The road to global pharmacogenomics

Dr Richard O’Kennedy, Vice-President for Research, Development and Innovation at Qatar Foundation, looks at the global potential within pharmacogenomics.

Twenty years on since the first human genome was sequenced, pharmacogenomics has the capacity to significantly change the world of medicine. The term pharmacogenomics encompasses all the genes in the genome of an individual that can affect the response to a drug.

It has only been a few short years since the field initially gained recognition but, within this timeframe, we’ve seen it produce significant contributions to human health. Drug therapies have improved markedly, making treatment more targeted and efficient, and researchers have identified hundreds of known interactions between gene mutations and drug responses.

Some of the most noticeable advances using pharmacogenomics have arguably been in drug use for cancer care. This would include the tailored use of drugs such as 5-Fluorouracil for treatment of colorectal carcinoma and breast cancer but there are many such examples. Such progress is likely to continue apace and, in time, we can also expect to witness perceptible progress in areas such as cardiovascular disease, Alzheimer’s disease, Parkinson’s disease, Crohn’s disease, HIV/AIDS and asthma.

Yet, pharmacogenomics holds far greater potential still. Some of the biggest shifts in healthcare that we will see in the coming decades are in personalised medicine. We are now in a position where we have the technology to understand and develop tailored treatments based on an individual’s health profile, and pharmacogenomics will take this to the next level. It can be viewed as a sort of ‘Rosetta Stone’ that will help to unlock the potential of personalised medicine, enabling health professionals to correlate a person’s genetic make-up with appropriate prevention and treatment strategies.

Scaling and diversifying

Pharmacogenomics-based drug design, discovery, development and prescription are still in early stages in pharma and biotech companies, as well as in regulatory bodies and public health systems, and the full potential is yet to be realised.

One of the main challenges lies in access to data. Large-scale genomics projects around the world have accelerated our mapping of populations; Genomics England, for instance, recently sequenced 1,000,000 genomes from patients across the UK in a multi-year project.

But in reality, even if we combine all of the data from genomics projects globally, we will have only scratched the surface. To date, there are very few projects that have been conducted with large populations on par with the UK research. Representation is another key challenge. The vast majority of data available today represents people of Northern European heritage, whereas information on the genomes of other global ethnic groups is very limited. As a result, there was a tendency towards over-reliance on Northern European data when it comes to drug discovery, with other ethnicities too often overlooked. The pharma sector needs to accelerate the diversification of data sources in order to deliver benefits to patients globally.

Two major barriers exist to increasing our data pools: cost and privacy. Studying genomics on a country-wide scale is not an inexpensive practice, and for a state to become involved in such a major exercise, sustained investment is often paramount. With governments currently under more economic strain than usual, as they try to recover from the impact of the Covid-19 pandemic, this investment is a difficult ask – even if it would pay dividends for public health in the long run.

There is also the issue of acquiring the support of a country’s population, in order to conduct the necessary studies. It is fair to say that – even when projects have overcome the financial barriers and are being undertaken – the popular mindset of wanting to keep personal health matters private has generally dissuaded people from participating in such programmes.

The matter of data and information security also comes into play here, as a genuine concern and interest to both individuals and the state. Genomic data banks are only viable if they are secure and people are confident that their personal information is safe. Without this assurance, the credibility of beneficial genomics endeavours could be severely compromised, setting back all of the many achievements accomplished to date and endangering further advancements in pharmacogenomics.

Nevertheless, in the face of these challenges, we are seeing progress – particularly when it comes to diversifying data sources.

Pharmacogenomics for Arab populations

Despite totalling over 400 million people worldwide, Arab populations have largely been overlooked in drug development thus far, with little information on their genomes having been collected to date. At Qatar Foundation – a non-profit organisation based in Doha – we are working to change that.

Qatar was among the first countries to launch its own large-scale, national genome project, back in 2015. It’s an ambitious project that is still underway, generating large databases that combine whole genome sequencing and other omics data with comprehensive phenotypic data. It’s the largest genome project in the Middle East and aims to promote genomic research and clinical implementation at a national level. Currently, the programme is working to sequence and phenotype 10 percent of the population; in due course, even larger segments of the population will be sequenced.

The focus of the programme is on achieving direct clinical impact. As such, it is supporting research targeting national priority diseases like diabetes and cardiovascular disorders, which affect large proportions of the local population.

Recently, the Qatar Genome Research Consortium, which brings together researchers from various institutions for the programme, published its first comprehensive study. The findings give us a better understanding of which genetic markers – specific to the Qatari population – indicate an individual’s risk of developing a certain disease.

The presence of this data means we now have a genetic reference point for Qataris. Going forward, it will significantly improve our ability to diagnose and manage certain diseases early. It will also mean that, when new drugs are designed, they can take into account the unique genetic variations present in the Qatari population, and offer a tailored solution. Additionally, it will enable researchers to draw informative comparisons between populations – for instance, by exploring variations that are rare in European populations but common amongst Qataris.

While the data pool from this consortium is specific to Qataris, the findings have much wider ramifications for other Arab populations too, given that they have been underrepresented in research to date. We are in the process of sequencing 3,000 of the country’s non-Qatari Arab residents to create the first comprehensive Arab reference genome. This first tangible, Arab-specific data is helping us develop a better understanding of the genetic risk factors specific to the Arab population at large, and can prove very useful for tailored drug development and utilisation. It is clear from the results that there are significant genetic variations between different ethnic groups and the study will advance our ability to recognise and cater to this in medical practice.

As the project continues, we hope to see pharma companies and researchers from around the world engaging with the data. International collaboration on research will be vital to advance the field of pharmacogenomics, given both the scale of the task and the variations that we now know exist between populations with different ancestral backgrounds. We will ourselves be conducting a cross-analysis with the national dataset from the UK, as part of our ongoing partnership with Genomics England. The findings from our recent study have also all been made publicly accessible, free of charge, and we hope to see specialists making use of the datasets to further their own research.

Harnessing genomics to tackle ASD

In addition to improving representation in drug discovery, there is great potential in the coming years to harness genomics in the analysis and treatment of clinically complex disorders, such as Autism Spectrum Disorder (ASD).

The Qatar Biomedical Research Institute (QBRI), part of Qatar Foundation’s Hamad Bin Khalifa University, is currently conducting a study that is identifying molecular biomarkers for early diagnosis of ASD and enhancing our understanding of the underlying molecular basis of ASD pathophysiology. The study involves a cohort of hundreds of individuals living with ASD, as well as their non-affected family members, recruited from across the MENA region.

Multiple angles are being pursued as part of the study, with a cadre of omics approaches being applied to blood collected from the cohort to identify biomarkers. For instance, RNA sequencing is being used for transcriptome profiling to identify specific coding and non-coding RNAs associated with the disease, in order to better understand the molecular basis of ASD and for biomarker discovery.

The study is also using some of the latest technology in genomics, including protein biomarker discovery platform Olink and the Sengenics Immunome Protein Array tool. With these, the researchers will be able to identify novel proteins and autoantibodies.

Additionally, metabolomics profiling is being used to screen blood samples to identify novel metabolic signatures of ASD. The research team are further characterising immune phenotypes in autism, to establish their association with the clinical severity of autism and patients’ history of complications.

From these combined research efforts, we have identified an extensive list of candidate molecular biomarkers. These candidates are now being validated using functional assays developed at QBRI, which include state-of-the-art electrophysiology and cell-based assays employing human neurons and organoids derived from patient-specific stem cells to model the pathogenesis and elucidate the molecular basis of ASD.

This knowledge will allow a much deeper understanding of ASD and the development and selection of the most appropriate treatments, be they drug-based or otherwise, and allow early interventions thereby significantly improving the welfare of patients.

A changing world

We now know that tailoring treatment to a particular subgroup of patients is inherently complex, but ultimately it is incredibly rewarding and effective, and will improve disease treatment significantly.

Encouragingly, we are already seeing public attitudes towards genomics beginning to improve. People are starting to see the importance of personalised healthcare when it comes to themselves and their families. Once they realise the role of genomic studies in augmenting personalised healthcare and that genomic data collection is only to their benefit, I believe we will start to see them really come forward in considerable numbers to be part of genomics programmes.

With wider participation, we can expect tailored drugs for the treatment of several diseases to follow – notably diabetes, asthma and particular types of cancers for which significant research has already been undertaken.

The pharma industry itself is also adapting. With many expensive treatments, pharma companies have moved to a pay-for-performance business model. In pharmacogenomics, they see a means to ensure that the treatments they develop are prescribed to patients that will benefit from them. Genetic research allows the industry to better target the causes of disease, and the ‘precision’ in the targeting of treatments results in improved outcomes for patients. From a business perspective, this ultimately means that pharmacogenomics can help pharma companies to maintain their margins and de-risks their pay-for-performance deals with health systems. Likewise, it benefits health systems by reducing unnecessary expenditure on costly failed treatments.

Moving forwards, we need to accelerate existing efforts and push for truly global pharmacogenomics. The more data that the health sector has at its disposal, the better it will be able to treat patients. Yet, only with a more diverse data set will clinicians genuinely be able to bring the benefits to all.

Pharmacogenomics will require increased collaboration in order to reach its potential. It is a combination of the research and development carried out by the pharma industry and the academic research supported by industry funding that provides hope for treatments for many of the life threatening and life altering conditions from which people suffer. Collaboration is also the grounding for making discoveries at speed – as the world has recently seen in the research response to the Covid-19 pandemic, and especially the Oxford/AstraZeneca Covid-19 vaccine, which saw industry, academia and the government come together to achieve the development and manufacturing of a vaccine in record time.

The best model for interaction with industry is a mutually beneficial collaboration. National genomics programmes can contribute access to the data and samples held within national biobanks to aid the R&D process. Industry, on the other hand, can gain access to data and the local research ecosystem in return for a contribution to the local research ecosystem.

At Qatar Foundation, we have recently embarked on a three-year collaboration with leading healthcare company Roche. Our work together plans to help take more personalised, tailored treatments from the laboratory stage to the point where they are being used in primary healthcare settings. During the first stage of the partnership, research will focus on how genetic markers can guide diagnoses and treatment decisions for diseases such as cancer. Both parties will also create registries and repositories of genomic data to support this process.

In addition, it will provide unique training opportunities for postgraduate students, researchers and clinicians to see advanced pharmacogenomics being applied in drug development and validation.

Accelerating progress

In many ways, pharmacogenomics is still very much in its infancy when it comes to treatment plans. As genetic analysis technology and methods improve, there is the promise of more discoveries in the future. It is important to remember, however, that genomics is only one part of the equation. For clinical and research purposes, genetic data is of limited use without associated deep phenotyping and medical history data to allow the linkage of genetic mutations with resulting medical conditions. It is critical therefore that the R&D community advances these two streams in tandem. Access to big data from both phenotyping and genome sequencing will translate into far greater progress for precision medicine than genomics alone.

Last year brought R&D advancements in healthcare at a pace that many previously believed impossible. As the world recovers from the pandemic, we must also welcome the many learnings it provided for the scientific community and the drug development process.  We are now at the dawn of an exciting era of precision medicine and, with appropriate collaboration and investment, could see tangible, tailored treatments being rolled out to much wider audiences sooner than previously expected.

Volume 22, Issue 3 – Summer 2021

About the author

Dr Richard O’Kennedy is the Vice-President for Research, Development and Innovation (RDI) at Qatar Foundation and Vice-President for Research at Hamad Bin Khalifa University. Prior to joining the Qatar Foundation, he was a Professor, Scientific Director of the Biomedical Diagnostics Institute, and Vice-President at Dublin City University, Ireland, and President of the Institute of Biology of Ireland. He has published extensively and is involved in the translation of research outcomes into tangible benefits for patients and the environment and for exploiting commercial opportunities across multiple research areas.

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