PARKINSON’S
V I R T U A L B I OT E C H
Most of the drug treatments we
currently have for Parkinson’s work
by replacing the chemical dopamine
inside the brain. But they cannot stop
the loss of brain cells, which means
symptoms get worse over time.
We now have a much better understanding
of how processes inside these precious
brain cells go wrong in Parkinson’s – causing
these cells to stop working properly and
Finding
molecules
Rigorous
testing
Drug
design
1. Finding molecules
The first step is to screen a large number
of drug-like molecules with a simple test
that swiftly identifies any that may have the
desired effect.
2. Rigorous testing
To find out more about the molecules, they are
tested in a range of more complex experiments
to identify those with the most promise.
3. Drug design
Now the group has been whittled down to
molecules with real promise, it’s time to start
honing and developing them into drugs.
This step needs skilled chemists who
are specialists in drug design. They will
painstakingly tweak the structure of the
molecules to improve their performance.
die. And this means we are ready to develop
treatments that can tackle the underlying
causes of Parkinson’s by changing the way
the brain cells work.
The key is finding small molecules that
are exactly the right shape and size – the
way a key fits a lock – and that target the
process that has gone wrong in the cell.
And crucially, they need to do this without
causing problems in other organs and tissues
that could produce serious side effects.
Selecting
the best
Safety and
effectivness
Testing
in people
This will help to ensure the drug gets to the
right place in the body, and has the maximum
beneficial effect with minimal side effects.
4. Selecting the best
With a set of experimental drugs with real
potential for treating Parkinson’s, the very
best ones are chosen to move into the next
stages.
5. Safety and effectiveness
Before any new experimental treatment
can be tested in people, it first needs to be
extremely rigorously tested in the lab to fully
understand safety and effectiveness.
6. Testing in people
New treatments that have been proven
safe and effective by all other methods are
carefully tested in people in clinical trials.
The stages of drug discovery
The majority of new treatments today come
from basic scientific discoveries, which often
happen in university laboratories. These
discoveries improve our understanding of
human conditions like Parkinson’s. However,
when a researcher makes a discovery, this is
just the start of the journey to developing a
new treatment.
What are we planning to do?
The crucial early stages of developing new
drugs and treatments are often led by
companies called biotechs.
They have special expertise in this vital stage
in the journey from a scientific discovery
to a new treatment.
But opportunities could be lost because
there's not enough investment from industry
to drive scientific discoveries forwards.
This is a major roadblock in our mission to
develop better treatments and a cure.
We believe we can step in here to bring new
treatments forward faster.
We’re calling this major new programme of
work the Parkinson’s Virtual Biotech because
we’ll be acting in the same way as a small
biotech company.
But unlike commercial biotechs, we will be
dedicated to developing new treatments
for one condition – Parkinson’s.
And instead of making money, our goal is
delivering better treatments that improve
life as quickly as possible.
How will the Parkinson’s Virtual
Biotech work?
We want to do the same type of drug
development work as a regular biotech
company, but we don’t want to build our own
labs, employ a huge team of scientists or buy
expensive equipment.
Instead, we will work in partnership with a
range of other organisations – these may be
companies, universities or other charities –
who have the facilities and staff to carry out
the scientific work for us.
We will carefully manage these projects with
guidance from a team of industry and scientific
experts who are volunteering their time.
We will bring these elements together to
create our own portfolio of projects – all at
different stages of the drug development
pipeline – in a manner similar to a commercial
biotech company.
This means we can deliver new treatments
at a fraction of the cost. And we can stay
agile – rapidly investing in the most promising
projects, and cutting off projects that turn into
dead ends, so that we make maximum use of
every pound we spend.
The discoveries in the past 10 years,
particularly in genetics, molecular biology
and biochemistry, provide us with a wealth of
promising ideas for new treatments that have
the potential to tackle the underlying biology
of Parkinson’s.
And that means treatments that can actually
slow, stop or reverse the development of the
condition are within our reach.
PARKINSON’S
V I R T U A L B I OT E C H
Developing drugs that protect brain
cells against oxidative stress
Finding
molecules
Rigorous
testing
Drug
design
Project background
Researchers in Sheffield have identified a
possible defence system that helps protect
brain cells in models of Parkinson’s and other
neurodegenerative conditions. They believe
activating this defence system may be the
key to saving the brain cells affected by
Parkinson’s. The defence system they’ve
identified helps protect cells from something
called oxidative stress.
Oxidative stress happens when there
are too many damaging molecules called
free radicals inside our bodies. Our bodies
constantly produce free radicals and
unchecked, these molecules can cause
damage to our cells and tissues.
Oxidative stress is believed to play a
key role in the death of brain cells in
Parkinson’s. Antioxidants are known to help
to protect cells from oxidative stress. There
have been studies to test antioxidants in
Parkinson’s, but so far the results have been
disappointing.
Selecting
the best
Safety and
effectivness
Testing
in people
A different approach to defending the
cells from oxidative stress may be more
effective. The damage that oxidative stress
causes inside cells is similar to that caused
in a house by a fire. Fires usually begin
quite slowly but once they are blazing are
difficult to put out. The team want to install
‘sprinklers’ that stop the fire early, rather
than calling the antioxidant ‘fire services’
after the fire has already taken hold.
The approach the researchers have been
working on involves a protein called Nrf2
that is part of the cells’ own defence
against oxidative stress. If a treatment
could be developed to activate Nrf2 it would
have the potential to slow or stop
the progression of Parkinson’s. But there is
a problem – small drug-like molecules that
have been shown to activate Nrf2 could be
damaging to cells and cannot enter the brain.
Dr Richard Mead has overcome these
issues by developing a technique to find
small molecules that promote the activity of
Nrf2 in a different way. Instead of activating
the protein directly, they are looking for
molecules that block another protein called
KEAP1, which usually sticks to Nrf2 and
interferes with it doing its job. With KEAP1
out of the way, Nrf2 can trigger the cells’
defence against oxidative stress.
Project details
Identifying small drug-like molecules that
have potential is the first step in the drug
discovery pipeline. This project will hit the
ground running as the Sheffield scientists
have already identified some promising
molecules.
The next step is to do further testing
to identify the molecules with the most
promise. To do this we are working in
partnership with Dr Richard Mead, Sheffield
University and a company called Sygnature
Discovery, who have the chemical expertise
needed to carry out this work.
Chemical specialists at Sygnature will tweak
the potential molecules to makes hundreds
of different molecules with very similar
structures. They can then compare these
molecules to understand more about how
they work and which will most effectively
activate the defence system in cells.
At the end of the project, we hope to have
generated drug-like molecules that target
oxidative stress by activating the Nrf2
pathway, have the correct properties to go
forward to intensive safety and effectiveness
testing, and later to clinical trials.
Cost and duration
£1million over 16 months
Partners
To complete this project, the University
of Sheffield and Parkinson’s UK have set
up a spin out company, called Keapstone
Therapeutics. This company will help to bring
the different partners together and ensure
that, if successful, the project is in the best
position to progress towards clinical trials.
Parkinson’s UK combines the expertise
and professionalism of a business with
the passion and focus of a charity to bring
breakthrough treatments to people with
Parkinson’s faster. Dr Janusz Kulagowski,
Drug Discovery Manager at Parkinson’s
UK, will be working closely with both the
University of Sheffield and Sygnature to
manage and deliver this vital project.
The University of Sheffield has a
strong commitment to drug discovery
and development and forms part of our
partnership to develop Nrf2. Dr Richard
Mead is lead academic and founder of
the Nrf2 project at the Sheffield Institute
for Translational Neuroscience (SITRAN),
University of Sheffield.
Sygnature is a leading provider of chemistry
services to the global pharmaceutical
industry. They work with many of the world’s
leading companies and charities in the UK.
Parkinson’s UK is the operating name of the Parkinson’s Disease Society of the United Kingdom. A charity registered in England and Wales (258197) and in Scotland (SC037554). © Parkinson’s UK 3/17 (CS2587)