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The basic concepts of therapeutic approaches for DMD
Université de Versailles Saint-Quentin-en-Yvelines, CHU Raymond Poincaré, Service de Pédiatrie, 92380 Garches, et UMR S 1179 INSERM, 78180 Montigny-le-Bretonneux
Duchenne muscular dystrophy (DMD) is the most frequent hereditary neuromuscular disorder in childhood. Over the past 30 years, increasingly better standards of care have considerably improved the quality of life as well as the life expectancy of DMD patients. Despite such progress in disease management, DMD remains a devastating disorder with continuous decline of motor and cardiac function. Only corticosteroid therapy moderately slows clinical progression. However, new therapeutic approaches are currently being developed. This review discusses the rationales and underlying molecular mechanisms of the new strategies and the progress made in recent clinical trials. The new therapeutic strategies have the potential to profoundly modify the future of patients with DMD.
© 2017 Elsevier Masson SAS. All rights reserved.
La dystrophie musculaire de Duchenne de Boulogne (DMD) est la maladie héréditaire du système neuromusculaire la plus fréquente chez l’enfant. L’amélioration de sa prise en charge depuis une trentaine d’années a fortement amélioré la qualité et l’espérance de vie des patients. Néanmoins, cette myopathie reste dévastatrice au niveau moteur et cardiaque. Seul le traitement par corticoïdes ralentit modestement la progression clinique, mais de nouvelles approches thérapeutiques sont en cours de développement. Nous présentons ici les rationnels et mécanismes moléculaires sous-jacents ainsi que l’état d’avancement des essais cliniques. Ces nouvelles stratégies thérapeutiques portent le potentiel de profondément changer l’avenir des patients DMD. © 2017 Elsevier Masson SAS. Tous droits réservés.
Retrospective studies have demonstrated that management of patients with Duchenne muscular dystrophy (DMD) using the following combination: i) vertebral arthrodesis to correct the scoliosis; ii) respiratory physiotherapy with intermittent positive pressure ventilation; iii) non-invasive ventilatory assistance to treat the respiratory insufficiency; and iv) cardiac protective treatment with angiotensin converting enzyme inhibitors enables an increase in the average life expectancy of the patients, who may now live 30-40 years [1,2] while life expectancy without that management was only 17-18 years. Nonetheless, the rapid loss of motor function remains unchanged and patients live longer in an increasingly critical condition, requiring increasing assistance.
2. Use of corticosteroids
To date, corticosteroids are the only drugs to have procured a benefit with respect to motor function in DMD. Their use is now widely recommended although the underlying molecular mechanisms giving rise to the therapeutic benefit remain poorly understood. The first studies of the effects of corticosteroids on DMD, conducted in a purely empirical manner at Johns-Hopkins hospital, date back to the 1970s : 13 of the 14 boys included in the study clearly showed an improvement in motor function, particularly walking. The interpretation of the data was nonetheless difficult and controversial. The authors were confronted with: i) the impossibility of a double-blind design because of the patent adverse reactions; ii) the difficulty of distinguishing between the therapeutic effect and the natural motor development of the young; iii) the question of a psychological effect related to enthusiastic participation in a study; iv) and above all a very modest therapeutic effect that was difficult to measure and thus contestable. Demonstrating therapeutic pertinence remains an issue for the clinical trials on biotherapeutic strategies, which are becoming increasingly sophisticated and onerous without, however, demonstrating any major impact on the course of the disease. Despite the countless clinical studies on the positive effects of corticosteroids that have been conducted since the initial findings , it has taken almost 40 years for the soundness of long-term corticosteroid therapy in DMD to be fully elucidated. This was made possible, in particular, by retrospective comparisons of the results of numerous studies of the natural histories of large cohorts of treated and untreated patients. It has been shown that:
- the mean age at which the ability to walk is lost is 14.5 years on continuous corticosteroid therapy, 12 years on intermittent therapy, and 10 years for the historical untreated cohorts ;
- cardiomyopathy is deferred with onset at age of 15.2 years on treatment vs. 13.1 years without treatment ;
- Only 20% of patients on corticosteroid therapy develop scoliosis necessitating vertebral arthrodesis vs. 92% of untreated patients ;
- corticosteroids improve respiratory function ;
- a marked reduction in mortality in patients on corticosteroid therapy vs. untreated patients .
All of the foregoing led to recommendations being formulated by an international multidisciplinary consortium of 84 specialists in compliance with the RAND Corporation-University of California Los Angeles Appropriateness Method [10,11].
In France, today, the majority of ambulatory patients are treated with corticosteroids while the majority of non-ambulatory patients have never been treated. However, no data on the therapeutic efficacy of corticosteroid therapy initiated before the ability to walk is lost are available. Nonetheless, a benefit is highly probable even after late treatment institution, as is suggested by a number of isolated clinical case reports.
3. New therapeutic approaches
In recent years, new therapeutic strategies have been developed for DMD with the aims of correcting the primary genetic defect, compensating for the pathological secondary impacts on cell metabolism and stimulating skeletal muscle growth in order to overcome muscle wasting. Herein, we will discuss five new strategies that have already been tested in DMD patients: i) exon skipping; ii) read through of the nonsense codons (stop codon read through) generated by point mutations; iii) overexpression of a microdystrophin by a gene therapy approach; iv) treatment of oxidative metabolism with idebenone; and v) blockade of the myostatin signaling pathway.
3.1. Exon skipping
The first of the new strategies is based on approaches aimed at modulating messenger RNA splicing, commonly referred to as exon skipping. The strategy reflects the fact that the clinical course is much less severe in patients whose DMD gene mutations do not modify the reading frame as is the case in Becker muscular dystrophy (BMD): the ability to walk is often retained throughout life and life expectancy is almost normal . Thus, large intra-gene deletions of up to 35 exons out of 79 give rise to a relatively benign BMD phenotype if the reading frame of the final mRNA is maintained [13,14], while smaller mutations, such as point mutations or deletion of a single exon may result in serious DMD when the mRNA reading frame is affected, completely abolishing dystrophin production [15-17]. The new drugs under development for exon skipping deploy their therapeutic potential at the level of maturation of pre-messenger RNA (pmRNA) into mature messenger RNA (mRNA) of the dystrophin gene, enabling transformation of out of phase DMD mRNA into in phase mRNA. In other words, the drugs transform the original mRNA inducing a Duchenne phenotype into an mRNA inducing a Becker phenotype . Mechanistically, the process is based on the targeted inhibition of reading certain exons during the DMD pmRNA splicing reaction. The inhibition is implemented using small synthetic oligonucleotide sequences known as anti-sense oligonucleotides (AON), able to hybridize and mask the consensual motifs defining the targeted exons at the limits of the mutation. The system is designed to selectively exclude one or several exons in order to restore an operational reading frame in the final mRNA, enabling the synthesis of a dystrophin that, while truncated, remains functional . Analysis of genetic databases has clearly shown that a large variety of DMD mutations may, theoretically, be converted into mutations whose reading frame is usable. The best known example, since it has already been clinically trialed, is skipping exon 51, which enables operational reading frame restoration for a set of DMD mutations accounting for almost 13% of patients according to the Leiden DMD database [15,20]. The set covers deletions of exon 50, exon 52, exons 49 and 50, exons 48 to 50, exons 47 to 50, and exons 45 to 50. Theoretically, 80 % of DMD mutations could be treated by this type of approach and the concept has already been applied to a large number of mutations using patient muscle cell cultures . Various chemical approaches for the synthesis of AON are available. To date, only drugs from the 2’-O-methyl-phosphorothioate (2OMePS) and phosphorodiamidate morpholino (PMO) series have been tested in DMD patients, in particular to target mutations that can be corrected by skipping exon 51. The pioneering clinical trials in that context have generated very promising results: the levels of dystrophin restoration in muscles biopsied after only a few weeks of systemic administration by the subcutaneous or intravenous route were of the order of 15% and 18%, respectively [21,22]. The results of a more recent double-blind placebo-controlled phase IIb study using AON of the PMO series (Etiplersen) suggest clinical stabilization of disease progression in a sub-group of patients during a 24 week open-label extension study, but not during the initial 24 week double-blind phase . This finding suggest that almost a year is required to detect measurable clinical effects at the dosage used in the study. However, another recent phase III study using 2OMePS AON (Drisapersen) unfortunately failed to demonstrate patent efficacy on ambulation as measured by the 6 minute walk test (6MWT) (press release, GlaxoSmithKline, published on 20 September 2013 in London, UK, and Leiden, the Netherlands). Surprisingly, a phase II study using 2OMePS AON (Drisapersen) at the same dosage, conducted concomitantly in some of the centers involved, evidenced a slight but statistically significant clinical effect as measured by the 6 minute walk test (6MWT) after 24 weeks, but not after 48 weeks .
These mixed results do not invalidate the underlying therapeutic rationale of exon skipping for DMD, but indicate that the AON generations currently available are still insufficiently effective [25,26]. Currently, several clinical trials using 2OMePS and morpholino AON are ongoing or nearing completion. The trials, which included ambulatory and non-ambulatory DMD patients, target skipping exons 44 (drug: PRO044), 45 (drug: PRO045), 51 (drugs: Drisapersen and Etiplersen) and 53 (drug: PRO053) (https://clinicaltrials.gov).
None of the studies cited above has yet resulted in a patent clinical improvement in DMD patients. Moreover, the AON compounds currently being trialed showed little or no action on cardiac muscle or the central nervous system during pre-clinical evaluation using animal models of DMD. Development of new drugs with greater efficacy is therefore indispensable in order to achieve a life changing therapy. Recent preclinical studies conducted by our team on mdx mice have shown that the chemistry of tricyclo-DNA, a new class of DNA analog, may enable achievement of that objective: tricyclo-DNA significantly improves motor, ambulatory, respiratory and cardiac function, and certain cognitive parameters following systemic treatment inducing a restoration of dystrophin in skeletal and cardiac muscles, and in the CNS that is markedly superior to that induced by the compounds currently being trialed on DMD patients .
3.2. Stop codon read through
Another therapeutic strategy aims to overcome nonsense mutations, also known as stop mutations, that are present in about 10% of DMD patients. These mutations consist in a change of nucleotide in any codon transforming it into a premature stop codon (UAA, UAG or UGA) in the middle of a coding sequence. Thus, translation of the mRNA is prematurely terminated, preventing dystrophin production. There is now a drug, PTC124, that decreases the number of those stop codons taken into account. The stop codons are inappropriate and not consolidated by the environment of the true stop codons located at the end of the coding sequences. Skipping those codons is termed stop codon read through . Treatment thus theoretically enables synthesis of a protein of normal size but which may contain an amino acid resulting from reading a nonsense (stop) codon as a missense codon. Although the treatment proved promising in the murine model (mdx) of Duchenne myopathy, a phase IIa study in DMD patients, which included 174 patients, failed to evidence clinical efficacy . However, further analysis evidenced clinical stabilization (slowing of the walking distance loss, in meters, as measured by the 6 minute walk test) after 48 weeks of treatment in a sub-group of patients receiving a dosage of 40 mg/kg/d, but not in the higher dosage group receiving 80 mg/kg/d. These ambiguous results necessitated a new phase III trial, currently ongoing, to determine whether the drug was indeed effective at a dosage of 40 mg/kg/d (http://clinicaltrials.gov/show/ NCT01826487). In the meantime, the European Medicines Agency (EMA) has authorized marketing the drug under certain conditions (approval date: 31/07/2014).
3.3. Overexpression of a micro-dystrophin by a gene therapy approach
The therapeutic strategies addressed above, exon skipping and stop codon read through, are only applicable to sub-groups of DMD patients presenting with the ad hoc mutation. A wider therapeutic approach would consist in supplying an artificial compensatory DMD gene congruent for all patients independently of mutation nature or site. The proof of principle of the approach was obtained 11 years ago by the intramuscular injection of a plasmid coding for the entire DMD gene into DMD patients. Dystrophin expression was restored locally . Since then, transgene and vector design have evolved considerably toward a veritable gene therapy on the whole body scale. The DMD gene has been reduced and amputated in silico and by genetic engineering to a size sufficiently small to enable it to be packaged in a viral vector (adeno-associated virus (AAV)). The gene produces a functional truncated dystrophin protein, known as micro-dystrophin [32,33]. Several pre-clinical studies have demonstrated the feasibility of the approach in animal models of DMD . Currently, a phase 1 clinical trial is ongoing and another has been completed but the results have not yet been released. The objective was to test two versions of AAV-micro-dystrophin with different promoters administered by intramuscular injection (ClinicalTrials.gov NCT02376816 and NCT00428935). However, numerous clinical and pre-clinical studies have shown very strong immune responses, cell-mediated and humoral, both to viral capsids and transgene product (in this case micro-dystrophin) resulting in the absence or loss of expression of the transgene . The immune response could, however, be controlled or contained by concomitant immunosuppression, resulting in successful treatment as suggested by the results in animal models [35,36].
3.4. Treatment of oxidative metabolism with idebenone
The absence of dystrophin decreases the oxidative metabolism of striated muscle by indirect mechanisms that have yet to be fully elucidated . Idebenone is a synthetic analog of coenzyme Q10. It was first shown to have a positive effect on cardiac function and exercise capability in a murine model of DMD . Particularly interestingly, a clinical trial in DMD patients showed that idebenone only improved respiratory function in the group not on concomitant glucocorticoid therapy. Idebenone did not exert any additional or synergistic effect in the group on corticosteroid therapy [8,39]. A phase III trial (DELOS) recently confirmed the protective effect with regard to respiratory function in patients not on corticosteroid therapy . For 52 weeks the authors treated 33 patients with placebo and 31 patients with idebenone (ages eligible for inclusion: 10-18 years). The principal endpoint, peak expiratory flow as percentage predicted (PEF %p), changed by -8.84%p in the placebo group (95% CI: -12.73-4.95) vs -2.57%p (-6.68 to 1.54) in the idebenone group, i.e. a difference of 6.27 %p (0.61 to 11.93). Despite those encouraging results, reflection is called for. What does the reduction in PEF %p really mean in light of the progression of the disease, particularly, with regard to the other respiratory parameters, which did not change during the study? While statistically valid, a moderate difference in only a few respiratory function values does not necessarily imply a real clinical benefit. It has therefore not yet been conclusively demonstrated that idebenone could be a veritable alternative to corticosteroid therapy. However, the duration of the study was 52 weeks. It cannot be ruled out that long term treatment may be more effective by procuring a series of small benefits that, taken together, may impact the general condition of patients.
3.5. Blockade of the myostatin signaling pathway
Lastly, several experimental strategies have been developed with a view to preventing muscle wasting in DMD patients. Various approaches have been tested in various animal models. Among those approaches, myostatin blockade has proved to be particularly promising. Myostatin is a growth factor of the TGF-β series. Blockade of its receptor, activin receptor IIB (ActRIIB), spectacularly stimulates muscle growth in various animal models . This finding provided the rationale for a clinical trial conducted in 2010 (ClinicalTrials. gov NCT01099761]. The aim of the study was to test soluble activin receptor IIB (sActRIIB-Fc or ACE-031] by the systemic route although the exact function of myostatin in the regulation of skeletal muscle and the role of its receptor in the regulation of multiple tissues and organs was not yet fully understood. The trial was, in fact, very rapidly suspended in light of potentially dangerous vascular adverse reactions: the patients treated rapidly presented with bleeding from the nasal mucosa and gums, and, more generally, cutaneous vessel dilatation (TREAT-NMD Newsletter no. 99. 21st April, 2011). In addition, recently published studies have shown that the myostatin signaling pathway plays a key role in oxidative metabolism . Thus, inhibition of the pathway by sActRIIB-Fc induces severe secondary mitochondrial myopathy in the murine model of DMD . Other drugs that interfere with myostatin signaling are under evaluation in the context of Duchenne myopathy (e.g.: ClinicalTrials.gov NCT02515669, NCT02354781). Given the multiple adverse reactions already observed in numerous clinical and preclinical studies, it would nonetheless appear that the therapeutic rationale for myostatin pathway blockade in the context of DMD should be reconsidered.
The main lesson to be drawn from the clinical trials conducted in recent years is that the candidate drugs, at best, exert a protective effect or slow disease progression. None of the approaches developed to date ensures a curative effect, particularly in patients with a long history of the disease or handicapped by it.
Most of the studies were conducted over a short period of less than one year. Under those conditions, the potentially protective effect of a drug is difficult to measure, particularly since the clinical progression of DMD is slow. Secondly, the inclusion of patients at about the age they lose their ability to walk complicates ascertaining the potential effect of a drug substance whose action is not immediate. Those specificities have necessitated changes in the design and conduct of DMD studies. More recent studies are conducted over almost 2 years and the age at inclusion has fallen to 4-6 years (ClinicalTrials.gov NCT02420379, NCT02255552). It will thus indubitably be necessary to pursue treatment over several years before formulating a conclusion as to the efficacy of a given drug. We should bear in mind that several decades were required to conclude that long-term corticosteroid therapy was sound.
Statement of interests
H. Amthor states that he has been a member of the AFM scientific board.
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