Update on gene therapy approaches to treating neurodegenerative disease

Every day there are two sets of talks going on at the same time during the International Symposium. On Saturday morning there was a symmetry to what was being discussed in these parallel sessions. Both were talking about the inherited form of motor neurone disease (MND). One as reported from Sara’s blog was from the clinical perspective of talking through the possibilities and implications of having a genetic test, if the inherited form of MND runs in the family. I was in the other set of talks going on – exploring ways to develop treatments for inherited MND.

For those with inherited MND there are not currently any treatments to prevent the effects of the gene damage that is being passed from one generation to the next. However, research is underway to find such treatments. As these treatments are, by definition, designed to alter how these faulty genes work, they’re collectively known as gene therapy.

Different approaches in gene therapy

All three talks in this session of the symposium talked about a different, complementary approaches. Adrian Krainer spoke about ways to alter how genes are read. In the following presentation Brian Kaspar explained his research into ways to get copies of the healthy, unaffected gene into the body and working to counteract the damaged gene. They both showed how gene therapy might work in the neuromuscular disease spinal muscular atrophy (SMA), however the principals of how they work can be applied to MND.

Prof Krainer’s ASO approach in SMA

In SMA there are two genes involved, one called SMN1 which doesn’t work at all, and a second gene SMN2 that works at a reduced level. The reason why SMN2 works at a reduced level is because of some over enthusiastic  editing of the gene once it has been read – so enthusiastic that a really important part of the instructions has been cut out.

Researchers already know that a reason for this over-editing is due to a sign in the code that says its ok to cut this bit. Imagine reading a thriller where you come across a heading saying ‘this bit is boring’ – you may be very tempted to skip this bit, but you might miss an important part of the plot. Prof Krainer’s approach was to use a chemical called an antisense oligo (ASO) to remove this header, and encourage the cells to read the seemingly boring bit of the instructions. This approach is currently in early stage clinical trials for SMA.

Over the barricades

As with all treatments, finding something that works to correct what’s going wrong in the body and whether it will be safe are important fundamentals of the research. However, working out how to get the treatment to the part of the body where it is needed, how much to give, how often and what happens to it afterwards are vital too.

A lot of work has been done to work out these practical considerations in gene therapy. “We know have unprecedented ability to target motor neurones and astrocytes – these were undreamt of a few years ago“. The headline from a science journal echoed Prof Brian Kaspar’s comments “Over the barrier and through the blood to the central nervous system delivery we go”. He give an elegant overview of steps along the way in the history of gene therapy to where we are now before talking about his current research.

Prof Kaspar’s approach was to create a delivery capsule containing ‘ready-to-read’ versions of the healthy copies of the faulty SMA gene. He has begun applying the same approach for a SOD1 gene therapy for MND. This is in an early stage of development and is not ready for clinical trials yet.

Why are advances in SMA helpful for MND?

The goal in SMA and in inherited MND is to target and correct faulty genes that cause the condition. The researchers showed two very elegant and different ways to make these corrections. These might be helpful in tackling the diversity of faults in the genes related to MND – for example C9orf72 is faulty in a very different way to the SOD1 gene.

Both SMA and MND affect the motor neurones, and much progress has already been made in the practical considerations of getting drugs to hard to reach motor neurones in the brain and spinal. In this way too, we hope that MND can piggy back on the exciting early results seen in SMA.