BreatheIN: Principal Investigator
Gene therapy has come to the forefront of personalized molecular medicine since the regulatory approval of new oligonucleotide therapeutics for systemic and neuromuscular diseases (e.g. the antisense and exon skipping mipomersen, nusinersen, & eteplirsen), and viral gene therapies for inherited diseases and cancer (alipogene tiparvovec, strimvelis, kymriah). More recently, the first positive phase III clinical trial data have been published for RNA Interference (RNAi) drugs, suggesting a first regulatory approval in early 2018.
Although there is great unmet need for lung disease (e.g. severe asthma, emphysema, cystic fibrosis, alpha 1 antitrypsin deficiency, pulmonary fibrosis, viral infections, bronchiolitis obliterans, etc.), we have shown that oligonucleotide therapies do not work in the airways, but they can reach and work in the liver and kidney if inhaled. Solutions involving GM viruses or virus-like nanotechnology do work, but are dangerous for patients whose well-being is at risk from the pro-inflammatory effect of such nanoparticles.We are working on basic and applied research to understand the function of airway cell receptors, to select amongst them appropriate molecular targets and their ligands, that will allow effective internalization of molecular therapy cargoes such as antisense, siRNA, miRNA, CRISP/CAS gene editing systems, and protein therapeutics. We are currently pursuing a biological and a small molecule chemical compound as simple, chemical conjugation-based, candidate solutions.
Predictive Pharmacogenomics: Principal Investigator
Most gene therapies involve the targeting of genes who are functioning improperly: too much gene expression, erroneous RNA processing (splicing), or mutations that stop the function of molecules key to normal cell biology. Many of these gene therapies, such as small interfering RNA, RNase H-active antisense, and gene editing tools such as CRISPR-CAS, function by identifying their molecular targets using Watson-Crick base pairing and then cutting them at a specific position. However, in many cases other, potentially dangerous, bodily responses can have the same net effect that might look like the drug is working.
In 2014 we were the first to develop a big data method that can measure digitally the effect and precision of target-cleaving molecular drugs. In 2017, we published a development of this method that combines viral genomics, genetic engineering, and big data analytics that can be used to measure the pharmacological effect of any single nucleotide variation/polymorphism in a gene targeted by cleaving molecular drugs.
This means that a simple, single cell culture experiment can now be used to assess which patients will benefit from such a drug, and by how much, before starting animal experiments or clinical trials. As a result, drugs can be therefore tested and later prescribed to patients in which they will work. We are working on advancing this technology to a single, bench-to-bedside test that can choose patients for treatment, predict drug response, quantify actual drug effect and monitor resistance evolution (important for cancer).
PULMOSCREEN: Principal Investigator and co-inventor
Our breath carries enormous amount of information regarding our well-being: from the number of drinks we’ve had on a night out, to information about the state of our liver or the extent of injury in our lungs. Whilst some technologies can help measure one or two molecules (e.g. breath alcohol), basic research and further expansion of this area is hampered by the unavailability of devices that can be operated reliably, reproducibly, and anywhere this might be necessary. We are addressing this market gap through a new breath sampling platform that is helping us understand the dynamics of the lung as a environment for microorganisms, and how these influence disease states (WestFocus PARK funding).
EBOLACHECK: r2hc, £620,000, Nov 2014-2015, Principal Investigator
The West African Ebola virus outbreak between 2014-2016 clearly articulated the need to take genetic testing out of the lab and into the field, be it the pharmacy, the airport terminal or the straw hut in rural Africa. To achieve this specifically for Ebola virus detection and quantification, I formed a team spanning three continents, two biotech companies and the biggest responders to the crisis, Public Health England and the United States Army Medical Research Institute for Infectious Diseases. Within 15 months, we took a sketch idea to a fully functional system and test, suited for use at the frontline of healthcare, with minimal training, up to 8 times faster, and at a cost relevant to the most affected nations.
By going back to basics and understanding the ground truths, the resulting QuRapID platform can detect and measure the genome of Ebola virus in a drop of blood from patients exhibiting the symptoms of the disease, as reliably as clinical molecular laboratory testing. The technology is now under further development for use in pre-symptomatic patients and for the detection of other infectious diseases where the levels of pathogen might be much lower than Ebola. We are exploring this point of need technology for uses in other neglected tropical diseases and conditions where fast, low-cost genetic diagnosis might be an advantage, such as meningitis.Shah K., Bentley, E., Tyler A., Richards K.S., Wright, E., Easterbrook, L., Lee, D., Cleaver, C., Usher, L.,1 Burton J.E., Pitman, J.K., Bruce C.B., Edge, D., Lee, M., Nazareth, N., Norwood, D.A., and Moschos S.A. Field-deployable, Quantitative, Rapid Identification of Active Ebola Virus Infection in Unprocessed Blood. Chemical Science, 2017, 8(11): 7780-7797 (IF: 8.688).
Theotokis, P. Kortschak, C., & Moschos, S.A. Profiling the Mismatch Tolerance of Argonaute 2 through Deep Sequencing of Sliced Polymorphic Viral RNAs. Molecular Therapy Nucleic Acids, 15(9):22-33 (IF: 6.392).
Moschos, S.A, Usher, L., & Lindsay M.A. Clinical potential of oligonucleotide-based therapeutics in the respiratory system. Pharmacology & Therapeutics, 2017, 169:83-103 (IF: 11.000)
Denise, H., Moschos, S.A., Sidders, B., Burden, F., Perkins, H., Carter, N., Stroud, N., Kennedy, M., Fancy, S.-A., Lapthorn, C., Lavender, H., Kinloch, R., Suhy, D. & Corbau, R. Deep sequencing insights in therapeutic shRNA processing & siRNA target cleavage precision. Mol. Ther. Nucleic Acids, 2014, 3:e145. (IF: 6.392).
Moschos, S.A., Frick, M., Taylor, B., et al. Uptake, efficacy & systemic distribution of naked, inhaled short interfering RNA (siRNA) & locked nucleic acid (LNA) antisense. Mol. Ther. 2011, 19(12):2163-8. (IF: 6.668)
Tsitsiou, E., Williams, A.E., Moschos, S.A., Jiang, X., Adams, O.D., Patel, K., Macedo, P., Woodcock, A., Fidock, M., Chung, K.F., & Lindsay, M.A. Transcriptome analysis show activation of circulating CD8+ T-cells in patients with severe asthma, J. Allergy Clin. Immunol. 2011, 129(1):95-103. IF: 12.485
NRL LinkSterghios is an RNA biologist with specific interest in Personalised Medicine and Gene Therapy. His work explores innovative ways by which RNA and big data can be used to better understand disease, measure with high accuracy and precision what happens to the patient, and use systems approaches to intervene optimally, eliminating the cause of disease where possible.
To meet these challenges, work in the Moschos lab is equally divided between bioanalytical innovation and overcoming the greatest bottleneck in molecular therapy with nucleic acid drugs: delivery. This is achieved by training multidisciplinary scientists on cutting edge biomedicine that integrates the latest computational, engineering and biotechnological advances in their work. The goal of his team is to perform industrial-grade orthogonal research, delivering highly reliable basic and applied outputs that transform the field, enable leap advances in diagnostics and therapeutics research, and ultimately revolutionise healthcare provision.
Working on gene therapies such as genome editing, RNAi (siRNA, miRNA), antisense and IVT-RNA, his group is exploring airway epithelial receptor systems for targeted intracellular delivery of nucleic acid drugs. This includes establishing a dedicated biomedical resource facility for receptor characterisation and ligand screening in 3D lung organoids, and the development of proprietary chemical and biological receptor-mediated delivery ligands. Furthermore, the team is working on patent-protected innovations around non-invasive deep lung molecular analytics, as well as advanced diagnostic-compatible methods suited to patient selection and stratification for gene therapy.
With over a decade of experience working with government and commercial organisations in the UK, USA, China, Japan, Korea and Australia, Sterghios is available globally for contract research, expert testimony and consultancy services. Such contracts have so far covered RNA Rx/Dx research, Biology-related information technology, biotech investment and intellectual property protection/analysis.
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