Spinal gene therapy

A gene therapy breakthrough for an inherited motorneurone condition called spinal muscular atrophy, or SMA, has been unveiled by scientists at Oxford University. Patients with SMA cannot make sufficient amounts of a protein called SMN - short for "survival motorneurone" - which is coded for by a gene called SMN-1. What Suzan Hammond and her colleagues are announcing this week is a DNA sticking plaster or "patch" that can boost the activity of a backup gene, called SMN-2, that can make up for the missing SMN-1. The way they get this genetic patch into the affected cells is by coupling it to a short protein, or peptide. Chris Smith found out how the technique restored a normal lifespan to mice with the animal equivalent of spinal muscular atrophy...

Suzan - Spinal muscular atrophy is an inherited disorder that mainly affects children and starts to present between zero and six months of age. It results in death in the motoneurons in the spinal cord and these motor neurons they reach out into the skeletal muscles.  So when they die the skeletal muscle becomes disused and it starts to become degenerated. It's caused by a mutation in the survival motor neuron gene - the gene that's inherited for creating SMA.

Chris - Given that this is a genetic disorder - how might we be able to tackle it then?

Suzan - So, in SMA, we have two forms of the gene that causes SMA - SNM-1 and SNM-2. And in most of us SNM-1 is fully functional and will give all the protein that is needed to survive and to be healthy but in patients there are mutations or deletions in SMA-1. So we left with SMN-2, which only gives about ten per cent of this protein that you need which isn't enough for survival. So what we try to do is we try to enhance the amount of protein that SMN-2 gives.

Chris - So there are two genes (SMN-1 and SMN-2). A healthy person who doesn't have this condition has a normally working copy of both but SMN-1 produces the vast bulk of the protein that you need from that gene. And in people who have damaged that gene, they get this condition but they do still have the SMN-2 gene limping along and you're saying - can we pep that up in some way in order to bring them up to the level that would make them healthy?

Suzan - Yes. So we're quite lucky to have the SMN-2 gene that every patient has so with one kind of treatment we can target on almost one hundred per cent of patients.

Chris - Right, So how do you try to persuade SMN-2 to rev up its production so that it produces enough of the stuff you need to keep the cells healthy?

Suzan - So, in SMN-2, it creates a product which isn't what we would call "functional." And what we have designed is these short bits of DNA, which  act as a patch, in which it can combine itself very well onto these products and, therefore, make it a functional product.

Chris - How do you get those patches into the cells that need them?

Suzan - On their own it's very hard to get these patches into the cells. We have designed something which we call "peptides" which you could think of as a passport or a key that you add to these patches and that really allows these to get into the cell that is required.

Chris - How do they work - how do they do that?

Suzan - It's a little bit unclear. It's very non specific - it's the type of charge that these peptides have and it seems to allow uptake of these patches into the cell.

Chris - So you have a lump of protein - these peptides which you couple to the patch so one's holding hands with the other. And the passport - the peptide gets it into cell and then the patch - the short sequence of DNA does the business once it's in the cell?

Suzan - Yes, exactly.

Chris - And does it go everywhere in the body or does it target the delivery to those motor nerve cells that are most vulnerable in this condition?

Suzan - It goes everywhere in the body.

Chris - So how do you know this works - what tests have you done to show that this has got legs?

Suzan - We've treated mouse models of SMA that are very, very severe, so these models will only survive till about twelve days after birth. And when we introduce these peptide patches into these mice on the day that they're born, they increase their survival to a mean of around four hundred and fifty six days.

Chris - From what - a daily dose or once?

Suzan - Twice - it the day of birth and then two days after.

Chris - Good grief! So two doses is enough almost to give these mice a normal life span because mice don't live that long do they?

Suzan - Yes, it's essentially a normal life span.

Chris - And it goes into the bloodstream?

Suzan - Yes.

Chris - What about the function in these mice? I know you're saying that they have a normal life span but do they appear to be functionally normal - do they get muscle problems or do they appear not to?

Suzan - They're essentially normal. They're as strong as normal mice; they're bigger than untreated animals and their what we call "neuromuscular junctions," which is the area where the nerve hits the muscle - that's completely normal as well.

Chris - And do you think that this protein - the peptide passport - will also work in humans?

Suzan - well we certainly hope so. If you inject pups on the day that they're born we say they have sort of less developed biological barriers so it would be a bit easier for this to get through the body. But we can do it in the adult animals and, in the adult animals, we still see it getting into the brain and the spinal cord. And so we really hope this will translate into humans.

Chris - And so, the next step?

Suzan - Well the next step is to try to make this a clinical trial. We are working to get this through all the things that need to happen to put it into a clinical trial - the safety data and that sort of thing. And then, in a couple of years, we hope to start recruiting for a clinical trial in this.