both small molecules and recombinant viruses as environmentally friendly pesticides, and the application of accelerator mass spectrometry to biological science. His laboratory pioneered the use of immunoassay for the analysis of human and environmental exposure to pesticides and other contaminants.His laboratory provides graduate training that is diverse in disciplines and research areas. He recently formed a company, EicOsis, to develop an orally active non-addictive drug for inflammatory and neuropathic pain for humans and companion animals."

Hammock, who joined the UC Davis faculty in 1980 from UC Riverside, has directed the UC Davis Superfund Research Program (funded by the National Institutes of Health's National Institute of Environmental Health Sciences) for nearly four decades. He is a member of the National Academy of Sciences, and a fellow of the National Academy of Inventors and ESA.

A native of Little Rock, Ark., Bruce received his bachelor's degree in entomology (with minors in zoology and chemistry) magna cum laude from Louisiana State University, Baton Rouge, in 1969. He received his doctorate in entomology-toxicology from UC Berkeley in 1973 with John Casida at UC Berkeley. Hammock served as a public health medical officer with the U.S. Army Academy of Health Science, San Antonio, and as a postdoctoral fellow at the Rockefeller Foundation, Department of Biology, Northwestern University, Evanston, Ill.

Read the feature story here.

Some Related Links:

• Bruce Hammock and EicOsis, Innovator of the Year
• Bruce Hammock Receives $6 Million Grant
• Bruce Hammock Water Balloon Battle: 15 Minutes of Aim
• Research Could Lead to Drug to Prevent or Reduce Autism, Schizophrenia 
• Hammock Lab Union Draws 100 Scientists from 10 Countries
• Bruce Hammock: Scientist Extraordinaire

(Editor's Note: Thanks to Lisa Junker, ESA's director of publications, communications and marketing, who reached out to "our publishers at Oxford" to grant free community access to this feature story in American Entomologist)