CHDI Report: Day 3

Growth factors

The final day of CHDI's therapeutics conference began with a session
devoted to growth factors. A growth factor is a chemical produced by
the brain, that enables neurons to grow, remain healthy and live
longer. Because of these abilities, researchers have naturally
wondered whether growth factors might be able to help neurons remain
healthy in people with the HD mutation.

There are lots of different growth factors in the brain, which makes
them a confusing part of HD. Not only are that, but each growth factor
has distinct receptors. A receptor is molecule that 'catches' a
signaling chemical released from another cell, triggering messages in
the cell where the signal lands. Growth factors have many effects on
brain cells depending on which receptor they encounter. Clive Svendsen
from Cedars-Sinai in Los Angeles gave a nice overview of the different
growth factors in the brain. He has previously shown that the direct
infusion of one growth factor, 'Glial cell-derived neurotrophic
factor' or 'GDNF', into the brains of Parkinson's Disease patients was
beneficial. These kinds of results explain why there is great
excitement about being able to use growth factors as a treatment for
HD.

If growth factors are so beneficial to neurons, why not just give them
to everyone? Like most things in biology, the action of growth factors
is in a very careful balance. Too much growth factor can lead to all
kinds of problems, including memory and mood decline in mice. Moses
Chao from New York University mentioned that these limitations had
deterred some drug companies from working on growth factors. His lab
has been trying to discover what happens after the growth factor finds
its receptor. If we understood exactly how growth factors produce
their beneficial effects, we might be able to try and cause those
changes directly, without having to try to get extra growth factors
into the brain. One chemical, adenosine, seems to mimic many of the
changes in cells caused by growth factors. Gaining a better
understanding of these effects might allow treatments based on growth
factors with fewer side effects.

Jordi Alberch from the University of Barcelona has been studying the
growth factor BDNF - brain-derived neurotrophic factor. BDNF is
produced by neurons in the cortex - the wrinkly surface of the brain -
which reach down into the deep brain areas that are most damaged in
HD, the striatum. BDNF made in the cortex cells helps cells in the
striatum to survive. We've known for a while that BDNF levels are
lower in HD brain and that the abnormal huntingtin protein is to blame
for that. Alberch's group has been trying to figure out why BDNF
behaves abnormally in HD. By recording the movement of BDNF from where
it's made to the more distant parts of cells, he's found that BDNF
can't move freely round cells with the HD mutation. He's also studied
two different BDNF receptors. Cells with the HD mutation seem to have
overactive 'p75' receptors and underactive 'TrkB' receptors, an
imbalance which probably makes the cells die sooner. This work is
revealing lots of possible targets for new HD treatments.

That was the perfect backdrop to Alex Kiselyov's presentation. He's
part of the team at CHDI working to hit those targets with new drugs.
He revealed the techniques CHDI is using to design drugs, based on our
understanding of BDNF and its receptors TrkB and p75. The bit of TrkB
that sits outside the cell resembles the wings of a phoenix, Kiselyov
suggested, and the best area to target with new drugs is the place
where the wings meet. It was fascinating to hear how CHDI's chemists
experiment with specially designed molecules to come up with and test
drug candidates, and that this team alone is also working on at least
three 'backup plans' in parallel, in case the first approach doesn't
work out.

CHDI's internal programs

The final session of the conference was an important one. For the
first time, CHDI chose to update the scientists in attendance on their
own programs. CHDI does a huge amount of work facilitating other
people's research, but they have a number of drug development programs
happening internally at the company. These are the projects that
they're placing the biggest bets on. Robert Pacifici, Chief Scientific
Officer, kicked off the session by giving an overview of some internal
changes in how CHDI is organized. Because CHDI has grown - 54 people
now work directly for the company - they've reorganized themselves
into specific teams of researchers working on different aspects of HD.
Each team has several projects that they're trying to turn into drugs.
At any time, CHDI is working full-speed on about 10 different drug
development projects. For a sense of scale, that's more programs than
most large pharmaceutical companies have in all areas of brain
research, including much more common diseases like Alzheimer's or
Parkinson's disease. CHDI is changing the pace and scope of HD drug
development.

With this understanding, the scientific program ended with detailed
presentations on two of CHDI's drug design efforts. Ignacio 'Nacho'
Muñuz-Sanjuan, Vice President of biology, talked about his team's
project to inhibit a protein called 'Kynurenine 3-monooxygenase', or
'KMO'. Several academic labs have noticed that the activity of this
protein is increased in mouse models of HD, and they think that
blocking it might help with symptoms. But designing a drug is
complicated, as Muñuz-Sanjuan demonstrated. Each protein in the body
is a tiny complex machine that's built to do something very specific.
Most drugs work by blocking these tiny machines in a targeted way,
because if they're not specific the drug will cause side effects by
blocking other targets. To understand whether blocking KMO would be
helpful for HD, CHDI has bred several new types of genetically altered
mouse, looked carefully in human tissues from donated brains, and done
an enormous amount of chemistry to design drugs that target it. HD
mice that have less KMO improved in some ways but fared worse in
others, so the picture is complex but there's agreement that
developing drugs to target KMO is still worthwhile. CHDI has several
tailor-made KMO drug candidates that they are honing further before
testing in HD animal models. Drug development is incredibly difficult,
and failure is very common - most ideas don't turn into drugs that
work. It's only by exhaustively testing each idea, as CHDI is doing
here, that we can find out what works and what doesn't.

The final presentation of the meeting was by CHDI's Vice President of
chemistry Celia Dominguez. As a medicinal chemist, she specializes in
finding and designing drugs to hit specific targets in the body. The
project she presented was looking for drugs to reduce the activity of
a protein called HDAC4. There are eleven HDAC proteins and they all
act to uncover the DNA in the nucleus of cells. One of the ways the
abnormal huntingtin protein causes damage is by altering which genes
are switched on and off, so if the activity of HDAC proteins can be
reduced, the DNA will be less exposed and some of those problems might
be avoided. HDAC inhibitor drugs have been shown to work in a mouse
model of HD but have bad side effects. Important work by Prof. Gill
Bates in London has shown that HDAC4 is the most likely of the eleven
HDAC proteins to be a good target for possible HD treatments.

Working with BioFocus, a drug development company, Dominguez has made
impressive progress towards making drugs that will act on HDAC4. The
first step is to understand what part of HDAC4 is active, and what the
shape of that part is. Dominguez described it as a "picky pocket"
because not many molecules have the right shape to fit into it.
Starting with existing drugs, the team makes small changes to the
structure and tests how well each new drug fits into the pocket, all
the while trying to balance the risk of side effects and maximize the
chance that the drug will get into the brain if given to humans. It's
a difficult process because, all too often, improving one aspect of a
drug's performance causes others to get worse. Dominguez is a
determined drug-hunter, though, and she feels confident she'll have a
candidate drug by June this year, with properties desirable enough to
test in an HD mouse. That optimism was a great note on which to finish
the conference.

Sunset Conclusions

At the close of this conference, there was a feeling that important
new research had been presented and the atmosphere had been one of
unprecedented openness and collaboration. We know that, to HD-affected
people, as each year passes with no effective treatments for HD, it
can feel like nothing is being done at all, but meetings like this are
an opportunity to take stock of how much has happened and the real
progress that's being made. Crucially, they enable scientists to make
new connections and boost each other's research.

We hope our daily updates have given you a flavor of the way science
moves forward in small but important steps towards our shared goal of
effective treatments. Finally, look out for our article on our
interview with three of CHDI's top scientists - coming soon.