How does scientific research happen?
Most scientific research into medical treatments can be divided into preclinical studies (prior to human trials) and clinical studies (human patient trials).
Preclinical studies include in vitro (outside the body) on patient cell samples and in vivo (inside the body) studies usually with animal models of the disease. There are a number of animal models of Duchenne. The most frequently used is the MDX mouse, a dystrophin deficient mouse that displays the features of Duchenne. Animal models are of great value in research. They not only give us insight into the biological function of dystrophin and Duchenne’s disease but they also play an important role in determining the efficacy, toxicity and safety of certain therapies such as experimental gene therapy.
Every model has advantages but also limitations. Despite the enormous importance of animal models, animals are not human. And while play an important role in determining safe trial protocols for clinical studies, they are not a substitute for the information that can be attained from a well performed clinical trial.
If the results from the preclinical studies are sufficiently convincing a clinical or therapeutic trial can be carried out. Clinical trials determine the safety, efficacy and possible side effects in humans.
Clinical trials are conducted in 4 phases:
These are usually performed on healthy volunteers. The goal is to determine the safety and toxicity of a treatment in humans, It also examines how the body metabolises the medication as well as the mode of administration.
This phase is where the optimal dose of the medication or treatment is determined while considering the tolerance and efficiency in a limited patient group.
These trials are constructed to demonstrate the therapeutic value of the medication and evaluate the risk-benefit ratio. These are comparative trials where the treatment is compared with the existing standard treatment or with placebo (a treatment with no pharmacological action). The possibility that a patient will receive a placebo can, understandably, be an emotionally difficult situation for patients and family. The importance of a placebo can often be misunderstood by their patients and families. The role of the placebo goes further than just displaying the normal progression of the disease. It also demonstrates the “placebo effect”. Many clinical studies have shown that the expectations of both the patients and researchers can influence the results of the study. The gold standard for a high quality clinical research trial is a double-blind placebo controlled trial where neither the patients not the treating doctors know who is receiving the medication and who is receiving placebo.
At the end of Phase III, the results may be submitted to the European Medicine Agency (EMEA) (or the US counterpart the FDA), which can then issue the license to market the drug tot he greater patient population.
Phase 4 clinical trials are performed after the drug reaches the market. They provide a better understanding of how a drug performs under real life conditions and examine its tolerance in the larger population. Rare side effects that were not detected in the Phase 3 trial can therefore be revealed during Phase 4.
Be careful when reading overoptimistic press releases
Every step forward in scientific research has its own challenges and difficulties. It is important to realise that with every challenge we overcome, there is yet another challenge waiting. It is therefore important to manage expectations and not to become too excited with every headline and press release reporting a cure for Duchenne. Even well intentioned reports can lead to misinformation and pseudo-scientific articles that can be targeted to parents and families. This can be very emotionally destabilising for the parents.
What research areas are there?
Progress is being made worldwide into the disease mechanisms behind Duchenne with the goal of finding new therapies. The progress in the various scientific fields and the complexity of the various symptoms in DMD have led to developments in diverse research directions. Physicians expect that in the future a cocktail of medication and treatments can make life more liveable for patients with DMD rather than finding a miracle cure.
Gene therapy approaches offer the possibility of delivering a functional copy of the dystrophin gene to muscle cells where it could restore production of the dystrophin protein. The most promising approach is based on the use of a harmless virus called Adeno-associated virus (AAV) which has been shown to effectively deliver genes to a range of different types of cells and tissues including muscle. One of the challenges is that the dystrophin gene is too big for the AAV vector. Researchers have made micro-dystrophin genes that have successfully been tested in animal models of Duchenne muscular dystrophy. A shortened but functional dystrophin is produced using this method. Different trials are planned and should be initiated soon.
CRISPR/Cas 9 is an exciting genetic engineering technique. It has two key components: Cas9 which is an enzyme that can cut DNA at a precise point and CRISPR, a short strand of RNA, a chemical messenger. Three research groups, working independently of one another, recently reported that they had used the Crispr-Cas9 technique to treat mice with a defective dystrophin gene. Each group loaded the DNA-cutting system onto a virus that infected the mice’s muscle cells, and ‘cut out’ an exon from the gene. Without the defective exon, the muscle cells made a shortened but functional dystrophin protein, giving all of the mice more strength. There are high hopes for the application of the CRISPR/Cas9 technology for Duchenne however, for now, the state of the science and the corporate interest is classified as early stage.
In 1989, scientists discovered that a protein called utrophin exists in muscle cells, principally at the junction where the nerve meets the muscle cell. Since that time, scientists have observed that utrophin could potentially operate as a substitute for dystrophin (and protect the muscle cell membrane), if muscle cells could be coaxed into producing utrophin at locations other than the neuro-muscular junction. This strategy could perhaps lead to an effective treatment for Duchenne, using a biological process substantially simpler than those involved in gene and cell therapies.
- Ezutromid (SMT C1100) – phase 2
- Clinical trials with Biglycan are expected to start in 2017.
Scientists have long theorized that the body normally contains compounds that limit muscle growth. For example, certain breeds of cattle develop substantially more muscle than ordinary cattle. Researchers have isolated the cause of this disparity to a mutation in the gene that codes for the production of a hormone called myostatin, which tends to limit muscle growth. Scientists searching for a treatment theorize that inhibiting myostatin in people with Duchenne will cause them to develop more muscle mass initially. Ideally, this surplus will offset the muscle loss associated with Duchenne, allowing the patients to retain their ability to function for a longer period of time.
- PF-06252616 (Pfizer, phase 2)
- Adnectin (BMS 986089) (phase 2)
Scientists are not attempting to replace the genetic code; instead, they want the muscle cell to ignore the defective part of the dystrophin gene and make a smaller version of dystrophin. Scientists believe that this therapy could change the reading frame of a deletion in the dystrophin gene, so that an out-of-frame deletion in the dystrophin gene could be transformed into an in-frame deletion. Their hope is that this change would cause the muscle cell to produce a form of dystrophin that is at least partially functional, which could result in a significant improvement in the quality of life. Eteplirsen is the first exon-skipping drug to have received approval from the FDA (for exon 51).
Drugs for stop codon readthrough
These drugs only work for patients with a "stop signal" mutation. These mutations do not affect the genetic code, but introduce a stop signal in the middle of the gene in addition to the one at the end of the gene that signifies protein translation is complete. This is the case for ~15% of Duchenne patients. The drugs can also be beneficial for individuals with stop codons in other genes (e.g. cystic fibrosis patients).
PTC Therapeutics was granted marketing authorisation for Translarna (ataluren, formerly known as PTC124) by the European Commission in August 2014. Translarna is approved for the treatment of ambulatory patients aged five years and older who’s Duchenne muscular dystrophy is caused by a nonsense mutation in the dystrophin gene in EMA countries.
Within the European Union Translarna is currently available in Germany, Austria, Denmark and Norway and the UK, with France, Italy and Greece having early access schemes. Outside of Europe Translarna has received approval for use in Israel, and is also available in Turkey, Brazil and Columbia. This list of countries will increase and availability of Translarna should be checked with PTC (firstname.lastname@example.org)
Coaxing muscle cells into producing dystrophin protein without recoding dystrophin's basic genetic code is another strategy that scientists have also developed potential strategies for. These proposed cell therapies attempt to at least partially offset the muscle damage caused by the flawed genetic code. Scientists have begun to develop cell therapy techniques that use stem cells derived from muscle. These are essentially immature muscle cells with the potential to develop into a variety of types of tissues, including skeletal muscle.
Pharmacological approaches to formulating treatments for Duchenne do not seek to repair or replace the missing genetic information in a muscle cell, or to otherwise devise mechanisms to cause the muscle cell to produce normal dystrophin. Instead, pharmacological approaches seek to treat the symptoms of Duchenne without necessarily addressing the root causes. While pharmacological therapy may seem less dramatic than some of the newer methods being developed, pharmacological strategies also sidestep some of the most daunting obstacles associated with gene and cell therapies, most notably difficulties in achieving systemic delivery and overcoming immune response.
Anti- inflammatory drugs and potential alternatives to steroids
Studies show that, overall, children with Duchenne who are treated with steroids, stay walking for longer than those who are not treated with steroids. However, there can be important side effects. For this reason, different new drugs which have the potential to better balance the benefit and side effects than the traditional steroids are being developed :
- Vamorolone (VBP15) – Phase 2
- Edasalonexent (CAT1004) – Phase 2 (not a steroid)
Clinical trials overview