Duchenne Muscular Dystrophy experiments in dogs by the Royal Veterinary College
The animal experiments
- The Royal Veterinary College (RVC) in Potters Bar, UK breeds, maintains and experiments on a colony of dogs with the canine equivalent of Duchenne Muscular Dystrophy (DMD). This is the most common form of the disease in humans. The rare condition is caused by a faulty gene which causes a lack of a vital muscle protein known as dystrophin.
- The breeding colony has been established from a family of dogs who were discovered to have the faulty gene and who were then crossed with beagles. The dogs, as well as being bred to deliberately suffer the effects of the disease, regularly undergo invasive procedures, including blood sampling and muscle biopsies. Due to the severe effects of the disease, involving muscle wastage and respiratory problems, the RVC dogs are routinely killed at approximately 18 months old. It is also likely that after being killed, their hearts are removed for examination.
- Breeding and use of the dogs in research at RVC has been highlighted in recent media articles by The Observer, The Guardian and Daily Mail
- The RVC will this year subject the dogs to a new, more experimental phase of the research programme. This will involve gene therapy, known as anti-sense, by way of the introduction of a new piece of genetic material. The goal is to alter their bodies so that they start to make the missing protein, dystrophin.
Scientific problems and species differences
- Breeding dogs to have canine muscular dystrophy and killing them at a young age cannot accurately reflect the natural progression of DMD in humans.
- To date, there are more than 60 animal ‘models’ of DMD, and the number is increasing. This is despite their widely published limitations. For example, there are reported to be genetic drawbacks in various breeds of dog as well as in genetically modified (GM) mice – some strains of which are considered not to experience the disease severely enough to provide an accurate comparison with humans. This failing is used as the justification for further modification to make yet more mice suffer more severe symptoms.
- The faulty DMD gene is found on the X chromosome, so the disease primarily affects males. Up to one in every 3,500 boys born each year inherit the disease, leading to approx. 20,000 new cases annually, worldwide. DMD patients need human-relevant research methods instead of cruel and inadequate experiments on animals, which have continued for decades, and yet there is still no recognized treatment.
- The RVC states that beagles are used as they have ‘fewer genetic problems’ than other types of dogs.
- The RVC also justifies the use of beagles on the grounds that they are closer in size and physiology to humans than are rats or mice, and will therefore give better insights into potential treatments. Yet, despite their failure to replicate reliably human DMD, at least one researcher from the RVC continues to use mice in DMD research.
- A review of decades of muscular dystrophy research using animals, such as mice, fish, rats, dogs and cats, reported that ‘the findings of animal studies should not be extrapolated to the human disease without caution’ and that ‘therapies that looked promising in animal models (such as myoblast transfer) have repeatedly yielded disappointing results in clinical trials’.
Some examples of these failures and inconsistencies are described below.
McGreevy et al (2015) ‘Animal models of Duchene muscular dystrophy: from basic mechanisms to gene therapy’, Disease Models and Mechanisms, no.8. pp.195-213.
- ‘Currently, there are nearly 60 different animal models for DMD, and the list keeps growing.’
- Neonatal death: dogs ~ 25% affected; in humans it is rare
- Loss of ambulation: In dogs, uncommon; in humans, common during early teenage years.
- Cognitive and CNS defects: for dogs, no information available; one third of humans are affected.
- The CKCS-MD model is ‘especially interesting because the mutation in this breed corresponds to a major deletion hot spot…in humans with DMD’.
- Humans with DMD show differing clinical manifestations and canine DMD (cDMD) ‘dogs also show variation in their symptoms. In extreme cases, affected subjects are essentially asymptomatic despite the lack of dystrophin in their muscles’.
- ‘About 20-30% of cDMD puppies die within 2 weeks of birth, likely due to diaphragm failure…However, this neonatal death is not seen in newborn DMD boys.’
- ‘Growth retardation is another canine-specific symptom…at 1 and 6 months of age, the bodyweight of affected puppies reaches only ~80% and ~60% of normal, respectively.’
- ‘…untreated humans with DMD usually lose ambulation during the early teenage years. However, complete loss of ambulation is not a clinical feature in young cDMD dogs.’
- ‘Humans with DMD suffer from both skeletal muscle disease and cardiomyopathy. It thus seems obvious that both skeletal and heart muscle should be treated. However, many existing gene therapy approaches (such as some AONs used for exon skipping…cannot efficiently reach the heart.’
- ‘Another drawback of AON therapy is the rapid turnover of the therapeutic oligonucleotides.’
- ‘Some aspects of the DMD pathology (such as neurocognitive deficiency) remain difficult to model. Furthermore, animals are not humans’.
Failed treatments for DMD
- There is currently no treatment or cure for DMD. Further issues with available trial drugs or therapies mean that they can often only be given to small groups of patients. For example, new drugs under trial in the USA target only one part of the dystrophin gene, and may therefore help just 13% of the DMD patient population who have a defect in that particular part of the gene
- Recently developed DMD drug Drisaspersen is under review. Drisapseren failed its main clinical trial and showed troubling side effects.
- Another new treatment, Ataluren, is also under discussion after failing to provide enough evidence of effectiveness in patients.
Alternatives to animals in DMD research
- The RVC states on its website that breeding dogs for DMD research is necessary, as not enough naturally-occurring cases pass through veterinary practices for study.
However, investment would be better spent on improving and formalising the use of existing human-based research data on DMD. There is a vast amount of such material available worldwide. It derives from clinical trials, genetic sequencing, gene therapy and cell therapy in patients. More than 300 clinical trials are currently officially listed. This is in addition to global efforts across Europe and worldwide to set up international database-sharing networks on the genetics of muscular dystrophy patients.
Effective use of this data by the research community is a scientific and ethical imperative. Research investment would also include national and international standardised collection and interpretation of both clinical case reports of DMD in humans, as well as veterinary cases presented to clinics.
- Investment by UK biotech into human-based genetic and in-vitro methods of DMD research can also be encouraged. For example, the EuroBiobank has been set up to provide a network of human cell, DNA and tissue samples to study rare diseases such as MD as part of the European TREAT-NMD programme.