MGA News Autumn 2003

As you may remember from previous MGA Newsletters, the muscle weakness in MG is caused by problems in nerve -> muscle triggering – the normal ignition system of the ‘voluntary’ muscles. When an electrical impulse arrives from the brain, it causes release of packages of ACh (acetylcholine) – the ignition keys. These cross the short gap and latch into the special ignition locks on the muscle surface – the ACh receptors (AChR) – and that then triggers a contraction. The spare ACh is broken down by AChE - our main focus now - to allow the muscle to relax again. In the myasthenias, there are usually not enough AChRs (in the LEMS, there isn’t enough ACh). We treat them with Mestinon® (an ‘anti-cholinesterase’); it works by directly blocking the AChE so that the ACh is destroyed more slowly and has a better chance of triggering the surviving AChRs in the meantime. Because these AChRs are completely different in the ‘automatic’ muscles in the guts, bladder and glands, they are not directly affected in MG. However, the AChE is similar there, and blocking it with Mestinon® can ‘overheat’ the automatic system, causing drooling, diarrhoea and the other side-effects you know well. The AChE comes in slightly different forms; one of them seems to be over-produced in MG – and somehow has damaged the nearby muscle.

Mestinon® is a chemical that latches into the AChE and directly stops it destroying the ACh. An imaginative new trick is to turn down the production of AChE – which EN 101 is designed to do. Like each of our proteins, the AChE is encoded by a precise genetic blueprint in our DNA (blue in diagram 1); we inherit it from our parents and go on decoding it throughout our lives. Normally, each blueprint is first copied into short-lived ‘messenger RNA’ (green) which is then ‘translated’ into one particular protein. This RNA can be selectively blocked by a tailor-made ‘mirror image’ ‘anti-sense’ RNA – of which EN 101 is a typical example. It ‘zips’ specifically onto the AChE messenger (red in diagram) and stops it getting translated into AChE. It was devised by Prof. Mona Soreq and colleagues at the Hebrew University in Jerusalem, and developed by Ester Neuroscience (who kindly gave us some of it to test). They think it particularly affects the damaging form of the AChE, and might be better for long-term treatment.

Its net effect is to cut down the AChE, which stays low for longer than with Mestinon®; however, after a day or two, the anti-sense gets used up and the AChE gradually gets replaced during normal ‘house-keeping’. Normally, our own RNAs are destroyed quickly, but that can be prevented by attaching synthetic chemical protectors; after doing that to EN 101, it even survives being taken by mouth.

The preliminary tests in MG were on 8 patients in Jerusalem, and 8 in my clinic in Salford who were monitored by Dr David McKee; we all knew who was getting EN101 and no one was given dummy pills. We chose 8 patients with myasthenia who were using moderate doses of Mestinon®, which they each stopped for the first 12 hours. Their muscles duly got weaker – as shown by their increased QMG score, a measure of weakness in the muscles of the eyes, swallowing, and limbs. EN101 doses were then slowly built up over two days; a medium dose was given on each of the next three days. The graph below illustrates the improvements in strength (fall in QMG), which were seen in 14 of the 16 patients. The average muscle score improved very significantly. Many patients seemed stronger on EN101 than they had been on their Mestinon®. However, one of our patients failed to respond to EN101, despite being very responsive to Mestinon® – which may hold valuable clues to how EN101 is working or is handled in different people.

One of the most interesting findings is that none of the patients got diarrhoea, one of the commonest ‘automatic’ side-effects found with Mestinon®. EN 101 seems to strengthen the ‘voluntary’ muscles particularly well, and could be even more specifically tailored to do that, to avoid the ‘automatic’ side-effects completely. Furthermore, it only needed to be taken once daily, the benefits apparently lasting at least 24 hours after it was stopped. Encouragingly, the improved muscle strength was seen within a few hours of giving an effective dose. While one might expect that fine-tuning and precise timing of the benefits would be harder than with Mestinon®, we did not notice any clear difference in this first trial. EN 101 would probably be more expensive than Mestinon®, so the NHS might want strong evidence of its advantages before accepting it.

I am very grateful to all those who helped conduct this study, especially Prof M Soreq, Ester Neuroscience and Dr D McKee.

MGA NEWS Autumn 2003

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