Interview of the Month for July

July 31, 2023

This month we sat down with Dr Dora Markati, a clinician scientist pursuing her PhD at the University of Oxford under the supervision of Prof. Laurent Servais and Prof. Carlo Rinaldi. Read on to learn about Dora’s career in rare diseases and her work to develop therapies for affected children. 

Please tell us about how you came to be at this point in your career and what your motivations are for being here.

Shortly after my studies in Medicine, I came to the UK. In the beginning, I started training as a junior doctor in Paediatrics and Neonatology. Having worked in paediatric wards for almost two years, I came across numerous genetic diseases which remain untreatable and for which our only option is to treat the symptoms of the disease and not the root cause. I struggled to believe that despite the scientific breakthroughs of the past several decades, we were still far, even though closer than previously, from genome-based therapeutics, which could transform the lives of these children. 

Following this period, I turned my focus from clinical practice to research. While pursuing an MPhil in Biological Science at the University of Cambridge, I worked towards unraveling the mechanisms of neural networking that take place during the critical periods of brain development. At that time, I realised the importance of early interventions during childhood, as these are the ones which hold potential for life-changing impact. 

These experiences steered me towards dedicating my forthcoming years to help accelerate genome-based therapies for rare genetic diseases. I am fascinated by following the scientific breakthroughs, especially those that make progress towards eliminating children’s suffering. I find my current research environment at the University of Oxford unique in leading scientific discovery from inception to completion.

What are the rare diseases that you work on and what do you hope to achieve?

Most of my work stands at the interface of pre-clinical and clinical research for candidate rare disease therapies. The teams I am participating in focus on neuromuscular diseases; however, the expertise is transferable to other conditions, which are also genetic in background. One of these diseases, which is central to my DPhil, is called Angelman syndrome. Angelman syndrome is a rare disease, and it is caused by lack of function of a single protein in neurons. Affected individuals suffer from severe cognitive impairment, movement difficulties and, in many cases, epilepsy. 

Although practically challenging, I am splitting my time between the hospital and the research lab. However, the exchange of insights between these two facets of my work is key in my research. In the hospital, I am running a Natural History Study in which I follow up a cohort of affected individuals over time. The results of such study type inform the design of clinical trials. They can also be used as a comparator to those individuals receiving a candidate treatment under testing in clinical trials. In the lab, my focus pivots to identifying candidate biomarkers that could serve several purposes: diagnostic, prognostic, or treatment response assessment. Thanks to all this clinical and lab work, we are also able to shed light onto the mechanisms of the disease pathology.

Through my involvement in Angelman syndrome research, I have had the chance to create meaningful collaborations across the university but also worldwide. These partnerships serve to expedite different stages of drug development for Angelman syndrome, which is the ultimate purpose of our work.

What are your hopes for what therapeutic options will be available to people with rare disease in the coming years?

Several different therapeutic approaches hold hope from a mechanistic point of view. However, there are many parameters to consider. My hope is to see the knowledge and expertise gathered by both academic institutions and the pharmaceutical industry, through years of developments in different rare diseases, to be leveraged towards a better overall understanding. It is crucial to keep continuity and worldwide cooperation if we want to see a change. 

We have entered a new era where novel therapeutics provide a feasible treatment to previously untreatable diseases. Among these new therapeutic options, we have antisense oligonucleotides, gene therapy, silencing RNAs, and genome-editing, which are entering clinical trials. In fact, some of these are already approved for diseases like spinal muscular atrophy. We are also observing the development of combination treatments for several rare diseases. Nonetheless, two of the biggest challenges we are facing now are the precise delivery of therapies to the cells and tissues where they are needed and the minimisation of their non-specific effects. Another thing to consider is that developments in rare diseases are often further complicated by the variability of these diseases in causes and consequently symptoms. I think this complexity needs to be carefully considered from the early stages of drug development to adopt the process optimally. 

We need to learn from the mistakes of the past and gather hope from successful stories in our effort to accelerate the drug development process for other rare diseases.