Special Focus on Neuroscience and Neurology

Looking at recent cutting-edge research in potential therapeutics for neurological conditions, plus additional news on autism breakthroughs, addiction treatment and more

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At the forefront of neurology
A quick look at some recent cutting-edge work in the neuroscience arena
If next month’s Special Report on Neuroscience is the gourmet meal with a particular culinary focus, consider this month’s special focus section the sampler platter of various world cuisines. And first on that menu, we wanted to cover some slightly-off-the-beaten-path topics that recently made the news rounds, beginning with what could be considered irony or synergy depending on your point of view: Artificial intelligence being put to work on human neurological concerns.
Specifically, BullFrog AI Inc., which focuses on artificial intelligence and clinical data analytics services, and the Lieber Institute for Brain Development, an independent, not-for-profit medical research institute working to accelerate efforts to find new cures for developmental brain disorders, recently announced a joint collaboration to apply BullFrog AI’s proprietary artificial intelligence platform to analyze antipsychotic drug responses.
Choosing and dosing antipsychotic drugs represents one of the most challenging areas for clinicians and patients alike, the partners note, with patients experiencing wildly differing responses to the different drugs on the market, particularly when it comes to the side effects: “The selection of the best drug for the particular patient then becomes a matter of educated guesswork, potentially causing distress and even harm to patients and those around them.”
To help turn the tide on that, BullFrog AI will utilize its proprietary artificial intelligence platform to analyze large multifactorial clinical data sets from patients who received antipsychotic medication with an eye toward making it possible to better predict which patients respond best to which medications.
“We are excited to partner with BullFrog AI on this challenging clinical problem,” said Dr. Kristin Bigos, an investigator at the Lieber Institute for Brain Development. “Until now there has been no effective alternative to the trial-and-error approach for matching patients to the best antipsychotic. Being able to understand and predict a priori which drugs will work best for which patients would be of tremendous benefit to both patients and the physicians that serve them.”
The bfLEAP analytics engine is purpose-built for analyzing extremely large and complex data sets, and it reportedly has demonstrated 99.9-percent accuracy in predicting the right targets across multiple data sets. The key to its success is the artificial learning, which requires no domain expertise, BullFrog AI maintains—instead, it uses unsupervised machine learning coupled with the world’s largest collection of analytical models, all operating in parallel.
And it’s not just clinical treatment with approved drugs where this effort could help, but also potentially in clinical trials.
“bfLEAP represents a true leap forward in terms of our ability to understand what is going on in a complex clinical setting,” said Vin Singh, CEO of BullFrog AI. “For the first time, we are able to analyze massive, multifactorial clinical datasets and determine the root cause of the observed clinical outcomes. Using our platform, we can examine clinical trial data and identify relationships between patient-specific factors and clinical response, which may aid in predicting clinical trial outcomes in the future. The potential impact of this type of information for the pharmaceutical industry is enormous, both in terms of the reduced cost and increased revenue from failed drugs as well as the positive impact on patients.”
New insight on potential neurological cell therapies
New research from Sanford Burnham Prebys Medical Discovery Institute (SBP) is reportedly among the first to describe how an mRNA modification impacts the life of neural stem cells (NSCs). The study, titled “N6-methyladenosine RNA modification regulates embryonic neural stem cell self-renewal through histone modifications” and published in Nature Neuroscience, reveals a novel gene regulatory system that may advance stem cell therapies and gene-targeting treatments for neurological diseases such as Alzheimer’s disease, Parkinson’s disease and mental health disorders that affect cognitive abilities.
“Being able to maintain viable stem cells in the brain could lead to regenerative therapies to treat injury and disease,” says Dr. Jing Crystal Zhao, an assistant professor at SBP. “Our study reveals a previously unknown but essential function of an mRNA modification in regulating NSC self-renewal. As NSCs are increasingly explored as a cell replacement therapy for neurological disorders, understanding the basic biology of NSCs—including how they self-renew—is essential to harnessing control of their in-vivo functions in the brain.”
NSCs are progenitor cells present not only during embryonic development but also in the adult brain. NSCs undergo a self-renewal process to maintain their population, as well as differentiate to give rise to all neural cell types: neurons, astrocytes and oligodedrocytes.
The SBP study focused on the self-renewal aspect of NSCs. Using knockout mice for the enzyme that catalyzes the m6A modification, Zhao’s team found that m6A modification maintains NSC pool by promoting proliferation and preventing premature differentiation of NSCs. Importantly, the researchers found that m6A modification regulates this by regulating histone modifications.
The importance in this lies in the fact that histones play an important part of turning genes on or off—these proteins bind and package DNA to either “hide” a gene from the cell’s protein-making machinery (off) or “loosen up” DNA for gene exposure (on).
“Our findings are the first to illustrate cross-talk between mRNA and histone modifications, and may lead to new ways to target genes in the brain,” says Zhao. “Conceptually, we could use the modification, which is the methylation of adenosine residues, as a ‘code’ in mRNA to target histone modifications to turn genes on or off.”
As SBP notes, drugs that can alter histones are far from a new concept in psychiatric and neurological care—the problem is they are often not very specific and affect the entire genome.
“Our current study addressed the interaction between mRNA and histone modification in a genome-wide scale. In the future, we plan to study such interaction on a gene-by-gene basis. Ultimately, by modulating mRNA modification and its interacting histone modifications at a specific genomic region, we hope to correct aberrant gene expression in brain disorders with precision,” explains Zhao.
Tamping down Tourette
Finally, looking at an underserved area of neurological therapy, Therapix Biosciences Ltd., a specialty clinical-stage pharmaceutical company focusing on the development of cannabinoid-based treatments, announced early in February that it has held a pre-Investigational New Drug (pre-IND) communication with the U.S. Food and Drug Administration (FDA) to discuss the regulatory pathway for the development of THX-110 for the treatment of Tourette syndrome.
“Following this informative communication with the FDA, we can confirm that the IND for THX-110 will not require any additional nonclinical data to support a Phase 2b study in the United States. We intend to submit the NDA via the 505(b)(2) pathway. We believe that this enables us to continue our clinical program with minimum risk, which is consistent with our platform of repurposing and reformulating for unmet and underserved needs for Tourette syndrome. We expect to evaluate THX-110 in a Phase 2b clinical study in the second quarter of 2018,” said Dr. Adi Zuloff-Shani, chief technology officer at Therapix.
THX-110 has the potential to become the first cannabinoid-based medicine for Tourette syndrome, which would be a big switch from the only two FDA-approved options now, both of which are antipsychotic agents: Haloperidol and Pimozide.
“However, these drugs are also often associated with significant adverse events,” said Dr. Ascher Shmulewitz, chairman and interim CEO of Therapix. “If approved, THX-110 could provide people who suffer from Tourette syndrome with a treatment alternative to the antipsychotic agents.”
THX-110 is a combination drug candidate for the treatment of Tourette syndrome and obstructive sleep apnea that is based on two components: dronabinol (an FDA-approved synthetic analog of ∆9-tetrahydracannabinol (THC, which is the psychoactive molecule in the cannabis plant) and palmitoylethanolamide (PEA, an endogenous fatty acid amide that belongs to the class of nuclear factor agonists, which are proteins that regulate the expression of genes). The combination of THC and PEA may induce a reaction known as the “entourage effect.” The basic tenet of the entourage effect is that cannabinoids work together, or possess synergy, and affect the body in a mechanism similar to the body’s own endocannabinoid system, which is a group of molecules and receptors in the brain that mediates the psychoactive effects of cannabis.
PEA may indirectly stimulate the cannabinoid receptors by potentiating their affinity for a receptor or by inhibiting their metabolic degradation, and by doing so, may increase the uptake of cannabinoid compounds, such as THC. Thus, it is speculated that the presence of the PEA molecule could increase the efficacy of orally administered THC, while reducing the required dosage and decreasing associated deleterious adverse events.
Tourette syndrome is a neuropsychiatric disorder characterized by physical and vocal tics—sudden, brief, intermittent, involuntary or semi-voluntary movements or sounds, respectively. The severity of the disorder can vary widely, from mild symptoms that do not cause serious impairment and often go unnoticed, to loud noises and forceful movements that can result in self-injury. Many with the condition experience additional neurobehavioral problems and co-morbidities, including obsessive-compulsive disorder and attention deficit-hyperactivity disorder.

A look at autism
News from various researchers and companies looking to manage the spectrum
Our overview of recent autism R&D begins with news from Cold Spring Harbor Laboratory (CSHL), discussing work that Prof. Michael Wigler conducted along with Ivan Iossifov from Cold Spring Harbor Laboratory (CSHL) and the New York Genome Center, as well as Andreas Buja, a statistician from the University of Pennsylvania who led the team. Pooling their talents, they tackled a new study of the genetic factors involved in the causation of autism spectrum disorders (ASD), thereby bringing new focus on the impact these illnesses have on motor skills, and more broadly on cognitive function.
“Diminished motor skills appear to be an almost universal property of children with autism,” said Wigler, adding that careful inference from the data suggests to him that the genetic factors causing ASD broadly diminish the brain’s cognitive functions.
These genetic factors are of two types: inherited mutations and de-novo mutations. The latter are changes to the DNA that do not appear in the genetic makeup of either parent and are new in the child, and past research at CSHL and elsewhere has revealed that the presence of these damaging de-novo mutations correlates with lower non-verbal IQ. The more severe the mutations, the more pronounced the impact.
The new study finds that diminished motor skills, like lower IQ, also correlate significantly with de-novo mutations in ASD, and are an even more sensitive indicator of the damage of a de-novo mutation than is IQ, say the researchers.
However, the research also revealed that defining core behavioral components of ASD—impaired social skills and communication—do not correlate with either the presence or severity of de-novo mutations. In other words, a child with autism who has a severe de-novo mutation is no more likely to have severely impaired social skills than is a child with autism for whom no such mutation was found, and who presumably has inherited causal factors.
Nonetheless, the near universality of diminished motor skills in children with autism is an indicator that the factors that cause the core behavioral defects also cause general cognitive dysfunction, Wigler explains. “As such, objective assessment of cognitive function should be a facet of any clinical evaluation of the patient, and included when monitoring therapeutic response.”
Motor skills also factored heavily into a recent study led by researchers at Indiana University (IU) and Rutgers University, where the scientists found that nearly imperceptible fluctuations in movement correspond to autism diagnoses, providing the strongest evidence to date that movement is an accurate biomarker for neurodevelopmental disorders, including autism—and likely other neurodevelopmental disorders.
The study’s results, reported Jan. 12 in the Nature journal Scientific Reports, suggest a more accurate method to diagnose autism. Current assessments depend on highly subjective criteria, such as a lack of eye movement or repetitive actions. There is no existing medical test for autism, such as a blood test or genetic screening.
“We’ve found that every person has their own unique ‘movement DNA,’” said senior author Jorge V. José, the James H. Rudy Distinguished Professor of Physics in the IU Bloomington College of Arts and Sciences’ Department of Physics. “The use of movement as a ‘biomarker’ for autism could represent an important leap forward in detection and treatment of the disorder.”
Unlike diseases diagnosed with medical tests, autism remains dependent upon symptoms whose detection may vary based upon factors such as the person conducting the assessment. The assessments are also difficult to administer to very young children, or to people with impairments such as lack of verbal skills, potentially preventing early interventions for these groups. Early intervention has been shown to play an important role in successful treatment of autism.
“Our work is focused on applying novel data analytics to develop objective neurodevelopmental assessments for autism, as well as other neurodevelopmental disorders,” said Di Wu, an IU Ph.D. student and the lead author on the study. “We really need to narrow the gap between what physicians observe in patients in the clinic and what we’re learning about movement within the field of neuroscience.”
Next, the researchers aim to conduct movement assessments on more people, including more research on the parents of children with autism to better understand the connection between lower parental scores on the movement assessment and their children’s risk for autism.
Remember what we just said a few paragraphs ago about there being no medical test—such as a blood test—for autism? Well, in other news from January, NeuroPointDX, the neurological disorders division of Stemina Biomarker Discovery, maintained that it had validated a first-generation autism diagnostic blood test panel in the Children’s Autism Metabolome Project (CAMP), its clinical study. The study has enrolled 1,100 children, age 18-48 months, over the course of two years. CAMP is the largest study ever conducted that examines the metabolism of children on the ASD spectrum.
“It is not an exaggeration to say that NeuroPointDX will revolutionize diagnosis and precision medicine,” said Elizabeth Donley, NeuroPointDX’s CEO. “By identifying imbalances in the patient’s metabolism, we can diagnose neurological disorders and identify targeted treatments. These interventions may be as simple as modifying diet or dietary supplements, or as complex as developing new drugs to correct the imbalance.”
Stemina was awarded a $2.7-million grant from the National Institute of Mental Health in August 2015 to support the CAMP study. The study is also supported by a $3.8-million investment from the Nancy Lurie Marks Family Foundation.

How the brain turns chronic stress into pathological anxiety
LA JOLLA, Calif.—In a new study, researchers at The Scripps Research Institute (TSRI) have described how two important molecules in the brain work together to trigger intense anxiety.
The new findings in animal models point to a novel interaction in the regulation of the brain’s stress response that may underlie the pathological anxiety related to symptoms of post-traumatic stress disorder (PTSD).
“Anxiety and stress disorders affect millions of people worldwide,” explained study leader Marisa Roberto, a professor at TSRI. “Understanding the mechanisms underlying these disorders is important for identifying potential new targets for therapeutic use.”
The researchers focused on the endogenous cannabinoid (endocannabinoid or eCB) system, which include natural lipid signaling molecules that bind to cannabinoid receptors in the brain. Cannabinoid (type 1) receptors control stress-mediating circuits by inhibiting neurotransmitter release—a sort of gating mechanism to keep anxiety in check.
In contrast to the stress-reducing properties of endocannabinoids, a peptide molecule called corticotropin-releasing factor (CRF) activates the stress response and promotes increased sensitivity to stress and anxiety when activated over and over again.
In the new study, titled “Constitutive increases in amygdalar corticotropin releasing factor and fatty acid amide hydrolase drive an anxious phenotype” and published in the journal Biological Psychiatry, the researchers investigated the interaction between the stress-promoting (CRF) and stress-constraining (eCBs) mechanisms in the central nucleus of the amygdala, a critical brain region involved in mediating emotional reactions. The findings suggest that overactive CRF signaling in this region produces a wide range of effects that override the stress-reducing capabilities of a major eCB called N-arachidonoylethanolamine (anandamide), turning chronic stress into unchecked, or pathological, anxiety.
“Anxiety is something that everyone experiences on a day-to-day basis,” said study first author Luis A. Natividad, a research associate in the Roberto lab. “But it is unclear what changes this otherwise natural process into something debilitating.”
To answer this question, Roberto’s lab teamed up with Roberto Ciccocioppo’s lab at the University of Camerino in Italy and the lab of TSRI professor Loren (“Larry”) Parsons, a renowned leader in the fields of endocannabinoid signaling, stress and drug addiction who passed away in 2016.
The researchers studied rats that were genetically selected for higher alcohol drinking and also display an anxiety-like phenotype. These rats exhibit a mutation in a gene called Crhr1 that increases CRF (type 1) receptor signaling.
Using behavioral, neurochemical and electrophysiological approaches, the researchers found that increased CRF signaling led to elevated activity of the anandamide clearance enzyme fatty acid amide hydrolase (FAAH). Increased CRF was also associated with drops in anandamide levels in the central nucleus of the amygdala. Together, increased FAAH activity and decreased anandamide signaling reduce inhibitory control of excitatory neurotransmission in this critical region, and lower the brain’s ability to regulate stress and anxiety.
The researchers concluded that long-term dysregulation of CRF-FAAH mechanisms in the amygdala keeps anandamide from doing its job. Without anandamide to balance out the system, the brain is primed to react to stress.
Follow-up experiments showed that inhibiting FAAH could blunt CRF’s effects and reduce signs of anxiety in the rats.
Roberto said the next step will be to further study this rat model to better understand relationships between high anxiety and alcoholism. She added that the rat model could also be useful for studying PTSD, where high anxiety is connected to a higher risk of developing alcoholism.
“The results of our study may be useful, not only in understanding the neurobiological basis of alcoholism, anxiety and possibly PTSD, but also in developing more efficacious pharmacotherapies to treat these disorders,” added Ciccocioppo.
The researchers dedicated this study to Parsons. Natividad added a note on Parson’s influence on the research and on the TSRI campus: “Larry’s guidance throughout the study was critical in bringing together a cohesive story exploring the relevance of endocannabinoid signaling with downstream neural processing in a way that is unique to the field and has translational relevance to the human condition. He serves as a role model for me not only as a scientist, but also in terms of being a good colleague, mentor and friend to those around him. I feel privileged to have been part of his lab, his teachings and mentorship. He will be dearly missed.”

Relmada acquires rights to dextromethadone for nervous system disorders treatment
NEW YORK—Relmada Therapeutics Inc., a clinical-stage company developing novel therapies for the treatment of central nervous system (CNS) diseases, recently acquired the global rights to develop and market dextromethadone (REL-1017), a novel N-methyl-D-aspartate (NMDA) receptor antagonist, for the treatment of neurological conditions including certain rare diseases with symptoms affecting the CNS.
The company expects to select and initiate development for additional indications in 2018. Relmada previously acquired the global rights to dextromethadone for the treatment of symptoms associated with a range of psychological and psychiatric disorders including depression, anxiety, fatigue and mood instability, and it plans to start to enroll patients in a Phase 2a randomized, double-blind, placebo-controlled study of two dose levels of dextromethadone as a rapidly acting adjunctive treatment in patients affected by major depression in the first half of 2018.
“The clinically proven mechanism of action of dextromethadone shows potential benefits in the treatment of a wide range of CNS diseases and conditions, including rare diseases that represent significant areas of unmet need in healthcare,” said Sergio Traversa, CEO of Relmada Therapeutics. “We believe that this new agreement is the most important transaction for Relmada since its inception, positioning us to target a wide range of development and global marketing opportunities for dextromethadone in the years ahead.”
The NMDA receptor is a therapeutic drug target for many CNS disorders and is a predominant molecular device for controlling synaptic plasticity and memory function, allowing for the transfer of electro-chemical signals between neurons. Based on this clinically proven mechanism of action, several NMDA receptor antagonists, including dextromethadone, are considered as therapeutic agents for CNS disorders.
In April 2017, Relmada announced that the U.S. Food and Drug Administration had granted Fast Track designation for dextromethadone for the adjunctive treatment of major depressive disorder. The company plans to advance the development program of dextromethadone to a Phase 2a randomized, double-blind, placebo-controlled study that will assess changes in depressive symptoms as well as the safety, tolerability and pharmacokinetics of two dose levels of dextromethadone as a rapid-acting adjunctive treatment in patients affected by major depression. The company has also initiated a preclinical program to identify the most appropriate additional neurological indications for dextromethadone, including certain rare syndromes affecting the CNS.
Relmada is currently developing dextromethadone as a rapidly acting oral agent for the treatment of depression. Working through the same brain mechanisms as ketamine, a non-competitive NMDA channel antagonist, but potentially lacking its adverse side effects, dextromethadone is fundamentally differentiated from all currently FDA-approved antidepressants, as well as all atypical antipsychotics used adjunctively.

TSRI receives $10M to study effects of alcohol on the brain
LA JOLLA, Calif.—The National Institute on Alcohol Abuse and Alcoholism (NIAAA) has awarded scientists at The Scripps Research Institute (TSRI) a $10-million grant to study how long-term alcohol use changes basic mechanisms of brain function. The researchers will then investigate how novel medications derived from this work may reverse those changes to treat alcohol addiction.
The five-year grant will support five individual research projects and three core resources at the TSRI Alcohol Research Center (TSRI-ARC), and will be led by Dr. Barbara Mason, the Pearson Family Chair and center director of TSRI-ARC. Together, the projects—involving molecular pharmacology, neurochemistry, electrophysiology, neurocircuitry and clinical studies—aim to better understand what happens in the brain during the extended withdrawal phase a person goes through when they stop drinking, and to develop ways to treat that phase and prevent relapse.
“After someone with alcohol use disorder stops drinking and undergoes acute withdrawal, there’s then a protracted withdrawal phase that’s characterized by activation of stress systems in the brain and symptoms of negative affect such as anxiety, dysphoria, and irritability,” says Mason. “These symptoms ultimately drive craving and relapse, and we want to stop that cycle.”
Around 80 percent of those who seek treatment for their alcohol use will relapse within a year. Animal models have hinted that reversing some of the changes in the brain caused by long-term alcohol use can prevent relapse. Mason and her colleagues want to probe that observation in more molecular detail and help translate it to humans.
“There hasn’t been a new pharmacological treatment for alcohol dependence in decades,” says Mason. “We want to change that and help facilitate a return to homeostasis in the brains of people with alcohol use disorder.”
Mason’s research has already revealed that when someone with alcohol use disorder stops drinking, their brain releases stress neuropeptides—molecules that turn on stress pathways in the brain. They’ve also homed in on the extended amygdala—an area of the brain involved in mediating emotional behaviors—as helping mediate the interactions between stress and addiction.
Resources at TSRI-ARC are available to not only TSRI scientists, but researchers throughout the region. The new grant includes funds to help facilitate outreach to the community about alcohol use disorder. Scientists will share their results as well as information on addiction resources through lectures and events at high schools, senior citizen centers and other public venues.

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