New from old: the search for Parkinson’s disease treatments

Current treatments for Parkinson’s disease are only symptomatic and fail to halt disease progression, leaving patients increasingly disabled and affected by drug side-effects over the course of their treatment. Dan Richards talks to Dr Maria Herva-Moyano, University of Cambridge who has this week been awarded an NC3Rs David Sainsbury Fellowship, to develop a new screen for drugs to treat Parkinson’s disease, using a method which drastically reduces the number of animals used and looks for new cures from old drugs.

What motivated you to focus your research on Parkinson’s disease?

Since I can remember I have been scientifically curious, being quite interested in finding out how nature works and what happen if things are altered. That’s probably why I came into the research world with a project on prions, the misfolded and pathological version of a normal cellular protein, because conceptually they challenged the central dogma of molecular biology. Suddenly proteins were not the end of the genetic information flow but an entity capable of transmitting conformational information that would shape its normal isoform into its aberrant form. This idea thrilled me and I dedicated myself to the study of prions and their transmission.

When I learned that the unique characteristic of prions was not that unique but shared with other proteins linked to pathology such as alpha-synuclein in Parkinson’s, tau in Alzheimer or huntingtin in Huntington’s disease, I realised that perhaps prions were not really an exception but a much more generalised mechanism of protein misfolding and disease. Then I thought that I could be able to apply my prion knowledge to many other diseases and I decided to move to Parkinson’s. This decision was also motivated because of an inner need to work in a patient’s closer environment, and translational research was growing on me.

Why did you apply for the NC3Rs fellowship?

Most of my early research was done in animal models because there was nothing else available to study prions. Later on, fast and reliable in vitro systems were developed and working with cell cultures and even test tubes became possible. When I moved to the Parkinson’s field it was already with the idea of trying to move away from in vivo to in vitro so I started working in a model that would allow me to do so.

During the early steps of developing my in vitro system it proved that it could be a useful system to study Parkinson’s disease focusing on alpha-synuclein and its aggregation. Then it was just natural to look towards funding related to the 3Rs as it will replace animal use in my research. Also, I felt encouraged and motivated by my two supportive mentors, who agreed that this NC3Rs fellowship would allow me to work in my own project, putting myself onto the pathway towards independence as a scientist.

How will you use the NC3Rs fellowship to advance your Parkinson’s disease work?

It is a three-step project that aims to study, first in a high-throughput approach and later on with two validating models, the effect of two libraries of already marketed compounds on the aggregation of alpha-synuclein.

Alpha-synuclein’s aggregation in intraneuronal inclusions called Lewy bodies is a hallmark of Parkinson’s disease. The spreading of this aggregated protein in the brain is related with the progression of the disease. So by inhibiting alpha-synuclein aggregation we could potentially stop these proteins spreading and alter Parkinson’s development. What I aim to do during the length of my fellowship is to use an initial high-throughput screen to search for drugs that would inhibit alpha-synuclein aggregation using as few animals as possible.

Afterwards the hits will be confirmed by the same method and another in vitro model. Finally the successful hits will be used in an animal model to establish their biological relevance. Conceptually, the project is designed in an inverted pyramid fashion so that in every step the number of compounds will be reduced and only a few will be tested in animals. In addition, the fact that all the information about the compounds is already publicly available will help refine animal work.

How is this method better than using the available animal models?

It can reliably provide plenty of information about the anti-amyloid potential of many compounds and discard many useless drugs before the final and so far unavoidable step of going to an animal model, before moving to a clinical trial. Furthermore, using libraries of already approved drugs can further reduce the number of animals needed as all the pharmacokinetic experimentation has been done before the treatment is made available to patients. The existing information about those drugs will also help refine the experimental design using animal models.

What impacts will this have for wider research looking for drugs to treat Parkinson’s disease, if your research is successful?

With the approach that is planned we will be able to test hundreds of compounds already available in pharmacies, from which we might get a compound or even several that would slow or detain the progression of Parkinson’s disease. It would have to go through clinical trials before even thinking of its use by patients, but compared with traditional drug development we would have saved an average of five years and hundreds of animals. So this approach not only will save time, but also animals and money.

In a wider context, protein misfolding, aggregation and pathology is common to many other diseases, so we might be able to apply this 3Rs approach to study the anti-aggregation effect of drugs in other diseases. This would exponentially increase the impact that this methodology has in decreasing the use of animal models for amyloid diseases.

How are you planning to disseminate this research?

I have already presented preliminary data of my in vitro system at an international meeting and I will present its progress in the World Parkinson’s Congress in October. In addition we are almost ready to submit a manuscript describing the technique and its potential, so hopefully the information will be made readily available to the scientific community. I believe that if implemented in other labs it would definitely help replacing a great number of animals in Parkinson’s and perhaps other amyloid diseases research, so the more people with access to the data, the better.

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