By Dr Jatinder Singh
Rare diseases are actually not that rare! By themselves, rare diseases are indeed uncommon but collectively there are between 6000 and 8000 rare diseases and 75% affect children(1). Around 30% of patients with a rare disease do not live past their 5th birthday (1).
Clinical trials have made some enormous strides in illuminating the molecular mechanisms underlying these diseases with a view to find treatments that can increase life expectancy and/or improve quality of life measures. Due to the inherent complexity of most rare diseases however, clinical trials are often plagued with challenges and sometimes we are perhaps too hasty to conclude ‘negative’ findings, for example, as was shown for Mavoglurant in adolescents and adults with Fragile X syndrome (2), a disorder which shares many common features with Rett Syndrome.
To a certain extent rising too fast to find treatments for rare diseases without having personalised outcomes measures in place and appropriate clinical trial design can return premature results.
What does this mean for Rett syndrome? MECP2 is an X-linked gene encoding the methyl-CpG-binding protein 2 (MeCP2) protein, a transcriptional modulator implicated in a variety of neuronal functions. A loss of the MECP2 gene was the smoking gun at the heart of the disease and even though Rett syndrome presents with a constellation of symptoms, having a distinct molecular target allowed researchers a unique window of opportunity to tease out the key mechanisms with a view to target symptomology.
To better leverage the heterogeneity of Rett syndrome, understanding the symptoms that matter the most for patients and how we can develop these into systematic methods for effective treatments, would allow researchers to step boldly into the next therapeutic frontier of personalised medicine. Animal models provide a gateway for deciphering the symptoms of the disease and might even allow us to take our first exploratory steps into personalised medicine. Small proteins have been shown to rescue behavioural deficits in a mouse model of Rett syndrome (3), whilst other studies using pharmacological agents have shown to reverse brain decline (4), improve respiratory measures (4), rescue synaptic plasticity deficits (5) and extend lifespan (6) in a mouse model of Rett syndrome. These studies have empowered researchers to advance their understanding of the neurological, behavioural and respiratory characteristics of Rett syndrome and provided therapeutic entry points for clinical trials. However, as was found for Fragile X, a good animal model needs to be taken more than at just face value and begs the questions to how findings in animal models can be extrapolated to the patient in order to achieve the best personalised care.
Research from animal models suggests a ‘one-size fits all’ therapy and although ideal, is highly unlikely in Rett syndrome. Animal models show great promise, however it is important to remain cautious when bridging the gap to human patients. The road to clinical translation is often strewn with obstacles. So how do we overcome these obstacles and move smoothly?
Adaptive clinical trial design can allow us to tackle and eventually overcome these obstacles as it allows for the development of more sensitive personalised outcome measures and is ideal for trials involving rare diseases where the patient population is small.
Dr Paramala Santosh, who is internationally recognized in the field of psychopharmacology and neurodevelopmental disorders, runs the Centre for Interventional Paediatric Psychopharmacology and Rare Diseases (CIPPRD) clinic at the Maudsley Hospital that specialises in the treatment of rare, complex, neurodevelopmental disorders in children and young adults. The CIPPRD focuses on developing a systematic method of treatment and monitoring of neurodevelopmental outcomes using e-Health strategies via HealthTracker, to ensure participatory and personalized care for patients such as those with Rett syndrome. The CIPPRD is uniquely placed to deliver personalised care as it can utilise the resources of the NIHR / Wellcome Trust King's Clinical Research Facility to deliver clinical trials in rare diseases in children at all stages including specialized assessments such as world leading neuroimaging techniques (MRI, fMRI, MRS etc), neurophysiological tests (EEG, evoked potentials, eye tracking etc), and neuropsychological testing. Dr Santosh can also leverage specific expertise on genetics, biomarkers and stem-cell derived techniques.
Taken together, this relationship can bridge the gap for the next generation of clinical trials in rare neurodevelopmental disorders such as Rett syndrome to begin. These factors will in no doubt hold us in good stead of being able to undertake clinical trials in rare diseases using new molecules or repurposed agents, with a view to accelerate the treatment trajectory by bringing patients such as those with Rett syndrome more effective personalised medicine sooner.
About the author
Dr. Jatinder Singh has substantial experience in the pharmaceutical and charity sector with an emphasis on regulatory, medical and scientific writing in several different therapeutic areas, which overlap with project management and dissemination. Dr. Singh’s research interests are varied and currently encompass different aspects of child and adolescent neuropsychiatry and rare neurodevelopmental disorders. Working alongside Dr. Santosh who runs the Centre for Interventional Paediatric Pharmacology and Rare Diseases (CIPPRD) at King's College London, Dr. Singh’s main focus is directed towards understanding the pathophysiology of Rett syndrome with a view to finding new routes for translation into clinical trials. Current projects include developing an instrument that embraces key behavioral and physiological aspects of Rett syndrome where it is hoped will serve as an indicator for improving the treatment trajectory for patients, compiling a detailed compendium of new molecules and/or repurposed agents with a view to evaluate their clinical utility in Rett syndrome and Bayesian adaptive clinical study design approaches for rare diseases.
2, Berry-Kravis et al. Mavoglurant in fragile X syndrome: Results of two randomized, double-blind, placebo-controlled trials. Sci. Transl. Med. 8, 321ra5 (2016).
3, Tai DJ et al. MeCP2 SUMOylation rescues Mecp2-mutant-induced behavioural deficits in a mouse model of Rett syndrome. Nat Commun. 7: 10552. (2016).
4, Bittolo T et al. Pharmacological treatment with mirtazapine rescues cortical atrophy and respiratory deficits in MeCP2 null mice. Sci Rep. 2016 6:19796 (2016).
5, Gogliotti RG et al. mGlu5 Positive Allosteric Modulation Normalizes Synaptic Plasticity Defects and Motor Phenotypes in a Mouse Model of Rett Syndrome. Hum Mol Genet. Mar 2. (2016).
6, Patrizi A et al. Chronic Administration of the N-Methyl-D-Aspartate Receptor Antagonist Ketamine Improves Rett Syndrome Phenotype. Biol Psychiatry. Aug 24. (2015).