Drug Development for Brain Disorders
From Artificial Intelligence to Cannabinoids, Psychedelics and Microbiome
In 2013, the glymphatic system (or glymphatic clearance pathway, or paravascular system) was described for the first time as a system for waste clearance in the central nervous system (CNS) of vertebrates, which cleans out toxic waste products from the brain during deep sleep, by flushing it with cerebrospinal fluid. Yes, during your sleep, you don’t only dream but your brain is taking a shower.
According to this model, the cerebrospinal fluid (CSF) flows into the space around cerebral arteries, where it combines with interstitial fluid (ISF) and parenchymal solutes - then coupled to a clearance mechanism for the removal of ISF and extracellular solutes from the brain and spinal cord - and then exits down venous paravascular spaces.
Unfortunately, disruptions to sleep – and therefore to this clearing glymphatic system – have been increasingly associated with neurological disorders such as Alzheimer’s.
So, it was not a surprise that last week (September 30, 2021) a “Brain-cleaning sleeping cap gets US Army funding”, for a team at Rice’s Institute of Biosciences and Bioengineering to develop a portable technology to measure and control fluid flow in the brain, to help not just soldiers but also patients, and improve our understanding of what’s going on in the brain during sleep, eventually leading to new treatments for sleep and neurological disorders.
Moreover, last month it was announced that a New Algorithm Can Identify Pre-Alzheimer's Brain Changes With Over 99% Accuracy, and that this method is able to pick out signs of mild cognitive impairment – a step between cognitive decline (usually associated with aging) and Alzheimer's.
On September 27, 2021, NervGen Pharma a clinical stage biotech dedicated to developing innovative solutions for the treatment of nervous system damage announced a partnership with Imeka Solutions Inc (currently the only neuroimaging company that combines AI and diffusion imaging to obtain high resolution images of white matter in the brain) to Use Novel Neuroimaging Technology in Clinical Trials.
Long thought to be passive tissue white matter forms the bulk of the deep parts of the brain and the superficial parts of the spinal cord, and affects learning and brain functions, acting as a relay and coordinating communication between different brain regions. Multiple sclerosis (MS) is the most common of the inflammatory demyelinating diseases of the CNS which affect white matter. Alcohol use disorders are also associated with a decrease in white matter volume while amyloid plaques in white matter may be associated with Alzheimer's disease and other neurodegenerative diseases. Moreover, white matter lesions on magnetic resonance imaging are linked to several adverse outcomes, such as cognitive impairment and depression.
Considering the importance of white matter, NervGen intends to utilise Imeka's imaging technology as a sensitive pharmacodynamic biomarker for its lead compound (NVG-291 a peptide) in its Phase 1b/2 clinical trial in Alzheimer's disease patients. So far, in animal studies, NVG-291 (targeting the protein tyrosine phosphatase sigma, a protein receptor that blocks nerve repair following injury) has shown enhancement of axonal regeneration, neuroplasticity and remyelination, reflecting its ability to repair the damaged nervous system.
Furthermore, this month it was announced that in a small study AI Analyzes Facial Expressions in Videos to Help Detect Parkinson’s and this type of biomarker could allow remote diagnosis. And last week Novartis Pharmaceuticals Canada Inc. announces digital innovation partnership in multiple sclerosis (MS) with Innodem Neurosciences. In particular, Innodem has an AI eye tracking software technology, capable of capturing and analysing eye movement biomarkers and gaze mapping biomarkers to assist a clinician's diagnosis and monitor MS progression.
Also regarding MS, Roche partners with Temedica to launch 'digital companion' app for multiple sclerosis. The Brisa app will collect daily data like activity, sleep and dietary habits and after analysing them, the “digital companion” will be able to pinpoint potential areas of improvement and suggest lifestyle changes that might help users better manage MS.
On September 30, 2021, Sunovion pens $890M Otsuka pact for a clutch of neuropsychiatric drugs. Under this agreement, the two Japanese pharmas (focused on serious neuropsychiatric disorders) will develop four clinical-stage assets: Ulotaront (SEP-363856, a serotonin receptor and trace amine-associated receptor 1 agonist): a phase 3 drug for schizophrenia, SEP-4199 (a non-racemic ratio of amisulpride enantiomers with increased potency for serotonin receptors relative to dopamine D2 receptors): a phase 3 study for treatment of major depressive episodes associated with bipolar I disorder, and SEP-378614 (a novel CNS-active molecule) and SEP-380135: both in phase 1 with the former being trialed in treatment-resistant depression and the latter focused on agitation in Alzheimer’s disease.
Other things you need to know:
Existing drug used to treat constipation may boost people's ability to think more clearly (a group of UK researchers have tested an existing approved drug, prucalopride, which targets the serotonin type 4 receptor, and found that it may improve cognition. Prucalopride is primarily prescribed for constipation and has an acceptable level of side effects), Shineco, Inc. Intends to Acquire Biotechnology Company to Jointly Develop Rapid-acting Antidepressant Natural Innovative Medicine (Shineco, a producer and distributor of Chinese herbal medicines, organic agricultural and hemp products and Beijing Wonner Biotech Co., Ltd. will jointly develop a rapid-acting antidepressant natural innovative medicine), Sage Therapeutics and Biogen Announce Consistent Clinically Meaningful Data for Zuranolone (new data from clinical development programs, evaluating the efficacy and safety of zuranolone - a GABA A receptor positive allosteric modulator - for the treatment of major depressive disorder and postpartum depression collectively showed reductions in depressive symptoms with zuranolone-treated patients such as consistent improvements in depressive mood, as well as rapid onset of significant effect by day 3) and SOM Biotech presents positive Phase 2a data with SOM3355 discovered through SOM Biotech’s proprietary AI-based computational technology (SOM3355, is an oral vesicular monoamine transporter 2 inhibitor for the symptomatic treatment of chorea movements associated with Huntington’s disease ).
Finally, if you want reliable measures of cognitive function then CognICA of Cognetivity Neuroscience (a medical technology company developing an AI platform for early detection of cognitive impairment, dementia and Alzheimer's disease) makes measuring cognitive function simple and accessible. And this week, Cognetivity Neurosciences reaches commercial agreement with one of largest mental health Trusts in UK’s National Health Service to deploy its Integrated Cognitive Assessment (ICA) across both primary and secondary care.
Let’s see now what happened in the psychedelic/cannabinoids CNS drug development world this week:
On October 5, 2021, Enveric Biosciences a biotechnology company developing mental health and oncology treatments by leveraging psychedelic-derived molecules and synthetic cannabinoids, announced that its Artificial Intelligence Platform, PsyAI™, Has Identified Viable Drug Candidates from its 'Psybrary' of Psychedelic Molecular Compounds, for further drug discovery from Enveric's initial list of 500 psychedelic molecular compounds.
Moreover, Delix Therapeutics closed a million Series A financing round. The Boston-based company applying modern tools of pharmaceutical development to some of nature's most ancient therapies, has a flagship drug development program, baptized “DLX-1,” where preclinical studies have shown that the compound could have the potential to produce some of the antidepressant effects of classic psychedelics without altering one’s perception or producing a mystical experience.
On October 5, 2021, MindMed Announces Strategic Research Collaboration with Sphere Health. Mind Medicine (a leading biotech company developing psychedelic-inspired therapies), and Sphere Health (a physician-founded employee benefits provider targeting treatments for people with severe mental illness) will jointly launch a study using existing consumer technology to provide a robust data set (MindMed's collaborator is Datavant), in order to identify biomarkers that show association with and prediction of symptoms of anxiety and depression.
Also this week Incannex Healthcare raises close to $18m, including $8m from chief medical officer. Incannex (clinical stage pharmaceutical development company) is developing medicinal cannabis pharmaceutical products and psychedelic medicine therapies for the treatment of generalised anxiety disorder, obstructive sleep apnoea, traumatic brain injury/concussion, lung inflammation, rheumatoid arthritis and inflammatory bowel disease.
Psilera to collaborate with NIDA on pre-clinical psychedelic studies. Psilera (a reimagining psychoactive natural medicines such as DMT company) has finalised a research and development agreement with the US National Institute on Drug Abuse (NIDA) to initiate pre-clinical studies on an intranasal formulation of N,N-dimethyltryptamine (DMT) and other psychedelic-inspired compounds.
Mydecine To Supply Lead Drug Candidate, MYCO-001, for Multi-Site NIDA Grant-Funded Smoking Cessation Study Lead by Dr. Matthew Johnson. Medicine (a psychedelic-assisted psychotherapy company), announced earlier this September that it had partnered with Dr. Johnson (leading drug and substance use researcher) to complete a Phase 2/3 smoking cessation clinical trial for MYCO-001, since previous clinical results by Dr. Johnson and his team at Hopkins have shown six-month abstinence rates as high as 80%, which is unheard of in the addiction space.
Finally, scientists have found that “Magic mushroom” anti-depressive psychedelic affects perception of music”, suggesting that music should be an active component of psilocybin therapy. This work was presented at the ECNP Congress in Lisbon.
Let’s talk now about microbiome and CNS drug development.
Plato stated, long time ago, that “love is a grave mental disease”, and 2500 years later we know that romantic love is basically an addiction with early-stage romantic love being characterised by some characteristics of drug addiction, such as similarities in the dopamine system, while significant differences in the oxytocin system.
But it is also true, and women have known for centuries, that “the way to a man's heart is through his stomach”.
To make a long story short, and after thousands of years of common wisdom, today we now that the gut–brain axis (occasionally used to refer to the role of the gut flora) is the biochemical signaling that takes place between the gastrointestinal tract and the CNS, while alterations between gut flora and brain are connected to anxiety disorders, mood disorders, autism and even Parkinson's disease.
“Sometimes there’s no cure for the crazy. I think we all just have to keep loving through it. Maybe that’s the cure”. ― Emme Rollins, Dear Rockstar
Gut-brain axis and CNCS
Just this week a preclinical study was reported (Alzheimer’s Disease Pathology Curbed Using Aromatic Compound in Basil), providing evidence that gut-derived short-chain fatty acids (SCFAs) (as a byproduct of gut microbiome metabolism) can bind and activate free fatty acid receptor 2 (FFAR2) on neurons in the brain, decreasing amyloid beta-induced neurotoxicity associated with Alzheimer’s disease. Interestingly, since the SCFA levels are reduced in Alzheimer’s disease patients, researchers tried to identify other natural compounds that mimic SCFAs and activate FFAR2 signaling by conducting a large-scale in silico screen of more than 144,000 natural compounds. In the end, the team narrowed 15 leading natural compounds to the most potent one: fenchol, a monoterpenoid and an isomer of borneol that occurs widely in nature and gives basil its characteristic scent.
The microbiome gut–brain axis, this super highway for signaling pathways of the enteric and central nervous system may be in fact, an effective therapeutic strategy for treating or mitigating many somatic and neural pathologies, including neurodegenerative disorders. For example, a Meta-analysis of the Parkinson’s disease gut microbiome suggests alterations linked to intestinal inflammation. In particular, enrichment of the genera Lactobacillus, Akkermansia, and Bifidobacterium and depletion of bacteria belonging to the Lachnospiraceae family and the Faecalibacterium genus, both important short-chain fatty acids producers, emerged as the most consistent Parkinson’s gut microbiome alterations. This dysbiosis might result in a pro-inflammatory status probably linked to the recurrent gastrointestinal symptoms affecting Parkinson’s disease patients.
Accordingly, BiomeBank is launching a trial in Australia to test whether its fecal microbiota transplantation therapy, which works to replenish gut bacteria, is a safe, tolerable and effective treatment of Parkinson’s disease symptoms, such as constipation. Changes in the composition of gut microbiota, which consists of bacteria, fungi, and viruses found in the gastrointestinal tract, are thought to also influence Parkinson’s course and patient response to medications, including levodopa. BiomeBank, is a biotechnology company based in Adelaide, and recently filed an application for regulatory approval in Australila of a first fecal microbiota transplantation therapy to treat ulcerative colitis.
Finally, Enterin Inc. a clinical-stage biopharmaceutical company in Philadelphia, is the first company to develop novel compounds that repair the dysfunctional gut-brain axis in patients with neurodegenerative diseases. It’s lead compound ENT-01 is an artificial compound derived from squalamine, a substance originally discovered in the liver and gall bladder of the dogfish shark (that displaces membrane-bound alpha-synuclein aggregates from nerve cells in the enteric nervous system and improves neural signalling between the gut and brain) is now progressing through Phase 2 clinical trials in an attempt to reverse the neurologic symptoms of Parkinson's disease.
PS: just one last thing about the brain:
“The human brain has 100 billion neurons, each neuron connected to 10 thousand other neurons. Sitting on your shoulders is the most complicated object in the known universe”. - Michio Kaku
And now a study at MIT - part of an ambitious project launched in 2017 by the “The BRAIN Initiative’s Cell Census Network (BICCN)” in order to create an atlas of all brain cells in the mouse - just revealed 🕵🏻 a new cell type in the outer layer of the cerebellum and different ways of categorising known brain cell types (Single-cell exploration of the mouse brain reveals new cell type).
Thank you for reading 💙
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