Muscular Dystrophy Association Inc, 36 - 38 Henley Beach Road, Mile End SA 5031
Postal address: GPO Box 414, Adelaide SA 5001| Email: info@mdasa.org.au | Tel: 08 8234 5266 | Fax: 08 8234 5866

Research

 

RESEARCH REPORT 2007

 

It is my pleasure to write another annual research report for you, this time for 2006-7.

 

Some people arrogantly or smugly claim that “there is nothing in my family”, meaning that they are promoting themselves as perfect because they do not know of any genetically determined disease in their family.

 

Most people, however, know little, if anything, about their family’s medical history back beyond that of their grandparents or great grandparents.  There are two obvious reasons for this, firstly, few of us know everything about our family histories for more than a few generations and, secondly, modern medicine has only had accurate descriptions and diagnoses of many diseases for less than 100 years and sometimes for less than the last five to ten years.

 

Also, because of spontaneously occurring mutations in our DNA (especially in the genes of the cells that develop into egg cells or sperm cells) it is impossible to prevent or predict the occurrence of genetically determined diseases – and so, irrespective of a person’s family history, these diseases can show up in them or in their children or in succeeding descendents.

 

While we should not, therefore, immediately become alarmed, we should, on the other hand, be sensibly vigilant.  Still, too often, we hear of mothers who notice something that is not right about their babies, infants or children, with their doctors wrongly reassuring them that there is nothing to worry about.  Mothers can, of course, be overly sensitive but reasonable assertiveness can be warranted and second opinions are always worth seeking.  The main reason for this is that the earliest possible diagnosis of most diseases is usually more helpful than later diagnosis with respect to treatments or possible cures, and this is equally true for the Muscular Dystrophies and related Neuromuscular Diseases.

 

Early post natal diagnosis of Duchenne Muscular Dystrophy (MD) and many other muscle wasting diseases has been possible for the last 30 or 40 years.  It is unfortunate that, during that time, some medical experts have argued strongly against performing the simple blood test that is necessary because a positive result would require disclosure to the parents that their new baby could have a serious muscle disease.  This has been seen as a special problem because of the absence of any successful therapy for most of these diseases.  But, even this argument, strong as it has been, now seems to be countered by reliable evidence that early intervention with steroid therapy, early employment of drugs that relieve the load on the heart (before there are any signs of damage) and perhaps modified nutrition, have a substantial effect on slowing disease progression and on prolonging and maintaining quality of life.  Not only this, but accurate genetic characterisation of these diseases is becoming essential as scientists and pharmaceutical companies are developing drugs that are likely to be beneficial, perhaps even curative, but only to people with specific gene defects.  The gene therapies that we hear about are never likely to be cure-alls for every condition, but will require careful design and matching to each genetic variant even within a single disease such as Duchenne MD.

 

In the case of some other neuromuscular diseases, such as Pompe Disease, early diagnosis is essential because successful therapy is now available and irreversible damage to both muscles and the nervous system can occur quite rapidly without the appropriate treatment.  In other diseases, such as Friedreich’s Ataxia, Spinal Muscular Atrophy and Charcot-Marie-Tooth disease, clinical trials are under way with every chance that early intervention, using one or other of the therapies being investigated, will soon be able to prevent the disabling consequences of these diseases.

 

Before writing more about potential gene therapies, I want to discuss the possibilities for stem cell therapies.  By now everyone will have heard that some cells found in adults and all cells found in early embryos (such as those made up of only a few cells) have the ability to become any kind of cell by a process known as “differentiation”.  Many of these stem cells are also each capable of growing and dividing into two new cells, time after time, rapidly expanding the total number of such cells into the millions (eg 1, 2, 4, 8, 16, 32, 64, 128, 256, 512, 1024, 2048, etc., until after only 24 divisions there would already be over 16 million cells).  This could, potentially, enable us to grow in tissue culture, inexhaustible supplies of particular kinds of cell, such as muscle or nerve cells, to replace those that are damaged and lost in neuromuscular diseases or in accidental traumas.  If this could be achieved it would allow any genetically determined muscle disease to be treated and, perhaps, cured if initiated early enough.  The difficulties, however, arise from our own immune systems.

 

Myoblast stem cells:

The possibility of using myoblasts to treat muscle diseases was suggested
around 20 years ago but, despite intensive research efforts, has not proven to be effective.  Healthy myoblasts from genetically unmatched donors or embryos initiate strong tissue transplant, rejection reactions, are attacked by cells and antibodies of the immune system and do not survive.  Even with quite strong immunosuppression this has not worked and strong immuno-suppressive drugs are also dangerous, especially for people prone to respiratory infections, as many are who have a neuromuscular disease.  There is the possibility that a patient’s own myoblasts, extracted from their own muscles, may be able to be genetically corrected, expanded in number and then transplanted back into the patient.  This would eliminate the tissue rejection problem but has not so far been achieved.

 

Mesoangioblast stem cells:

These cells are derived from the walls of tiny growing blood vessels.  We know that such cells are continually repairing blood vessels as they are damaged by everyday wear and tear, being torn during exercise, bruising and minor skin abrasions, for example.  It seems that they have a capacity to develop into muscle cells under some conditions and to produce the protein, dystrophin, which is missing in Duchenne MD.  Unfortunately, the published results from trials using mesoangioblasts in animals with MD are not convincing.  Also, the same problems arise with the immune system, as for myoblasts.

 

Bone marrow stem cells:

 

Most people will know that bone marrow transplants have been used successfully for many years to treat certain blood diseases, provided that the donor bone marrow is very closely matched to that of the recipient.  What is less well known is that bone marrow contains stem cells that can restore, not only many different varieties of blood cell, but can also differentiate into many other kinds of cell including nerve and muscle cells.  Again, unfortunately, several factors, at present, work against successful use of bone marrow stem cells for the treatment of MD.  They are rare among bone marrow cells, are not especially easy to expand in tissue culture and the immune system is still a problem.

 

Menstrual blood stem cells:

An unlikely source of muscle stem cells has recently been discovered in menstrual blood.  This discharge contains not only blood cells but also lining cells from the walls of the uterus that are discarded and then regrow each month.   They could be easily obtained, without the trauma associated with the aspiration of bone marrow from a donor or the necessity for operations to obtain muscle or skin biopsies to extract other stem cells and special ethical approval for collecting them would generally be unnecessary.  Not only this, but their numbers can apparently be readily expanded in tissue culture. This raises the interesting possibility that young women might be able to be readily treated with their own stem cells (provided that these cells had been genetically modified, as appropriate).  Being treated with their own cells should cause no tissue rejection.

 

Embryonic stem cells:

Although embryonic stem cells hold considerable potential, the scientific understanding of them is still really in its infancy and ethical difficulties associated with studying them will add to delays in their therapeutic use into the foreseeable future.

 

Much of my commentary on stem cell therapy may sound quite negative.  On the other hand, if it could be made to work, then it could really be a cure-all, at least for all of those neuromuscular diseases in which the primary defect lies in the muscle cells, themselves.  New muscle derived from the stem cells could, perhaps, replace the diseased muscle, no matter what the disease.

 

I now want to return to gene therapy.  Genetic errors of the kind that occur in the neuromuscular diseases can, theoretically, be corrected or compensated in a number of ways.  Clinical trials of several of these methods are at present under way, some in Europe and the United Kingdom and others in the United States.

 

Exon Skipping and Antisense OligoNucleotides (AONs)

Small pieces of nucleic acid, called antisense oligonucleotides, have been known for many years to stick to our genetic material (the nucleic acids, DNA and RNA).  These AONs act a bit like a very fussy kind of velcro, that is, they will only stick to a particular length of nucleic acid if the two are exact, but opposite or antisense, matches to each other.  Think of a thousand chocolate bars and snapping each of them in the middle.  If you then take any of the halves, it will only exactly match its original opposite number.  But the AON will not only match but also stick, only to its opposite number.  Now, what is the use of that?  More than 10 years ago, a Japanese scientist Masafumi Matsuo suggested that such an AON might be able to be made to a certain segment of the dystrophin genetic material and then chemically “nailed down”.  If correctly designed, the AON at this point could divert the gene reading machinery into a detour, around disastrous genetic errors, only to return to reading the normal gene again well beyond the error.  He reasoned that this could be used to convert some of the more serious Duchenne MD cases, lacking dystrophin, into the less severe Becker MD where the dystrophin protein may be shorter than normal but still functional.  This has since become an area of intense research with a preliminary clinical trial in the Netherlands completed and one in the United Kingdom just starting.  Results from the Dutch trial have been reported at a conference in Ottawa, Canada, last May, but not published in full.  The most information that I have about it at present comes from the Muscular Dystrophy Association USA website, as follows:

“Gert van Ommen at Leiden (Netherlands) University presented what many consider the most exciting new data. He announced that four DMD-affected boys in the Netherlands who were given an exon skipping compound targeted to their genetic errors all began producing what appears to be functional dystrophin.  Van Ommen, with colleagues at Leiden University and at Prosensa, a Dutch biotech company, gave each of the 10 to 13-year-old boys a single injection of an exon skipping compound into a front lower leg muscle.”
It should be pointed out that this was a trial to test the safety of the drug and the muscle injection procedure.  There was almost certainly no expectation that muscle strength would be improved and probably no testing to see whether it had.
The trial just beginning in the UK is similarly lacking in specific details.  About all that we know is that it involves the use of one or more similar exon skipping compounds injected into one tiny muscle on the upper surface of the foot.  This trial again involves a small number of boys (believed to be nine in total).  One report says that they must be over 16 years of age to give their own informed consent for participation in the trial while another gives their ages as 12 to 17.  This trial is, again, mainly to test the safety of the procedure and whether functional dystrophin is produced.  It is a major concern of mine that the participants in the trial may not have been given accurate and ethical information with respect to what they can expect from it.  One 16 year old participant has, for example, been quoted on the BBC’s website, where the announcement was made, as being “hopeful that taking part in the trial will transform his prospects”, and saying:
"I will be able to move around a bit more, and have some independence, and maybe take my Mum out."
It seems very doubtful that any of this is likely to be achievable using exon skipping therapy as a result of this trial or in the near future for reasons that I will mention briefly later.

 

Read through of nonsense mutations

 

The pharmaceutical company PTC Therapeutics has received a great deal of publicity in the last couple of years with respect to its compound PTC124 which, it claims, has been able to treat Duchenne MD successfully in some preliminary clinical trials by causing read through of nonsense mutations.  Nonsense mutations modify just one code letter in a gene to cause the reading of that gene to stop at that position and before the normal end of the gene.  Read through enables the full length of the gene, in this case for dystrophin, to be read and the dystrophin to be produced and correctly used in the muscle cell.  Once again, however, insufficient details are available.  The company’s publicity and reports on the MDA USA website suggest that “dystrophin protein was restored in about half of 12 boys” treated with PTC124 for one month.  There is no information about the level of restoration, eg, 10% or 50%, nor is there any mention of the specific nonsense mutations in those boys who were treated.  This is especially important as it is well known that agents promoting read through work best with only some nonsense mutations.  Benefit from PTC124 might, therefore, be quite significant in some Duchenne MD boys with nonsense mutations but be without effect in others.  And just what is meant by “about half of 12 boys”?

 

Gene supplementation

 

In many animal models of genetically determined muscle diseases it has now been shown to be feasible to supplement defective DNA with correct versions of genes using viral transfection.  This involves encapsulating the relevant gene inside certain virus types that transmit the gene to muscles while otherwise being unable to cause any disease, themselves.  Again, intensive research is under way in this field, with clinical trials beginning or proposed. 

At this stage in my report, I find it necessary to state the following.  Incredible scientific and medical advances are being made, daily, with respect to neuromuscular diseases, but the hype generated by the media must be recognised as such, as it is mainly there to attract ratings and advertising revenue.  So, although there is much cause for hope of future treatments and cures, few, if any, of these are likely to be available tomorrow.

 

Meanwhile, what should we do?
Everyone has heard of the term “scarred for life”.  This becomes obvious when we receive a significant skin wound but it is equally true of our skeletal and heart muscles and of our brain and nervous system.  Neuromuscular diseases scar people’s nerves and muscles for life.  Once the scar tissue is present, it is difficult or impossible to restore nerve or muscle function.  In this regard, too, a great deal of research is being undertaken to discover ways to prevent or suppress inflammation in damaged tissues and the scarring that accompanies it.  The take-home message, therefore, is to seek the earliest possible diagnosis of any neuromuscular condition and then to use the best ways known for keeping the disease from progressing and the scar tissue from forming.  We already know some ways of doing this for Duchenne MD, as I have mentioned, above.  Where there is a treatment, as in the case of Pompe Disease, the earliest possible diagnosis and therapy is imperative.  For the other diseases, ask questions, find out if there is anything on the horizon and try to slow disease progress as effectively as is currently possible.  This will give the best chance for repair at a later date.  It is important to be aware that none of the therapies that I have mentioned, so far, can repair tissue that has been “scarred for life”.  Perhaps, at some time well into the future, we will find a way to soften or dissolve scar tissue so that it can be replaced by normal nerve or muscle cells - but not yet.  Therefore, as a Muscular Dystrophy Association, as clients, parents, carers and other stakeholders and as compassionate citizens we must work to ensure that appropriate care is provided where it is needed.  We must lobby governments for appropriate help.  We should stop whinging about paying taxes and lobby for them to be increased rather than reduced so that the help we want can be paid for as it is in Scandinavian countries.  We must also raise more of our own funds, for services and for research.  When I became president of MDA South Australia in 1975 our annual gross income was $1,500.  In the 10th year of my presidency it was $100,000, an increase of more than 60 fold.  Our gross annual income is now $1,500,000.  I would like to see us aim towards $100 million in the next 10 years, another 60 fold increase.  “Impossible!” you might say.  To us in 1975, $100,000 looked equally impossible.

 

Impossible things

In the latest issue of The Adelaide Review, Mark Twain’s visit to Adelaide in 1895 is remembered.  He is reported to have stated, “Truth is stranger than fiction because fiction is obliged to stick to possibilities; truth isn’t.”
In a similar vein, an article in a recent issue of MDA USA’s magazine Quest, quotes Lewis Carrol’s writings from “Through the Looking-Glass and What Alice Found There” which followed his better-known children’s book, “Alice in Wonderland”.  In the quotation, Alice is saying to the Queen, “There is no use trying …one can’t believe in impossible things.”  The Queen replies, “I daresay you haven’t had much practice.”
We all need practice at believing in impossible things.  We can raise impossibly more funds than we do right now.  We must think impossibly.  We can achieve the impossible with respect to the services we provide and with respect to the amount of research that we support.  And above all, those impossible treatments and cures can be achieved.  As Mark Twain is saying, impossible things can be true.

 

Allan Bretag
Director of Research and Acting President