‘From Bench to Biopharma’ International Conference on Translational Research in Autism – Day 1 Recap
Synchrony symposia, organised by The BRAIN Foundation in partnership with UC Davis MIND Institute and CalTech, is the first and only international conference on translational research in autism that brings together academia, biotech, pharmaceutical companies and venture partners from around the world with the mission to improve health and quality of life of people with autism.
Synchrony 2020, titled ‘From Bench to Biopharma’ is taking place on line on 7 consecutive Sundays (and one Saturday) starting 1 November.
DAY 1 (Sunday 1 November) Synchrony 2020 conference recap:
Day One of the Synchrony 2020 conference featured presentations across two main topics: Understanding autism through animal models’ and ‘Translating genetic findings into therapies and treatments’.
The sessions were chaired by Sarkis Mazmanian Ph.D. Luis B. and Nelly Soux Professor of Microbiology at California Institute of Technology. Professor Mazmanian opened the day by providing a brief overview and rationale for using mouse models as a starting point to help understand autism in humans.
He explained how animal models, while not being a close match to human autism, can still help us to gain general insights into how various biological pathways affect brain functioning. By closely studying animals in controlled settings we can observe how disturbances in biological systems lead to behaviours and symptoms that are related to human autism.
For example research using mice and other animals can help explain the effects of genetic mutations on behaviours, or the role and the effects of the immune system, metabolic system, and gastrointestinal tract and microbiome in autism-related symptoms.
Animal models are also extremely valuable for developing new therapeutics – when exploring novel ideas for treatments researchers first test them on various animal models of autism, before moving on to human trials.
In short, animal models provide us with a roadmap in how we understand and treat autism in humans.
Gut Microbial Metabolite p-Cresol Promotes Autistic-like Behaviours in Mice Through Remodelling of the Gut Microbiota
Laetitia Davidovic, Ph.D. from the Institut de Pharmacologie Moléculaire et Cellulaire (Valbonne, France), CNRS next presented her findings on how some specific chemicals that are produced by some gastrointestinal bacteria can negatively influence brain function and behaviours.
Her group used as a starting point the fact that there are increased levels of p-Cresol in autism compared to typical population. p-Cresol (also known as 4-Cresol) is a chemical produced by certain type of gut bacteria. When animals in this experiment drank water that had p-Cresol added to it, they developed abnormal behaviours similar to those present in human autism, including repetitive and stereotyped behaviours.
Giving p-Cresol to animals also resulted in changes in their microbiota and in brain signalling – brain recordings showed decreased activity of the types of neurons that are involved in social reward behaviours, which are reduced in humans with autism.
On a positive note, when these affected mice were given fecal transplant from healthy unaffected animals, the researchers observed restoration of their brain function and reversal of social deficits.
This points to a possibility that changing the composition of gut microbiota in humans could improve aberrant behaviours and brain functioning.
Modulatory Roles of the Immune System in Shaping Animal Behaviours
Jun Huh, Ph.D. from Huh Laboratory at Harvard Medical School, talked about potentially beneficial effect of inflammation and fever in autism. While it is well established that chronic inflammation and immune system disturbances negatively affect brain development and function, and are involved in etiology of at least a subtype of autism, in certain circumstances some type of inflammation is beneficial and could be used as a therapy.
A subset of children with autism show temporary but considerable improvements in autism symptoms during episodes of fever. Results from Dr Huh’s lab show that a specific inflammatory molecule, IL-17a is crucial in this effect.
Animals who are exposed to infections during pregnancy develop chronic inflammation and abnormal social behaviours. The brain function of those animals can be improved, and their behaviours can be reversed in the lab by exposing those animals to short bursts of inflammation that activates this IL-17a molecule.
Levofolinate Treatment for ASD: What We have Learnt from the Rat Model
Edward Quadros, PhD from Departments of Medicine and Cell Biology, SUNY explained in his presentation how folate receptor autoimmune disorder is emerging as the single most common abnormality in the immediate family and the affected children with autism.
Blocking and / or binding autoantibodies against the folate receptor alpha have been identified in approximately two thirds of children with autism. These antibodies can block folate transport from the mother to the fetus and in infants, folate uptake into the brain; resulting in cerebral folate deficiency.
Evidence in support of the observations has come from animal models of folate deficiency and during gestation, which produces severe learning, memory and cognitive impairment in animals. Exposing animals to maternal folate receptors antibodies produces local inflammation in the placenta and blocks folate delivery to the fetus.
Those experimental studies have also shown that co-administration of folinic acid and dexamethasone (a steroid anti-inflammatory medication) can prevent behavioral deficits in pups. Restoring cerebral folate can normalize multiple metabolic functions including neurotransmitters and gene expression.
This has clear implications in the treatment and prevention of ASD associated with folate receptor autoantibodies. In clinical trials so far folinic acid treatment has already shown significant efficacy in improving the core symptoms of autism.
Keynote: Gut Microbial Metabolities in ASD
Sarkis Mazmanian was back for a keynote presentation after a short conference break (which featured entertainment by talented array of performers and artists, each of whom have their own unique talents and are on the autism spectrum!) to talk about the findings from his lab that shed more light on how chemical produced by different types of gut bacteria can impact the functioning of brain, including learning, memory and behaviours.
Human and animal behaviours are shaped via the integration of sensory and molecular cues from the environment. The gastrointestinal tract is a major site of exposure to environmental cues, where components of diet are transformed by gut bacteria and then disseminated to all organs of the body, including the brain.
Molecules from the gut can affect the brain via several pathways: the enteric nervous system (gut nervous system), the vagus nerve, the immune or endocrine systems, or may directly reach the brain through the circulatory system.
Certain gut bacteria can produce neurotransmitters (the chemicals that brain neurons use to communicate with each other) including classical and well know neurotransmitters such as dopamine, norepinephrine, serotonin and gamma-aminobutyric acid (GABA).
Prof Mazmanian’s lab is currently researching the production of novel classes of neuroactive chemicals by the microbiome, such as 4-ethylphenyl sulfate (4EPS)
This microbial metabolite is elevated in a mouse model of autism. Colonising the guts of healthy and normally behaving mice with gut bacteria that produces it, results in changes in behaviours and brain activity. 4EPS also caused nerve injury and changes in the expression of genes that are implicated in autism.
The researchers then reversed these changes and abnormal behaviours by giving mice a chemical that blocked 4EPS.
These findings provide further evidence that a gut microbial molecule can impact the function of the brain and modulate complex behaviours.
Unraveling Gut-Microbiota-Brain Interactions in Neurodevelopment Disorders
Mauro Costa-Mattioli, Ph.D. Professor and Cullen Foundation Endowed Chair Director of Memory and Brain Research Center from the Baylor College of Medicine discussed in his talk the different approaches his laboratory is using to illuminate the exact mechanisms and ways in which particular gut microbes (and chemicals that they produce) can impact brain development and function.
Amongst other things Costa-Mattioli and colleagues are studying the powerful ways in which maternal obesity and metabolic disorders in animals affect the composition of their offspring’s gut microbiome and social behaviours. His group managed to reverse behavioural abnormalities by populating the guts of these young animals by a specific population of bacteria called L reuteri, which increases the levels of oxytocin (the ‘bonding hormone’) and strengthens social behaviours.
L reuteri had the same normalising effect in several different mouse model of autism, including mice with a particular Shank3b mutation which exhibit deficits in social behaviours.
The researchers next studied the ways through which L reuteri normalised social behaviours in all the different animal models of autism and vagus nerve emerged as the crucial player.
Vagus nerve, a long nerve that connects the brain with the gut, is the main mechanism through which L reuteri increases the levels of oxytocin hormone in the brain.
Glitches in the Gut Brain Wiring: Understanding Gastrointestinal Issues in Autism
Elisa Hill-Yardin, Ph.D.Associate Professor at RMIT University presented on her findings in animal models of autism-related Neuroligin-3 genetic mutation. In addition to brain and behavioural changes, including aggression and asocial behaviours, R451C mutation in this gene also leads to changes in the enteric nervous system and gastrointestinal dysfunction in mice.
The mice with this mutation also show changes in both the gut microbiome and in immune cells, suggesting that this mutation impairs inflammation pathways.
The work done by this group of researchers indicates that some of the genetic mutations that are associated with autism could also impact the immune system and the gut, and likely cause gastrointestinal dysfunction in some individuals. Furthermore, these findings provide novel treatment targets for individuals with such genetic forms of autism.
Translating Genetic Findings in ASD to Therapy: Searching for Convergence
Two of the day’s sessions were dedicated to translating genetic findings in autism into meaningful therapeutic options. The first presentation was by Dan Geschwind, M.D., Ph.D. Gordon and Virginia MacDonald Distinguished Professor of neurology, psychiatry and human genetics at the UCLA School of Medicine, and the Senior Associate Dean and Associate Vice Chancellor of Precision Medicine at UCLA.
Dr Geschwind explained how a major challenge facing modern medicine is translating advances in genetics and genomics into a better understanding of disease mechanisms and treatments. This is especially evident in disorders such as autism, where over 100 risk genes have been identified.
His lab is now using system biology approaches to ask whether autism risk genes converge on specific pathways. Further, they are working with colleagues to develop in vitro systems based on stem cells to study these pathways.
Dr Geschwind and colleagues in his lab propose that the genomic data from these studies may be used for unbiased drug screening based on gene expression.
From Genes to Novel Therapeutics in Autism Spectrum Disorder
In the afternoon session Joseph Buxbaum, PhD is a Professor of Psychiatry and Director of Seaver Autism Center for Research and Treatment at Icahn School of Medicine at Mount Sinai repeated the difficulties in translating genetic findings into treatments in complex disorders such as autism.
Dr Buxbaum stressed the importance of precision medicine in autism, and gave examples of how gene discovery can contribute to novel therapeutics – the genes that have been identified so far to increase the risk of autism can be studied in animal models to provide windows into the biology processes that lead to autism. Such insights from animals can in turn lead to novel therapeutic approaches for those rare genetic disorders.
Once a drug is approved for a rare genetic form of autism then it can be tested in and used in other, non-syndromic cases autism.
Therefore the best strategy would be to seek rare syndromes with autism as one of the consequences, and once a treatment is found for such syndromes it could then potentially be applied across other types of autism.
Dr Buxbaum then identified and discussed another critical question in autism, which is how to engage academia and industry as joint partners towards drug discovery for autism.
While academic researchers are good at basic bench lab research and in identifying pathways and novel treatment targets, putting these findings together and translating them into real life solutions requires wider involvement of stronger commercial/industry players with access to large funding, screen development knowhow, and knowledge of regulatory landscape.
In other words for novel treatments for autism to become a reality it will take joint efforts and collaboration between academia, patient groups, regulatory and funding agencies, pharma and biotech ventures.
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