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CMT – the Approach to Developing Treatments

Professor Mary M Reilly MRC Centre for Neuromuscular Diseases,mreillyportrait
National Hospital for Neurology and Neurosurgery and Institute of Neurology,
Queen Square, London, UK

Charcot-Marie-Tooth disease (CMT), and the related disorders distal hereditary motor neuropathy (HMN) and hereditary sensory neuropathy (HSN; also called hereditary sensory , and autonomic neuropathy {HSAN}), are a continuum of disorders where patients with CMT have both motor and sensory involvement and those with HMN have only motor involvement and those with HSN only sensory involvement. CMT is more common that both HMN and HSN but in considering treatments it is best to think of them all together as CMT and related disorders as many of the genes that have been found to cause CMT can also cause HMN and HSN. For the rest of this article I will refer to CMT and related disorders as CMT for simplicity.

The first causative gene for CMT (CMT1A due to a chromosome 17 duplication containing an extra copy of the gene peripheral myelin protein 22 (PMP22) was identified in 1991 and to date 78 causative genes have been identified for CMT.

Recent studies from our group in the UK as well as from a large CMT clinic in the US have found that currently about 65% of patients with CMT get an accurate genetic diagnosis after attending pecialised clinics. This represents a dramatic change over the last two decades and reflects the increasing number of new genes being identified. At the same time it is very frustrating for patients that although we have been very successful in identifying genes we have not been as successful in developing therapies. In my clinic, patients are frequently surprised to learn that 23 years after the identification of the first causative gene for CMT, we still have no specific treatments. Why is that? Some of the reasons reflect the difficulties in developing treatments for genetic conditions and some of the reasons are specific to CMT.

It is important to acknowledge that we have treatments for many of the complications of CMT and therefore although we have no disease specific treatments to either halt the progression or cure CMT, we can manage the condition in most patients. Current treatments include physiotherapy, orthotics, occupational therapy, pain and fatigue management and when indicated orthopaedic surgery, speech therapy and respiratory support to name a few. The reason it is important to mention these treatments is that patients are sometimes told by their GPs that because there is no treatment for CMT, there is no point in them being referred to specialists such as neurologists, paediatricians, orthopaedic surgeons etc. For patients, seeing clinicians who have expertise in CMT can be very helpful, especially expert physiotherapists and specialised orthotic clinics.

One of the main challenges in developing therapies for CMT is the number of causative genes identified. CMT1A is the commonest form of CMT in the UK accounting for about 60% of patients. CMTX1 due to mutations in the gap junction protein beta-1 gene (GJB1, which encodes for the protein connexion 32) is the second commonest cause accounting for about 10% of cases.

The remaining 76 genes affect the other 30% of the CMT population and there are more genes yet to be identified. This means that other than the 2 common genes the other forms of CMT are very rare with many affecting just a few families and in some cases just a single family.

The second major challenge in developing treatments for CMT is that fortunately CMT (especially CMT1A) is a very slowly progressive disease that does not usually affect life expectancy. This means that any treatments developed have to be very safe especially as most forms of CMT start in childhood; in developing treatments we need to remember they are likely to have to be started in children so need to be even safer as treatments would need not to interfere with their normal development.

I think there are three ways to approach developing treatments for CMT.

1. Firstly treatments that correct the underlying genetic defect can be explored. These kinds of treatments are being developed and trialled in many genetic conditions and the rationale behind these treatments is not specific for any genetic disorder but can be adapted to specific diseases. For example, the anti sense treatment for Duchenne’s muscular dystrophy (currently being trialled) is one of these treatments. The aim of anti sense treatment is to fool a patient’s cell into producing a normal or near normal protein by altering the way the defective DNA is decoded. There are many other genetic therapies like this in development. The challenge for CMT is three fold. Firstly we do not yet fully understand the risks of these types of treatments and some of them do involve using viruses to deliver the genetic treatments which have their own potential risks. In CMT, which is a very slowly progressive condition, we would need to have absolutely safe therapies to justify using them. This is not to say that we should not be looking carefully at potential genetic therapies like these, and many groups in the world are, but safety is of paramount importance in a slowly progressive condition.

The second challenge, which is a major challenge, is that these treatments usually need to be given to the tissues in the body where the defect is, which in CMT are the peripheral nerves. Our peripheral nerves are protected from the circulating blood by what is called the blood / nerve barrier, so drugs which are either taken by mouth or by intravenous injection are present in high concentration in circulating blood but are not efficiently delivered into the peripheral nerves. Currently research is trying to develop ways of penetrating the blood nerve / barrier.

The third challenge is that with 78 causative genes identified for CMT to date, each gene would need to have its own gene specific therapy developed and this may not be feasible.

2. The second way to develop therapies for CMT is the way most of the progress has occurred to date. This is based on understanding the pathogenesis of CMT. What this means is that once a causative gene is identified for CMT e.g. the chromosome 17 duplication for CMT1A, research is done to understand how the genetic defect causes the disease.

With CMT1A, this research has shown that a major part of the problem is having too much PMP22 protein because of the extra copy of the PMP22 gene. Laboratory studies then showed that reducing the amount of the PMP22 protein helped laboratory models of CMT1A and hence compounds were identified that could reduce the amount of PMP22. One of these compounds was vitamin C (ascorbic acid) and there have now been two large international trials of CMT1A patients taking vitamin C for 2 years (including the UK / Italian trial) both of which were negative i.e. there was no evidence that vitamin C slowed down the progression of CMT1A. This does not mean that reducing the amount of PMP22 is not the right approach just that vitamin C may not be the best way to do so. Currently other compounds that can reduce the amount of PMP22 are being explored at the laboratory level. This general approach to understanding the pathogenesis of different types of CMT is still the key to developing therapies both for gene specific therapies and for understanding pathways as described in 3 below. Like the genetic therapies described in 1 above a potential limitation to the pathogenesis approach to developing therapies is that with 78 causative genes identified for CMT to date, each gene would need to have its own treatment developed based on the individual pathogenesis of that genetic defect.

3. The third approach to developing treatments for CMT is what I like to term the “treating nerves” approach. This is based on trying to develop therapies that are not specific to a particular gene but that help damaged nerves repair. This is a little bit like treating high blood pressure. Many patients have high blood pressure. Doctors often do not know the exact reason in an individual patient why the blood pressure is raised but they have very good drugs for reducing the blood pressure. There are many causes of neuropathy as well as the genetic causes but there have been no drugs developed to date that can repair damaged nerves regardless of the cause.

Nerve growth factors, which we know are needed for nerve development, have been trialled in diabetic neuropathy and also in a limited number of patients with CMT, to date these are too toxic to use but research is ongoing in this area. One of the most exciting developments from the identification of so many causative genes for CMT and the understanding of their pathogenesis is that we are beginning to discover common pathways in nerves that many different genes are involved in. For example, the pathways involved in axonal transport, i.e. how nutrients and essential building blocks for nerves are transported down from the nerve bodies in the spinal cord to the ends of the nerves and how the waste products from nerve endings are transported back to the cell bodies, are gradually being understood. Many of the genes identified especially for CMT2 and HMN are involved in axonal transport and developing drugs to help axonal transport may help many different forms of CMT. Similarly other pathways are being identified that involve more than one gene including the CMT1 genes. I think this pathway approach to developing therapies shows great potential.


I hope this article has highlighted the specific challenges in developing treatments for CMT and also explained the current approaches to developing therapies.


First published in ComMenT, Spring 2014

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