HeliCure: towards a new therapy for Parkinson's disease

Can you tell us a bit about the new technology you are developing?

 So we work on Parkinson's disease. Parkinson's disease is the second most prevalent neurodegenerative disorder, and in fact is the one that is growing faster. It's around 10 million people affected by the disease at this time, but we calculate that in 2040 it will be more than 20 million people, so it's growing very fast.

Parkinson's disease is caused, at the end, by the death of certain neurones, which are called dopaminergic neurones, that are the ones that coordinate motor, and the death of these neurones causes these motor symptoms we see in the patients, but also some problems of cognition and some problems in the gastrointestinal tract. So, so far, we don't have any cure for this disease. We cannot stop it; we cannot slow down the progression.

The only thing we have is something to treat the symptoms, which essentially is administrating a kind of dopamine, which is what the patients are losing. And there is a connexion between the loss of dopamine and the aggregation of a protein, which is called alpha-synuclein, and therefore there is hope.

So, there is increasing evidence of a connexion between the loss of dopamine and the aggregation of a protein which is called alpha-synuclein. Therefore, stopping this reaction is seen as a hope for the therapy and this is where we are working in. 

What are the innovation aspects of your project? 

So, the aggregation of alpha-synuclein of this protein in the brain is a super complex process and generates many species. The best known are what are called amyloid fibrils and for a long time targeting these amyloid fibrils in the brain has been a therapeutic strategy. Unfortunately, this strategy didn't work and now there is evidence that there are smaller aggregates called oligomers that form early in the reaction of the aggregation, which are the real culprits of the disease. In fact, they  are the ones responsible for the dissemination of the disease in the brain. So now there is a new hope that targeting these specific species and blocking them could be a therapeutic strategy.

The thing is, that this is extremely difficult because these species are super transient and mobile. What we did is, first, try to understand the structure of these molecules and once we understand how they were, we designed something that could bind to these molecules specifically. We had the idea that a peptide that could be helical with two sides: one side that will be hydrophobic, the other side will be charges positively, thus being the perfect molecule to bind to these toxic species.        

The peptide is bound specifically to these oligomers with an increasing affinity. It's something amazing: it's nanomolar so this is in the same affinity of the best antibodies you can have and, more importantly, it doesn't touch the functional form of the protein.

This functional form of the protein works in the synapses in transmission, so you don't want to touch t  hem, right? So, it should be something which is selective. This blockage of these oligomers has two results. The first one is aggregation doesn't progress anymore, the second one super important is that you don't have neurotoxicity because you block the neurotoxic species. So essentially in a very small molecule you have the two properties you want to stop: the aggregation and the neurotoxic effects.

What is the status of your research? 

The idea is that the first studies we made were done with a model peptide, but we want something which is therapeutic. Our lab uses both computational and experimental strategies, so we designed an algorithm using artificial intelligence to identify the brain peptides that are like the one we studied before and indeed neuropeptides. After we synthesised five of them, we found out all of them work. This means our hypothesis is valida, but one of them works better than the other: HeliCure, the subject of this project. 

 So, once we validated HeliCure in vitro, we infused this peptide in the brain of mice that have Parkinson's model, and the results were very impressive. Essentially, these animals recovered motor symptoms and, more importantly, what we saw there is that they target specifically oligomers in the brain, so the molecular targe   it is the one we intended. The second thing is that preliminary data was telling us that this causes an increase in the levels of dopamine, which is what you want to have, to increase the level of dopamine in these people that have Parkinson's disease. 

What are the next steps? 

The next step of our research is essentially trying to find a way to administrate the peptide in a clinically relevant manner. We are focussing in two objectives:

1. The first one is a formulation for intranasal delivery, so the peptide arrives at the brain through the nasal area.
2. The second one is validating that this intranasal delivery has the impact we want to: not only that motor symptoms of the animal are regained but that the levels of dopamine are increasing in the areas where they have a relevant function- this is the objective and the cure.

What do you need to do to move forward? 

To move this project forward, we need additional funding. The idea is putting this funding in preclinical studies for two things: first, to ensure the safety of the peptide and second, to analyse which are the doses we must administrate to have the right effects.

Have you done this project collaboratively? Who has contributed?

In terms of this work, it has involved a significant number of collaborations because we have moved from the structural biology into animal models, so this could not be possible without several groups. I must mention Universidad de Zaragoza, where people helped us validating the activity of the peptides; University of Leeds in UK; University of Aarhus in Denmark; the Centro Nacional de Veterinología in Madrid, where people helped us on the structural studies. I don't want to leave aside Analia Bortolotti, our collaborator in all the animal studies and she's in Barcelona.

What is the potential impact of your therapy? 

If HeliCure works we will have a huge impact on two things: the first thing is the quality of life of the patients, second thing will be the timeline of these people. Essentially the idea is that we could extend the time where they don't have symptoms. This will also have an impact in health security systems because you will save the money you have to the board to the early stages of the cure of the patient. And, of course, to the families. So, all in all, I think that if HeliCure works, and we have evidence that it's going in the good direction, it will be a change in piloting in the way we tackle Parkinson's disease.

https://www.youtube.com/watch?v=evWGegJveQM