Advances in neuroscience drug discovery

Neurones in the brain

Lu Rahman looks at neuroscience drug discovery – advances and challenges – and how breakthroughs in this field are helping address areas of unmet need. 

Recent advances in biomarkers, research into the central nervous system and breakthroughs in human iPSC cell models, have bolstered neuroscience drug discovery research.

According to Alzheimer’s Research UK (ARUK): “In the UK, dementia was the leading cause of death in 2022 and has been the leading cause of death for women since 2011 – maintaining its position throughout the Covid-19 pandemic. Dementia is the only major cause of death without a treatment to prevent, slow or stop disease progression.

“In 2019, dementia accounted for 1.8 million deaths worldwide”1.

Alzheimer’s is just one part of the picture. With the breadth and range of central nervous system disorders – for example Parkinson’s disease and multiple sclerosis – facing the global population there is an unmet need within this area of drug discovery. We should not overlook neuropsychiatric conditions such as depression, anxiety and addiction either.

Challenges to this area of drug discovery remain. According to Medicine Discovery Catapult, these include: “Navigating the complexity of the CNS; understanding the disease pathology, and accessing predictable in vitro and in vivo cell models2”.

ARUK3 adds that while the UK government increased funding in dementia research from £28.2m to £104.7m per year there are additional issues. For example, it can take up to it three years to recruit enough participants for a dementia clinical trial. This compares to the 2.3 years it takes to complete an entire cancer clinical trial.

The organisation also notes that only 1% of the people that can take part in dementia clinical trials actually do so.

A Deloitte Insights report points out: “Science should be coming to the rescue, but innovations in neuroscience essentially stalled in the latter half of the last century. In the early 20th century, a combination of hard work and luck produced three broad types of psychiatric drugs: antidepressants, antipsychotics and anxiolytics. But psychopharmacology developments petered out, and few new drugs reached the market during the last four decades. Further, the treatments on offer today often only delay the progression of the disease without recovering lost brain function4”.

The authors of the report go on to say: “However, with advancements in brain disorders lagging behind treatments in other fields, such as cancer or treatments for the heart, new energy and ideas are flowing into neuroscience. There is now hope that new treatments will arise to overcome the limitations of existing therapies and relieve the millions of patients suffering worldwide4”.

The report also highlights that the global neuroscience market (GNM) “was worth $612 billion in 2022 and could grow to $721 billion by 2026.

Neuroscience advances

At the time of writing The Guardian newspaper led with the headline:” Scientists hope weight-loss drugs could treat addiction and dementia”, reporting that “medications with semaglutide such as Ozempic and Wegovy are being studied to see if they can help other conditions.” One of these is dementia. 

The publication writes: “Even dementia researchers are turning to drugs such as semaglutide, after studies suggested people who took GLP-1 analogues for type 2 diabetes had a reduced incidence of such conditions.”

Dr Paul Yates, a consultant geriatrician and Deputy Director of aged care research at Austin Health, Australia, is among those working in the area. He said GLP-1 and its analogues appeared to have beneficial effects in the brain” and that his current study “is aiming to slow [dementia] down, as it is recruiting people who already have symptoms.” 

There are other breakthroughs taking place in this field. Late last year, the work of Benoit Coulombe, Director of the Translational Proteomics Laboratory at the Clinical Research Institute of Montreal (IRCM) and a professor of biochemistry and molecular medicine in the Faculty of Medicine of Université de Montréal, highlighted a new drug with potential to treat incurable neurodegenerative myelin diseases5.

Riluzole offers hope for the future treatment of some leukodystrophies, neurodegenerative diseases in young children that progressively affect their quality of life, often leading to death before adulthood.

Published in the journal Molecular Brain, the research showed that the drug Riluzole, approved by the US Food and Drug Administration to treat certain forms of amyotrophic lateral sclerosis, can at least partially correct the molecular cause of some leukodystrophies.

“Indeed, we have shown that the causative mutations of some leukodystrophies affect the subunits of an important cellular enzyme, RNA polymerase III, preventing its normal assembly – it turned out that Riluzole can counteract this assembly defect,” says Maxime Pinard, the researcher responsible for the project in Coulombe’s lab.

‘’For diseases as serious and debilitating for patients and their families as leukodystrophies, learning about such advances in knowledge carries a great deal of hope, which IRCM warmly welcomes,” adds Dr Jean-François Côté, the IRCM’s President and Scientific Director.

Leukodystrophies are rare and almost exclusively genetic diseases characterised by a process of demyelination (damage to the myelin sheath) of the central and peripheral nervous system. The process is primitive in appearance and non-inflammatory and leads to cerebral sclerosis.

“More work is needed to evaluate the effect of Riluzole on patients in order to advance the development of therapeutic avenues for these diseases,” cautions Marjolaine Verville, co-founder the Leukodystrophy Foundation, which funded the research.

She adds: “The research from Dr Coulombe’s laboratory is generating a lot of interest and hope in the community.” Her husband and Foundation co-founder, Éric Tailleur, agrees: “It clearly suggests that Riluzole could be used as a drug to treat this disease.”

Alzheimer’s disease

Eisai and Biogen announced what Biogen’s CEO Christopher Viehbacher has called a “breakthrough in the treatment of Alzheimer’s disease”. The FDA has approved the supplemental Biologics License Application (sBLA) supporting the traditional approval of LEQEMBI (lecanemab-irmb) injection, for reducing the rate of disease progression and to slow cognitive and functional decline in adults with Alzheimer’s disease (AD).

“The FDA approved LEQEMBI under the traditional approval pathway, making LEQEMBI the first and only approved anti-amyloid Alzheimer’s disease treatment shown to reduce the rate of disease progression and to slow cognitive impairment in the early and mild dementia stages of the disease,” says Haruo Naito, Chief Executive Officer at Eisai. 

Interesting work is also coming out of Western University, Ontario, Canada6 which has received $24 million in support from the federal New Frontiers in Research Fund (NFRF) in relation to its work in neurodegenerative diseases.

Led by Professor Ravi Menon, a team of researchers has developed what is said to be a groundbreaking approach to identify promising therapies for diseases, such as Alzheimer’s and Parkinson’s and expedite their journey to market. Their platform brings together a series of tests focused on evaluating how potential therapies impact cognition, such as memory, thinking skills and learning, from cell cultures to animal models. It also has the ability to study high-quality disease biomarkers and brain imaging, leveraging Western’s cognition testing platforms, molecular and imaging techniques and existing industry and academic partnerships. Thorough consideration of sex and gender will also be included, as therapies often work differently in men and women.   

“We are creating a one-stop shop to identify and predict the success of drugs in human trials faster and cheaper,” says Menon, Scientific Director of the Centre for Functional and Metabolic Mapping (CFMM). “By putting appropriate testing models together, with the best technology and world-leading experts under one roof, we’re going to make it less risky to develop treatments for these brain diseases, we’re going to save a lot of money, and we’re going to get effective therapies to patients faster.”

According to the Public Health Agency of Canada, annual healthcare costs for Canadians affected by dementia alone are expected to reach $16.6 billion by 2031, doubling what was spent two decades earlier.    

However, the number of therapies in the pipeline for these disorders is low and drug development can cost more than $50 million to bring a single compound to clinical trial and more than $1 billion to move forward to market approval.    

Menon’s platform aims to narrow the gap across the ‘valley of death’ – the phase between lab testing and human trials of drugs and their subsequent commercialisation, where most compounds fail. This will be achieved by focusing on the fundamental aspect of neurodegenerative diseases often overlooked – cognition.    

“Neurodegenerative diseases impact cognition – mental processes that enable us to carry out everyday tasks, solve problems, make decisions, and interact with our surroundings. However, millions of dollars are invested in developing drugs without evaluating their impact on cognition and invariably, the human clinical trials of such drugs fail,” says Menon.

Antihistamine success

Interesting research has made its way out of the University of California San Francisco (UCSF)7. A decade ago, UC San Francisco scientists Ari Green and Jonah Chan identified an over-the-counter antihistamine – clemastine – as a treatment for multiple sclerosis (MS) using MRI scans to study the drug’s impact on the brains of 50 participants in a clinical study. Today researchers have developed an approach to measure the drug’s effectiveness in repairing the brain, making it possible to also assess future therapies for the devastating disorder.

In the brain, water trapped between the thin layers of myelin that wrap nerve fibres cannot move as freely as water floating between brain cells. This unique property of myelin allowed imaging experts to develop a technique to compare the difference in myelin levels before and after the drug was administered, by measuring the so-called myelin water fraction, or the ratio of myelin water to the total water content in brain tissue.

In their study, published May 8, 2023, in PNAS, the researchers found that patients with MS who were treated with clemastine experienced modest increases in myelin water, indicating myelin repair. They also proved that the myelin water fraction technique, when focused on the right parts of the brain, could be used to track myelin recovery.

“This is the first example of brain repair being documented on MRI for a chronic neurological condition,” says Ari Green, Medical Director of the UCSF Multiple Sclerosis and Neuroinflammation Center and a member of the Weill Institute for Neurosciences. “The study provides the first direct, biologically validated, imaging-based evidence of myelin repair induced by clemastine. This will set the standard for future research into remyelinating therapies.”

In the study, patients with MS who enrolled in the ReBUILD trial were divided into two groups: the first group received clemastine for the first three months of the study and the second group received clemastine only in months three to five. Using the myelin water fraction as a biomarker, the researchers found that myelin water increased in the first group after participants received the drug and continued to increase after clemastine was stopped. In the second group, the myelin water fraction showed decreases in myelin water in the first portion of the study, under the placebo, and a rebound after participants received clemastine.

Clemastine works in this setting by stimulating the differentiation of myelin-making stem cells. This places the medication a generation ahead of existing MS drugs that work by dampening the activity of the immune system, calming inflammation and reducing the risk of relapse. It still isn’t ideal, though. Green says: “Clemastine can only be partially effective at the doses we can use. It can be sedating, which may be undesirable in patients with MS. We are hopeful better medications will be developed, but clemastine has proven to be the tool to show remyelination is possible.”

Gene modification

In the UK a team of scientists has discovered that modification of a gene in the brain can reduce anxiety levels, offering an exciting novel drug target for anxiety disorders8. The discovery, led by researchers at the Universities of Bristol and Exeter in the UK, is published in Nature Communications.

Anxiety disorders are common, with one in four people diagnosed with a disorder at least once in their lifetime. Severe psychological trauma can trigger genetic, biochemical and morphological changes in neurons in the brain’s amygdala – the brain region implicated in stress-induced anxiety.

However, the efficacy of currently available anti-anxiety drugs is low, with more than half of patients not achieving remission following treatment.

In this study, scientists sought to identify the molecular events in the brain that underpin anxiety. They focused on miRNAs, which regulate multiple target proteins controlling the cellular processes in the amygdala.

Following acute stress, the team found an increased amount of one type of molecule called miR483-5p in a mouse amygdala. Importantly, the team showed that increased miR483-5p suppressed the expression of another gene, Pgap2, which in turn drives changes to neuronal morphology in the brain and behaviour associated with anxiety.

Together, the researchers showed that miR-483-5p acts as a molecular brake that offsets stress-induced amygdala changes to promote anxiety relief.

This is the first step towards the discovery of novel, more potent and much-needed treatments for anxiety disorders that will enhance this pathway.

Dr Valentina Mosienko, one of the study’s lead authors and an MRC Fellow and Lecturer in Neuroscience in Bristol’s School of Physiology, Pharmacology and Neuroscience, says: “While low levels of stress are counterbalanced by the natural capacity of the brain to adjust, severe or prolonged traumatic experiences can overcome the protective mechanisms of stress resilience, leading to the development of pathological conditions such as depression or anxiety.

“miRNAs are strategically poised to control complex neuropsychiatric conditions such as anxiety. The miR483-5p/Pgap2 pathway we identified in this study, activation of which exerts anxiety-reducing effects, offers a huge potential for the development of anti-anxiety therapies for complex psychiatric conditions in humans.”

Despite the challenges within this sector of drug discovery, global innovation is strong and continues to push the boundaries of what may or may not be possible to further the development of neuroscience drugs. As we hear talk of drug compounds, vaccines and gene therapy being used in this area, there is much to feel optimistic about as researchers continue to find and develop new solutions for these neuroscience and CNS disorders.

DDW Volume 24 – Issue 4, Fall 2023 – Neuroscience Guide



Lu RahmanAbout the author

Lu Rahman is Publishing Director of DDW. She has over 25 years’ experience in B2B journalism, ten of those being in life sciences. She was previously DDW’s Editor in Chief and previous roles include Head of Life Sciences Content.

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