13 / 11 / 2023
Reflections on Drug Repurposing to Replace Animals on World MS Day
A personal perspective from FRAME Research Manager Juliet Dukes
Today, Tuesday May 30th, is World MS Day. More than 2.5 million people across the world have Multiple Sclerosis (MS), with over 130,000 of us in the UK. The immune system mistakes myelin, the coating of nerve fibres in the brain and spinal cord, for a foreign body and attacks it. This damages the myelin and nerve cells, neurons too, causing disability to accumulate over time.
Everyone’s MS is different – no two of us have the same range and severity of symptoms, even if we’re closely related. MS is not directly inherited from parents, but family members do have a higher risk of developing it. My maternal aunt had it, my paternal grandmother had it, and so does my sister-in-law. What causes MS is still unclear, but it seems that genes make up half the risk, and combine with other factors in the world around us to set it off.
An insight into the brain of Dr Juliet Dukes
I was diagnosed in 2015. During each of the following two years, I spent a week as an outpatient at Barts and the Royal London hospitals receiving an infusion of a drug called ‘Alemtuzumab’. Alemtuzumab is an antibody against CD52, a protein expressed on the surface of mature lymphocytes (white blood cells), key components of our immune system. Alemtuzumab results in a dramatic and long-lasting reduction in blood lymphocytes, which can leave patients vulnerable to infection, at least in the short term.
But this incredible antibody didn’t start life as an MS therapy…
Alemtuzumab has many purposes
Alemtuzumab was originally developed in the 1970s to prevent rejection of bone marrow transplants in blood cancer patients and to treat vasculitis (inflammation of blood vessels). It has been used against rheumatoid arthritis, and in 2001, was approved in Europe for the treatment of chronic B-cell lymphocytic leukaemia. It has also been used to immunosuppress liver, kidney and pancreas transplant recipients (1).
Using the same drug to treat different diseases
Many clinical trials for people with MS are testing repurposed drugs (like Octopus) – drugs already approved and licensed to treat a different disease. How do researchers get a lead on whether a drug can also be used for something else?
- Side effects of drugs happen because they reach multiple parts of your body and can act in many ways. What can be unwanted side effects in some patients, may be beneficial to others.
- Medical records can be used to look at the effects of a drug on conditions for which it was not originally prescribed. Data is ‘mined’ retrospectively to develop a “virtual prospective” drug repurposing study (2), (3).
- In silico modelling and bioinformatics allow hundreds or thousands of existing drugs to be tested for a different condition and reveal a new use for them.
Repurposing drugs can help replace animals
MS doesn’t occur in other animal species, but an approximation of it is induced in animals as Experimental Autoimmune Encephalomyelitis. This group of diseases, with some similarities to MS(4), (5), is generated in mice, rats or non-human primates by injecting them with protein fragments derived from the central nervous system, which are emulsified in an adjuvant.
This can result in a severe level of suffering for them (6).
As a patient, a scientist, and animal advocate, the knowledge that animals undergo procedures in this way, to try and benefit me, and other people with MS, is very difficult to live with.
In theory, because we know the drugs are safe for healthy humans, and patients with the original target disease, repurposing should speed up the drug discovery process and allow us to go straight to clinical trials in humans.
However, preclinical studies in animals are often still done to increase confidence in the drug’s safety and efficacy for its new purpose. But if the disease mechanisms are poorly understood (as with many neurological conditions, like MS) and the associated animal ‘model’ shows poor translatability, preclinical animal studies might be at best irrelevant, and, at worst, misleading. Misleading data could result in the development of a vital drug that is safe and effective in humans being abandoned, or mean a drug only effective in treating the ‘model’ disease in animals goes on to be tested in humans.
What I would like to happen
The potential for using old drugs for new treatments is clear. The NHS Medicines Repurposing Programme has been established in the UK, and LifeArc and the Medical Research Council have since developed a drug repurposing toolkit to help stakeholders (researchers, charities, etc) overcome obstacles in the process. In the absence of a suitable existing disease model they state “Non-clinical data may not be a requirement for your programme to progress – funders and MHRA may be able to offer advice on your individual case.”
I would like to see a commitment from the drug development community to use the recently proposed repurposing research criteria (7), to waive the need for licensed drugs to undergo preclinical safety and efficacy testing in animal ‘models’.
This change could speed up getting novel therapeutic approaches to patients without untoward risk, reduce the overall waste of inadequate animal ‘models’, and improve the precision of research efforts. This is all the more imperative when the current animal ‘models’ do not represent the complexity and spectrum of human disease, such as MS, and can lead to confounding results.
With a stated commitment to this, thousands of animal lives will be saved and patients will have speedier access to treatments.
- Meyler’s Side Effects of Drugs
- Mining Retrospective Data for Virtual Prospective Drug Repurposing: L-DOPA and Age-related Macular Degeneration
- Levodopa Positively Affects Neovascular Age-Related Macular Degeneration
- In Vitro and In Vivo Models of Multiple Sclerosis
- Mouse Models of Multiple Sclerosis: Lost in Translation?
- Reducing suffering in experimental autoimmune encephalomyelitis (EAE)
- When Enough Is Enough: Decision Criteria for Moving a Known Drug into Clinical Testing for a New Indication in the Absence of Preclinical Efficacy Data
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