Nemaline Myopathy Support Group

Research

Prof. Nigel G. Laing (Australia)

Genetic Research on Nemaline Myopathy

Prof. Nigel G. Laing (Perth) is co-convener, along with Dr. Carina Wallgren-Pettersson(Finland) of the ENMC International Consortium on Nemaline Myopathy.

NMC04 helps the scientists : To see mention of the NM Convention 2004 published in the Australian science magazine, ask me for a copy of the paper!

2014

Genetic testing available in Australia.

2013

Dr. Gina Ravenscroft who works alongside Winthrop Prof. Nigel Laing in Western Australia has recently published about two new genes discovered in nemaline myopathy. Meaning KLHL40 and KLHL41 are now the 8th and 9th genes found to cause NM. A newspaper report is available here.

2012

Dear David,
Good to hear from you. As a diagnostic service we screen: Skeletal muscle alpha-actin (ACTA1), slow alpha-tropomyosin (TPM3) and beta-tropomyosin (TPM2). We also analyse cofilin (CFL2) but that is still on a research basis.
Yours, Nigel


Dr. Kristen Nowak and her team have excited the nemaline myopathy community by creating a world's first. A cure for the actin mutation in mice. (About 20-30% of "Nemaliners" have a mutation in their alpha actin gene.) This cured a congenital muscle disorder, extending the mouse's life from the expected 9 days to 2 years!

Below is a list of news articles as supplied by Dr. Nowak.

Nigel and Kristen have very kindly written about their recent breakthrough especially for us and this website. The widely published media statement is farther down this page.

1997 : Nemaline myopathy : Current Concepts

K.N. North, N.G. Laing, C. Wallgren-Pettersson and the ENMC International Consortium on Nemaline Myopathy.

A paper written in 1997 by Dr. Kathryn North.

Makes very interesting reading, although a little hard going, since it is written for scientists. I can email this document in MS Word (.doc) (92k), Rich Text Format (.rtf)(831k) or plain text (.txt)(14k). Requests to David: davidmcd_@hotmail.com

Saving mice lacking skeletal muscle actin with heart actin

Dr Kristen Nowak and Professor Nigel Laing
Centre for Medical Research - University of Western Australia, Western Australian Institute for Medical Research, B Block, QEII Medical Centre, Nedlands, Western Australia 6009, Australia

Recently we, with colleagues in Western Australia and around the world, published a research article in the Journal of Cell Biology, the title being "Rescue of skeletal muscle alpha-actin-null mice by cardiac (fetal) a-actin" (http://jcb.rupress.org/cgi/reprint/185/5/903).

What we have done is show that heart actin can rescue skeletal muscle actin knockout mice (eg mice with no skeletal muscle actin protein). We have thus shown that heart actin will work in post-natal skeletal muscle as an effective replacement for skeletal muscle actin.

Since we first found skeletal muscle actin disease in 1998/1999 we have always wondered whether heart actin would work in skeletal muscle and would thus be a target for possible therapies for skeletal muscle actin diseases.

Heart actin is not only the actin that works in the adult heart, but for unknown reasons, heart actin is also switched on and working in skeletal muscles during development in the womb. It however, also for reasons unknown, is normally turned off by the time of birth.

In 1999 we published that defects (mutations) in the skeletal muscle actin gene (ACTA1) could cause nemaline myopathy, intranuclear rod myopathy and actin aggregate myopathy. We now know that mutations in actin also cause core myopathies and congenital fibre type disproportion. We also know that mutations in skeletal muscle actin cause about 20-25% of all nemaline myopathy cases.

Most of the mutations identified to date in ACTA1 are dominant mutations, meaning that only one defective copy of the gene is sufficient to produce disease, even when there is a normal copy present. However some of the mutations in ACTA1 are recessive (meaning that two defective copies are required to lead to disease) and in most patients with recessive disease, they do not produce any skeletal muscle actin protein in their skeletal muscles at all.

In our latest work we have used two different lines of mice: 1) - skeletal muscle actin knockout mice and 2) - mice with heart actin in their skeletal muscle, which were made by using genetic modification which specifically allowed the heart actin gene to switch on in skeletal muscles after birth as well as during development in the womb.

The skeletal muscle actin knockout mice are like human patients with recessive skeletal muscle actin disease in that they do not have any functioning skeletal muscle actin protein. The skeletal muscle actin knockout mice have a severe muscle disease and normally die between birth and 9 days after birth.

Our theory was that heart actin could replace skeletal muscle actin in skeletal muscles. If we were right, then when we bred the two types of mice together, the heart actin genetically modified (transgenic) mice would cure the skeletal muscle actin knockout mice, and that is exactly what happened. By breeding the two mouse lines together, we generated mice with only heart actin in their skeletal muscles.

Some of the mice with only heart actin in their skeletal muscles have now survived for over 2 years, which is old age for mice. These "rescued knockout mice" also had skeletal muscles that functioned virtually as well as normal skeletal muscle. On some tests the rescued knockout mice actually performed better than normal mice.

Our work unfortunately does not yet relate to patients, but this is an important step on the way, and one which we hope in the future will lead to help for patients. Our work so far has only been done in mice. The importance of the work is that we have shown that heart actin can totally overcome the absence of skeletal muscle actin in skeletal muscle after birth. This indicates that heart actin is worth pursuing as a possible therapy, especially for patients with recessive ACTA1 disease, where the patient has no functioning skeletal muscle actin. Prior to this work, we could not be entirely sure that heart actin was worth pursuing as a possible future therapy, as perhaps for some important reason it gets switched off at birth and might have in itself led to disease if activated after birth.

Our work does relate to nemaline myopathy, but only to patients with nemaline myopathy caused by actin gene mutations and currently specifically only to those rare patients with recessive disease caused by absence of skeletal muscle actin. Our work as yet does not relate to patients with dominant mutations in skeletal muscle actin and not to the majority of nemaline patients, those with mutations in nebulin (NEB).

We now have to test whether heart actin can overcome dominant mutations in ACTA1 too, as although we have reasons to be hopeful that it will, for at least some mutations, we do not know whether heart actin could be a therapy for these types of mutations as well as for the recessive ones. We are currently doing these experiments.

We have previously shown that the recessive patients lacking skeletal muscle actin have themselves retained expression of heart actin in their skeletal muscle. Many of these patients are still severely affected. The best functioning of the patients lacking skeletal muscle actin have the highest retained levels of heart actin. Our results in the mice suggest that if we can increase the level of heart actin in these patients even more, we could improve the strength and abilities of the patients. We are currently therefore trying to find a way to keep heart actin switched on, or to reactivate it, in skeletal muscle in patients, so that we can attempt to do something similar to what we have done genetically in the mice. One way that we are trying to do this is that we are screening just over 1,000 different drugs to see whether any of them will reactivate heart actin in skeletal muscle, or keep it "firing" rather than it stopping working around the time of birth.

The drugs we are testing are all drugs that have already been approved for use in humans, but for other diseases/purposes, such as treating high cholesterol or blood pressure for example. What we hope is that one of these drugs will have as a "side effect" the capability of reactivating cardiac actin. In the best case scenario, if one of these drugs were able to do what we hope, theoretically this drug could be translated reasonably quickly into use in patients, as the drug would have already been shown to be safe to administer in humans. We are currently funded by A Foundation Building Strength to do this work.

If none of these 1000+ already-approved drugs can reactivate cardiac actin, then we would have to start screening other "libraries" of drugs that are available, but not yet shown to be safe to give to humans, or indeed find an alternative way to deliver cardiac actin to skeletal muscle. These approaches could unfortunately take a very long time to pursue, however we are very dedicated to trying to find a cure for these diseases.

Harry Perkins Institute of Medical Research

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Supporting MAP Nemaline

In 2010 Meriel (aged 21 months) was diagnosed with Nemaline myopathy, a very rare muscle condition with no treatment or cure, which changed the lives of her family overnight. Setting up a family fund like MAP Nemaline is a great way to fundraise for Muscular Dystrophy UK to keep our vital research moving forward.

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