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In the past five years, the number of drugs being developed by large pharmaceutical companies for psychiatric and neurological disorders fell by 50 per cent. However, due to a number of promising new breakthroughs in the field, that is now changing. Last year, more than $3.3 billion (€2.8 billion) was invested internationally in pharmaceutical research for the treatment of psychiatric illness. That is more than was invested in this field in the previous 10 years. Details of the reverse trend come courtesy of a study carried out by NI Research and published in its industry newsletter, NeuroPerspective.
Asked for his thoughts on this by the Medical Independent (MI), Dr John Hillery, Director of Communications and Public Education, College of Psychiatrists in Ireland, said: “There are lots of advances in the genetic underpinnings of mental illness, some of which seem to be leading to breakthroughs as to what treatments might work. But despite that, in Ireland, individuals with mental illness are still facing stigma at work and in the search for employment. This was highlighted in the recent yearly update from St Patrick’s Hospital.”
According to the World Health Organisation (WHO), uncertainty over the cause or development of multiple sclerosis (MS) implies that prevention is not currently a realistic option, and that while a number of disease-modifying drugs have been developed, which reduce the number of attacks in the relapsing/remitting form of the disease, no curative treatments are available. Thus the current treatment goals of MS are to shorten the duration and severity of relapses, prolong the time between relapses, and delay progression of disability.
However, promising new knowledge discoveries are being made, increasing the hopes of more curative-type treatments one day.
While MS was traditionally considered a disease of the brain’s white matter, recent University of California research shows grey matter may have much more of a key role than originally believed. Approximately 70 per cent of disabilities associated with MS are explained by grey matter abnormalities in the spinal cord and this finding could explain why progress towards discovering the exact cause and a curative treatment for MS has been so elusive.
Dementia now stands alongside cancer as one of the greatest enemies of humanity
In addition, the possible benefits of immunotherapy in MS were outlined in a report in the Annals of Neurology, which suggests that some primary progressive MS patients with a biomarker of highly-active inflammatory disease may benefit from such treatment.
Research published in The Lancet is also promising. It indicates that statins may slow the progression of progressive MS when taken in high doses (80mg daily).
Preventing the progression of MS is also the aim of scientists in Australia’s Walter and Eliza Hall Institute, who developed WEHI-345, a new drug-like molecule that inhibits a key signal that triggers inflammation.
WEHI-345 binds to and inhibits a key immune signalling protein called RIPK2, which prevents the release of inflammatory cytokines.
The researchers examined WEHI-345’s potential to treat immune diseases in experimental models of MS.
“We treated preclinical models with WEHI-345 after symptoms of MS first appeared, and found it could prevent further progression of the disease in 50 per cent of cases,” one of the project’s key researchers Prof Andrew Lew explained. “These results are extremely important, as there are currently no good preventive treatments for MS.”
Associate Professor Guillaume Lessene, who developed the molecule with colleagues in the Institute’s ACRF Chemical Biology Division, believes WEHI-345 has great potential.
“This molecule will be a great starting point for a drug-discovery programme that may one day lead to new treatments for MS and other inflammatory diseases,” he said.
“Not only is this a potential new treatment, it is a great tool we can use to unravel this signalling pathway and identify other important proteins that control inflammation that could be a drug target,” his colleague Dr Ueli Nachbur added.
Meanwhile, in Ireland a number of new therapies for the treatment of relapsing-remitting MS, most notably the disease-modifying fingolimod, natalizumab and dimethyl fumarate, have been approved for reimbursement by the HSE in recent years, while a subcutaneous injectable treatment peginterferon beta 1a is also now available.
In addition, at the beginning of this month, Fampyra (prolonged-release Fampridine tablets), an oral drug used for the symptomatic treatment of walking impairment in adults with MS, was finally approved by the HSE for reimbursement after a long campaign by Irish MS patients. It is the first treatment to address walking improvement in individuals living with MS and can be used alone or in combination with disease-modifying therapies. In clinical trials, patients responding to the drug had an average increase in walking speed of 25 per cent and a clinically meaningful improvement in walking.
According to MS Ireland, those who had been receiving Fampyra for free up until July 2014 under a special access scheme found that the drug had a significant impact on their ability to remain independent. Forced to live without the drug, for even a short period of time, patients who had been taking Fampyra found their ability to complete even the simplest of tasks severely restricted, the organisation said, welcoming the HSE’s decision to reimburse the medication in cases where people with MS prescribed the medication ‘satisfy a responder protocol’.
Dr Chris McGuigan, Consultant Neurologist, St Vincent’s University Hospital, Dublin, added: “People with MS consider their mobility to be their most important function and so as the only therapy available to treat walking disability in MS, this is most welcome news.
“We were involved in the clinical trials programme for Fampyra at St Vincent’s University Hospital and having seen the benefits of this treatment in our MS patients, I am delighted that people living with relapsing and progressive MS may benefit from this treatment.”
Of course along with the advances, there have been setbacks. The risk of progressive multifocal leukoencephalopathy (PML), a rare brain infection, is still an issue with some of the more effective disease-modifying MS treatments and there is a dearth of therapies for primary and secondary progressive MS, compared to the relapsing and remitting forms.
For Prof Orla Hardiman, Consultant Neurologist at the National Neuroscience Centre, and Clinical Professor of Neurology, Trinity College Dublin, the big success story for MS during her career span has been the development and roll-out of disease modification therapies: “I’ve been in practice for 32 years, 30 of which have been in neurology. When I started out, there were no drugs with which to treat MS. After a time, injectable drugs emerged. Then disease-modifying medications for oral administration came onto the market. Now there’s a wide choice of treatments available, with medicines that can significantly reduce the burden of, and change the course of, the disease.”
As for advances in the treatment of epilepsy, Prof Hardiman says there is great work being done, with notable research being carried out in Ireland. “Dr Colin Doherty, a Senior Lecturer in Neurology at TCD, and Prof Norman Delanty, a Professor of Neurology at the RCSI, are currently working on epilepsy-related pharmacogenomics projects,” she said. “This is hugely important and it’s happening under our noses.”
On the role that genes play in the field of medical advances, she added: “We’re using the knowledge we have about the genes that impact diseases, to better define patient subgroups. We’re building data programmes with genetics, family stories, imaging and biomarkers. We’re building patterns within subgroups that give us a degree of precision that allows us to categorise together the patients that are more alike.”
When a beekeeper who had Parkinson’s disease was injected monthly with the venom so as to become desensitised, he found that his Parkinson’s symptoms were reduced and researchers have now examined this phenomenon in the laboratory
Noting that there is now a movement in neurology research towards turning off ‘faulty’ genes, she said: “It’s about finding out what happens when you silence genes that are not working properly; what happens when you take out the defective parts and replace them with corrected versions? The view is that interventions like that might heal disease.”
One research team currently working in this field of science is based at the University of Massachusetts, US. They are researching silencing the gene mutations that are linked with amyotrophic lateral sclerosis (ALS). In July of this year, the US Angel Fund for ALS Research announced that these researchers first silenced the SOD1 gene in a Petri dish. Then they silenced it in mice and found that when this was done within a day of birth, the onset of ALS was delayed by several months. They are currently working with Massachusetts General Hospital on the design of a human trial.
More notable work in this area is being done at the University of Bristol, UK, where researchers say they have discovered how to ‘switch off’ autoimmune diseases. Rather than the body’s immune system destroying its own tissue by mistake, the study, funded by the Wellcome Trust, discovered how cells convert from being aggressive to actually protecting against disease.
It is hoped this latest insight will lead to the widespread use of antigen-specific immunotherapy as a treatment for many autoimmune disorders, including MS, type 1 diabetes, Graves’ disease and systemic lupus erythematosus (SLE).
Alzheimer’s disease and dementia
Researchers across the world are in a race to find curative and preventative treatments for Alzheimer’s and dementia, which, given the increasing ageing population in Western society, are now rapidly rising to the top of the global disease burden. Earlier this year in the UK, Prime Minister David Cameron announced that more than £300 million (€404 million) is to be spent by his Government on research into dementia.
Outlining new plans to tackle what he described as “one of the greatest challenges of our lifetime,” he said an international dementia institute will be established in England over the next five years in a bid to make the UK a world leader for research and medical trials.
A separate multimillion-pound fund was launched to help establish a large-scale, international investment scheme to discover new drugs and treatment that could slow down the onset of dementia or even deliver a cure by 2025.
“Dementia now stands alongside cancer as one of the greatest enemies of humanity. In the UK alone, there are around 800,000 people living with dementia. Worldwide, that number is 40 million and is set to double every 20 years. We have to fight to cure it. I know some people will say it’s not possible, but we have seen with cancer what medicine can achieve,” Mr Cameron commented.
In the US, research into brain diseases such as Alzheimer’s, Parkinson’s and traumatic injury got a major boost this month with a $100 million (€87.4 million) pledge from a US foundation and seven universities. The additional funds will add to a $300 million (€262.3 million) programme led by the White House and known as the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, launched by US President Barack Obama in 2013.
A number of pharmaceutical companies and scientists have also made promising announcements in the field in the last couple of years.
‘In that time, I’ve found that Irish people are incredibly generous when it comes to taking part in clinical research. While knowing that a treatment might not work, they’re happy to participate, if that might mean helping to find cures for disease’
Janssen is “fully committed to brain research,” according to Dr Husseini K Manji, Global Head of Neuroscience Research and Development at the company. “While the work remains very challenging, we’re making progress in Alzheimer’s disease and severe mood disorders, and continuing our legacy work in schizophrenia and pain,” he says. “We’re making progress with a novel treatment for Alzheimer’s dementia that has potential to be disease-modifying.”
Biogen Idec Inc announced late last year that in a small early-stage study, its B11B037 drug, which blocks the beta amyloid protein, cut brain-plaque levels and significantly improved cognition when tested on patients with mild symptoms of, and possible signs of, Alzheimer’s.
The so-called ‘killer protein’ is currently the subject of Elan Pharmaceuticals’ clinical trials for its AN-1792 vaccine for Alzheimer’s disease. According to reports in Nature, the vaccine attacks the build-up of the beta-amyloid protein, to halt the disease and repair damage done. To date, the drug has only been tried on mice, but it is hoped that a treatment for humans will be on the market within five years.
While most Alzheimer’s research over the past 25 years has had an amyloid focus, Mayo Clinic neuroscientists in the US, while accepting that protein accumulates as the disease progresses, believe the collection of the abnormal tau protein in the brain could well be the main cause of the disease. When scientists from the Gladstone Institute of Neurological Disease in San Francisco tested the anti-inflammatory drug salsalate on mice with frontotemporal dementia, they found that the drug not only reversed all aspects of tau toxicity, but also protected against shrinkage of the hippocampus, which plays a core role in memory retention. The drug blocked the p300 brain enzyme, which triggers tau acetylation, which is typically raised in the brains of those with Alzheimer’s. The research findings were reported in the journal Nature Medicine.
In a further development in the area of existing medicines being found to have new applications, this month the journal Science Daily published the findings of research by Rutgers University, New Jersey, US, which found that a medication currently being used to treat cancer might help those with dementia and Alzheimer’s by helping to sharpen memory. The drug — the HDAC3 inhibitor RGFP966 — makes neurons in the brain more plastic and better at connecting, thus aiding the transmission of memories between brain cells.
Another study published in NeuroImage: Clinical shows that very low doses of the atypical antiepileptic levetiracetam calms excess activity in the hippocampus in patients with amnestic mild cognitive impairment — a condition that often leads to Alzheimer’s disease. The recent study validates the initial conclusions of a Johns Hopkins research team published in the journal Neuron three years ago and paves the way for a large-scale, longer-term clinical trial.
According to WHO statistics, schizophrenia affects more than 21 million people worldwide. Those with the illness are up to 2.5 times more likely to die early than the general population. For all that is known about the illness — an interaction between genes and a range of environmental factors are at the root and psychosocial factors may also be linked with the development of the illness — much remains to be learned.
Treatment-wise, WHO research confirms that while more than 50 per cent of those with schizophrenia are not receiving appropriate treatment, 90 per cent of those who are untreated live in developing countries.
On a positive note, a report in the Proceedings of the National Academy of Sciences confirms that researchers have developed a blood test for detecting schizophrenia. Because those with the condition have a higher-than-normal number of dopamine receptors in their white blood cells, the scientists propose to analyse those cells as a potential diagnostic test for schizophrenia.
More good news comes courtesy of a report in Nature, where the Schizophrenia Working Group of the Psychiatric Genomic Consortium (PGC) confirms that a global genome study has identified 108 genetic locations associated with schizophrenia. The fact that the 108 variations explain just 3.3 per cent of the human risk of schizophrenia shows the scale of the research yet to be carried out on this condition.
Rather than focusing on the individual genes that are associated with schizophrenia, researchers at the Washington University School of Medicine in St Louis, US, focused on the interactions between them, in an effort to identify the cause of the illness. They analysed the DNA of over 4,000 schizophrenia patients and concluded that the illness is not a single inherited disorder, as is commonly thought, but is eight separate genetic disorders that can combine in clusters and carry significant risks for the illness.
According to the WHO, bipolar disorder affects approximately 60 million people worldwide and it is estimated that approximately 40,000 people in Ireland are bipolar.
Scientists from the University of Bonn, the Mannheim-based Central Institute of Mental Health, and the University of Basel Hospitals, recently discovered five genetic regions that may be connected with the disorder.
US researchers at the UMass Medical School and the University of Miami Miller School of Medicine have also made a notable breakthrough. Their research, published in Nature Molecular Psychiatry, identifies what is thought to be a key genetic pathway underlying the condition. They found that Ellis van-Creveld (EvC) syndrome protects against bipolar affective disorder. Because EvC dwarfism results from genetic mutations that disrupt the signalling pathway known as sonic hedgehog (Shh), it is thought that the Shh pathway plays a role in bipolar disorder.
While most new treatment progress comes from research laboratories, sometimes potential natural therapies present in everyday settings. When a beekeeper who had Parkinson’s disease was injected monthly with the venom so as to become desensitised, he found that his Parkinson’s symptoms were reduced and researchers have now examined this phenomenon in the laboratory. Studies carried out at the Michael J Fox (Parkinson’s research) Foundation have found that bee venom slows the degeneration of dopaminergic neurons. Apitherapy (the medicinal use of honey bee products) is currently being investigated as a tool in the battle against Parkinson’s by a team at the Pitié-Salpêtrière Hospital in Paris.
Motor neuron disease
There have been a number of promising discoveries in the area of motor neuron disease (MND) recently, which remains one of the most devastating neurological diseases.
Disease-causing mutations in the C9ORF72 gene were first reported in 2011, and it is now linked with the familial strains of both frontotemporal dementia and MND. A repeating expansion of this gene has now been found in about 30 per cent of people with familial ALS and frontotemporal dementia, and 5 per cent of MND and frontotemporal dementia patients without a family history of disease. The discovery has allowed better understanding of the mechanisms leading to MND, which is critical for the development of future treatments.
Of the gene, Prof Hardiman says: “It’s important, as it causes approximately 10 per cent of the MND in Ireland.” One of the key researchers behind the discovery was Irish neurologist and scientist Dr Bryan Traynor, Senior Investigator at the National Institute on Ageing, US, whom Prof Hardiman reveals, with just a hint of pride: “I trained him.”
Advising that the next step in the treatment of MND will be gene therapy, she says that right now, what we are seeing is huge progress in the field of neuroregeneration. “This relates not only to MND, but also to Alzheimer’s, some forms of dementia and Parkinson’s.”
Studies are also now being conducted into how stem cells can be used to change the environment in which the brain works, Dr Hardiman continues. “Neuroregeneration is a very interesting scientific idea,” she says. “Under very strict control and research conditions, some of the hypotheses may be tested.”
Would it be difficult to find participants for investigations of that nature? “I’ve been linked with research for 20 years now,” Prof Hardiman replies. “In that time, I’ve found that Irish people are incredibly generous when it comes to taking part in clinical research. While knowing that a treatment might not work, they’re happy to participate, if that might mean helping to find cures for disease. The late RTÉ broadcaster Colm Murray was one such individual. He, like so many Irish, was brilliant in that way — incredibly generous and most altruistic indeed.”