Public Funding for Medicines Discovery Catapult Limited

"The ORAC project will develop a new head-up display for scientists to navigate complex information spaces and improve the efficiency and accuracy with which they access scientific knowledge. It will provide scientists with a simple and comprehensive tool to correlate, annotate and navigate the widest range of data overcoming existing barriers between data sources. This will be delivered seamlessly within their current browser via a simple plug-in that identifies concepts on any HTML/PDF page and annotates them with semantically and contextually accurate information. The ORAC plug-in will automatically identify key scientific concepts such as 'disease', 'gene', 'chemical', 'bioassay', 'person' and link these to other resources for further study, hypothesis generation and verification. These will be derived from a wide range of data sources including definitions, attributes, supplemental datasets, and documented relationships to other types of concepts. This will enable much faster discovery and interpretation of information, and navigation between concepts whose descriptions may be held in different data sources. ORAC will take advantage of a comprehensive semantically normalized knowledge graph of all publicly available biomedical literature, including PubMed, Arxiv, USPTO, ChEMBL, OMIM, ClinicalTrials.gov, DBPedia etc. This knowledge graph will be automatically built and maintained by extensions to RowAnalytics' highly innovative spot.my deep semantic learning engine. RowAnalytics' spot.my deep learning engine provides major advantages over existing keyword, AI or NLP systems, as it learns the semantic meanings of text as documents are indexed, through detailed analysis of the patterns of co-occurrence of all concepts with all other concepts, and their distribution across all documents in a corpus. This makes it incredibly simple, efficient and scalable in use, and highly adaptable to a broad range of emergent new scientific terms. In the ORAC project, this will be extended to enable automated ontology construction and curation without expensive, time-consuming and inaccurate manual intervention or continually retraining of neural networks. The ORAC system will also provide personalized knowledge channels which users can set up around any topic to summarise and/or alert them to new information relevant to their subjects of interest. These unprecedented 'deep personalization' capabilities deliver smart AI searching in a fully private and secure manner with no sharing of personal data. They enable exploration of the scientific literature by biomedical researchers and clinical practitioners, for example to contextualize advice for a specific individual based on their combination of genomic, clinical and phenotypic attributes."

There is an urgent need for improved mental health therapeutics, underscored by the staggering economic impact, estimated at £117.9 billion annually in the UK. In spite of the recognised unmet need, there are a lack of clinical assets in late-stage pipelines for mental health conditions. This is because there are significant barriers to innovation, (e.g., accurate models of the blood-brain-barrier, lack of understanding of distinct patient populations) leading to high failure rates once therapeutic assets reach the clinic. Our national R&D platform, called the 'Psychiatry Consortium' will provide a collaborative platform, bringing together partners from pharma, SMEs, charities, and academia to co-develop drug discovery technologies that will address 'innovation barriers' within mental health drug discovery - dismantling bottlenecks and enabling the development of new therapeutics. These innovation barriers will be identified during the seed corn funding stage and transformed into what we call 'Grand Challenges' -- which will be a collection of innovation streams bringing together diverse partners to co-develop enabling drug discovery technologies.

There is an urgent need for improved mental health therapeutics, underscored by the staggering economic impact, estimated at £117.9 billion annually in the UK. In spite of the recognised unmet need, there are a lack of clinical assets in late-stage pipelines for mental health conditions. This is because there are significant barriers to innovation, (e.g., accurate models of the blood-brain-barrier, lack of understanding of distinct patient populations) leading to high failure rates once therapeutic assets reach the clinic. Our national R&D platform, called the 'Psychiatry Consortium' will provide a collaborative platform, bringing together partners from pharma, SMEs, charities, and academia to co-develop drug discovery technologies that will address 'innovation barriers' within mental health drug discovery - dismantling bottlenecks and enabling the development of new therapeutics. These innovation barriers will be identified during the seed corn funding stage and transformed into what we call 'Grand Challenges' -- which will be a collection of innovation streams bringing together diverse partners to co-develop enabling drug discovery technologies.

There is an urgent need for improved mental health therapeutics, underscored by the staggering economic impact, estimated at £117.9 billion annually in the UK. In spite of the recognised unmet need, there are a lack of clinical assets in late-stage pipelines for mental health conditions. This is because there are significant barriers to innovation, (e.g., accurate models of the blood-brain-barrier, lack of understanding of distinct patient populations) leading to high failure rates once therapeutic assets reach the clinic. Our national R&D platform, called the 'Psychiatry Consortium' will provide a collaborative platform, bringing together partners from pharma, SMEs, charities, and academia to co-develop drug discovery technologies that will address 'innovation barriers' within mental health drug discovery - dismantling bottlenecks and enabling the development of new therapeutics. These innovation barriers will be identified during the seed corn funding stage and transformed into what we call 'Grand Challenges' -- which will be a collection of innovation streams bringing together diverse partners to co-develop enabling drug discovery technologies.

There is an urgent need for improved mental health therapeutics, underscored by the staggering economic impact, estimated at £117.9 billion annually in the UK. In spite of the recognised unmet need, there are a lack of clinical assets in late-stage pipelines for mental health conditions. This is because there are significant barriers to innovation, (e.g., accurate models of the blood-brain-barrier, lack of understanding of distinct patient populations) leading to high failure rates once therapeutic assets reach the clinic. Our national R&D platform, called the 'Psychiatry Consortium' will provide a collaborative platform, bringing together partners from pharma, SMEs, charities, and academia to co-develop drug discovery technologies that will address 'innovation barriers' within mental health drug discovery - dismantling bottlenecks and enabling the development of new therapeutics. These innovation barriers will be identified during the seed corn funding stage and transformed into what we call 'Grand Challenges' -- which will be a collection of innovation streams bringing together diverse partners to co-develop enabling drug discovery technologies.

There is an urgent need for improved mental health therapeutics, underscored by the staggering economic impact, estimated at £117.9 billion annually in the UK. In spite of the recognised unmet need, there are a lack of clinical assets in late-stage pipelines for mental health conditions. This is because there are significant barriers to innovation, (e.g., accurate models of the blood-brain-barrier, lack of understanding of distinct patient populations) leading to high failure rates once therapeutic assets reach the clinic. Our national R&D platform, called the 'Psychiatry Consortium' will provide a collaborative platform, bringing together partners from pharma, SMEs, charities, and academia to co-develop drug discovery technologies that will address 'innovation barriers' within mental health drug discovery - dismantling bottlenecks and enabling the development of new therapeutics. These innovation barriers will be identified during the seed corn funding stage and transformed into what we call 'Grand Challenges' -- which will be a collection of innovation streams bringing together diverse partners to co-develop enabling drug discovery technologies.

There is an urgent need for improved mental health therapeutics, underscored by the staggering economic impact, estimated at £117.9 billion annually in the UK. In spite of the recognised unmet need, there are a lack of clinical assets in late-stage pipelines for mental health conditions. This is because there are significant barriers to innovation, (e.g., accurate models of the blood-brain-barrier, lack of understanding of distinct patient populations) leading to high failure rates once therapeutic assets reach the clinic. Our national R&D platform, called the 'Psychiatry Consortium' will provide a collaborative platform, bringing together partners from pharma, SMEs, charities, and academia to co-develop drug discovery technologies that will address 'innovation barriers' within mental health drug discovery - dismantling bottlenecks and enabling the development of new therapeutics. These innovation barriers will be identified during the seed corn funding stage and transformed into what we call 'Grand Challenges' -- which will be a collection of innovation streams bringing together diverse partners to co-develop enabling drug discovery technologies.

There is an urgent need for improved mental health therapeutics, underscored by the staggering economic impact, estimated at £117.9 billion annually in the UK. In spite of the recognised unmet need, there are a lack of clinical assets in late-stage pipelines for mental health conditions. This is because there are significant barriers to innovation, (e.g., accurate models of the blood-brain-barrier, lack of understanding of distinct patient populations) leading to high failure rates once therapeutic assets reach the clinic. Our national R&D platform, called the 'Psychiatry Consortium' will provide a collaborative platform, bringing together partners from pharma, SMEs, charities, and academia to co-develop drug discovery technologies that will address 'innovation barriers' within mental health drug discovery - dismantling bottlenecks and enabling the development of new therapeutics. These innovation barriers will be identified during the seed corn funding stage and transformed into what we call 'Grand Challenges' -- which will be a collection of innovation streams bringing together diverse partners to co-develop enabling drug discovery technologies.

Melanoma, or skin cancer, is the 5th most common cancer in both men and women and kills more than 6 people each day in the UK alone. In the last decade, immunotherapies have shown great promise in treating this disease, but with just over 50% of patients respond to this treatment. With a price-tag running at 100's of thousands of pounds for treatment per patient and a relatively high number of serious adverse effects, there is a clear unmet clinical need for new alternative treatments. KLAS therapeutics offers a unique solution to this, by providing an alternative therapy for this cancer that can be used both independently and in combination with current treatments. Our technology works by utilising a process known as photodynamic therapy (PDT). Light is used to activate our compound, known as KLAS-PDT, which then converts otherwise harmless oxygen into a hyper reactive form that kills the cancer cells. By stimulating the body's immune system, KLAS-PDT can be combined with existing immunotherapies leading to significantly reduced cost and improved patient outcomes. This project seeks to enhance the commercialisation of this exciting new technology, by generating a data package that will confirm the optimal parameters for light activation and dosing regimen. Rendering the technology closer to achieving actual patient benefit while at the same time developing new methods that can be carried forward and translated for the analysis of our eventual clinical data.

Ribonucleic acid (or RNA) based therapy is the treatment or prevention of diseases using RNA-based molecules. The recent sucess of messenger RNA vaccines in response to the COVID-19 pandemic has highlighted the potential of this technology and greatly increased research and industrial interest. RNA offers the potential to produce almost any functional protein or peptide in the human body by introducing mRNA as a vaccine or therapeutic agent. RNA therapeutics and vaccines often require specific, targeted delivery to be effective medicines, and a leading technology platform is Lipid Nanoparticles, along with alternative Nano Delivery Systems. This applies to a range of RNA based therapies such as mRNA/self-amplifying RNA, siRNA, antisense oligos, as well as cutting-edge and potentially curative therapeutic approaches such as gene editing technology, via CRISPR/Cas9, base or prime editing. There is an opportunity to "anchor" commercial scale design and manufacturing of these new classes of therapies in the UK and act as a global hub for research, development activities and trials -- but given the early stage of this technology it requires investment in early to mid-stage R&D to solve scientific, manufacturing, clinical and commercial challenges. Challenges to address include: creating more thermostable medicines; understanding and controlling immunogenicity and adverse reactions, developing better characterisation methods; more efficient and high productivity process development and manufacturing; and targeting a range of different organs and cell types to enable the treatment of a wider range of diseases. We are proposing to upgrade existing facilities to create state of the art capability, along with an ambitious, large scale research programme focused on building the knowhow to create disruptive innovation in the field of product design, formulation, manufacture and characterisation. This includes the ability to rationally design next generation LNPs, create a step change in the area of in vitro methods to predict drug/ vaccine human clinical response, and finally develop a digitally enabled LNP manufacturing process that will act as a lighthouse project for advanced manufacture in Pharma. With public investment we will create the knowhow and capability to catalyse an explosion of R&D investment in the UK - increasing the translation of our high quality academic base, boosting industrial R&D, clinical trials and ultimately creating a new ecosystem via company growth, enhanced productivity, onshoring and supply chain development.

Alchemab Therapeutics has a new way of approaching drug discovery by focussing on what keeps people well, sometimes against the odds. All of us produce a vast repertoire of different antibodies as part of our usual immune responses to fend off pathogens and to help the body maintain its health status. We believe that some individuals are able to use this mechanism to protect themselves against diseases to which they are pre-disposed. Huntington's disease (HD) is a devastating neurodegenerative disease, without any current medicines to slow or stop its progress. It has a genetic cause that is screened for in members of HD high-risk families. Alchemab analysed B cells (which produce antibodies) of patients resilient to various neurodegenerative disorders and identified antibodies common to those individuals resisting disease and not present in those patients who are showing symptoms. We have identified antibodies which we believe may be of particular utility in slowing progression in Huntington's Disease. This grant will accelerate the pre-clinical development of our lead antibody to demonstrate the safety, efficacy and manufacturability profile required by regulators for first in human clinical trials, to prepare for later stages of development and to attract the funding required to take us through an innovative clinical program to the market. Our aim is to develop and test these antibodies as therapies to help individuals living with a HD diagnosis that may not have been so lucky as to develop a protective antibody response themselves, which could be transformative in slowing the course of the disease. We hope this will help us to bring much needed therapies to Huntington's Disease patients faster than traditional drug discovery.

SMi is developing a new technology that analyses patient samples by directly visualising the single molecules that are responsible for different diseases. Using this approach SMi applies a patient sample to the surface of its consumable diagnostic chips and places these chips inside a specialised, benchtop, super-resolution microscope that can scan a large number of samples (96 or 384) in less than 1 second per patient. This resolution is unprecedented in diagnosis and yields an extremely high quality of accurate data that includes the exact number of disease particles. This enables clinicians to rapidly diagnose patients and to monitor disease progression. SMi prints a microscopic pattern of diagnostic reagents onto the diagnostic chips which allows multiple diseases to be tested simultaneously. Such an approach is ideal for cancer as an improved diagnosis is given when a pattern of cancer particles (termed biomarkers) are screened at the same time. In 2018, a clinical study of 1005 patients identified 100 biomarkers that could be used for accurate diagnosis, but their routine use is hindered by the complexity of current test procedures, the high level of training/expertise required, the time needed to run tests, and their prohibitive costs. SMi's new technology is ideal for utilising these biomarkers as it can directly visualise and count the exact number of each different one. In this research project, SMi will micro-print reagents that detect these biomarkers onto its consumable diagnostic chips. When a patient sample is added to the chip, SMi will use complex mathematical formulae to analyse the pattern of results to predict the diagnosis. The use of biomarkers that have already shown success allows the original results to be reappraised and for SMi to prove that its technology produces a similar outcome. Importantly, by partnering with the Medicines Discovery Catapult (a national research laboratory at Alderley Park) SMi can test samples on its own pre-production devices and compare these to the same samples tested on other devices that are commonly used in a clinical setting. A positive outcome from these experiments would validate a valuable set of cancer biomarkers, transform their use for routine cancer screening, and allow real-time monitoring of treatment efficacy. As SMi's technology can visualise any single molecule, a successful validation of the approach in this study would provide further evidence to support adoption of this ground-breaking technology for diagnosis of numerous other diseases, both infectious and non-infectious.

Although great progress has been made in the treatment of some common cancers there remain many where there has been little improvement over decades. One of these is aggressive brain tumours, which have a median survival time of 14.6 months -- a figure that has not improved over the last four decades. The current best-supported care is surgery, which removes as much of the tumour as possible, followed by radiotherapy and chemotherapy. Cancer regularly reappears in this region and progresses rapidly. A unique nanoparticle loaded hydrogel will be developed which will release nanoparticles in areas of residual cancer. These nanoparticles improve the effectiveness of radiotherapy. This project will bring together Xerion Healthcare Ltd, a SME developing radiotherapy enhancing nanoparticles, and the Medicines Discovery Catapult (MDC), a CRO that specialises in pre-clinical development and imaging to develop a unique product that will enhance the effect of post-surgical radiotherapy on aggressive brain tumours and reduce the prospects of cancer regrowth. This project will enable Xerion to take the product forward to clinical trials. Given the critical clinical need for new treatments for this devastating disease, Xerion expects the rollout and uptake to be rapid.

SUMMIT aims to develop and validate Sixfold's oligonucleotide delivery system, MergoⓇ, for delivery of (simultaneously developed) short-interfering RNA (siRNA) gene silencing cargo to a specific tissue type (undisclosed). SUMMIT combines multidisciplinary partners with highly complementary expertise and experience in delivering successful projects, with rapid scientific and commercial progress towards early-stage R&D collaboration. Compared to small molecule and antibody-based drugs, siRNAs can act on virtually unrestricted choice of--otherwise "undruggable"--therapeutic targets, with high specificity and potency; while their easy manufacturing facilitates rapid lead optimization\[1\]. Therefore, siRNAs have the potential to effectively treat numerous diseases. Initial regulatory approvals of Alnylam's siRNA therapies for liver disorders in 2018-19 \[1-2\] validated clinical and commercial opportunity for such therapies. However, the major limiting factor for further success remains the lack of effective platforms for systemic delivery of siRNAs to specific diseased cells\[4\]. Current approaches, primarily GalNAc-conjugates, lipid nanoparticles and viral vectors, are sub-optimal given their limited cell targeting specificity, cargo loading capacity, high toxicity, and complex/expensive manufacturing that limit the addressable disease indications. MergoⓇ addresses this challenge through its modular design based around a central RNA nanoscaffold. This can be functionalised with therapeutics and targeting molecules that recognise biomarkers on specific cells of interest only. This allows the platform to target only diseased cells, thus significantly reducing toxic side-effects from the therapy in other cells and tissues. Although previous MergoⓇ data demonstrated promising _in vitro_ and _in vivo_ results, highly competitive safety and favourable cost profiles, further validation of mechanism-of-action is required for specific tissue types. SUMMIT will develop an in-house siRNA targeted towards a specific extrahepatic tissue, and exploit the versatility of MergoⓇ using nucleic acid chemistry to improve delivery via tissue targeting. This will generate an in-house asset(s), speed candidate development, and act as a demonstrator for application of MergoⓇ to deliver diverse cargo (mRNAs, CRISPR therapeutics) and to target other indications. Consequently, MergoⓇ represents an attractive opportunity to capture a significant portion of the thriving gene therapy and delivery markets and could accelerate other Advanced Therapy Medicinal Products (ATMPs), through improved safety, efficacy and reduced cost of goods, especially compared to viral technologies. Pharmidex and MDC's unique expertise in advanced preclinical screening and imaging enables generation of preclinical data-pack for rapid commercialization and clinical advancement via licensing. Sixfold's broad IP portfolio and licensing strategy engages the entire biopharmaceutical supply chain, providing diverse benefits to the wider UK life sciences sector. \[1\]Lam\_J.K.W\_et\_al.\__Mol\_Ther\_Nucleic\_Acids_\_2015\_4(9):e252\. \[2\]Alnylam\_Press\_release\_10\_August\_2018\. \[3\]Payne\_D\__Nature_\_574\_S1\_2019\.

The covid 19 pandemic underlined the importance of quick and efficient development of drugs and vaccines, that are safe to deploy for wider use. Despite impressive developments during the pandemic, drug discovery remains a very long and expensive with very low probability of success. Identifying useful substances with suitable properties for specific diseases is very difficult task, even for the most powerful supercomputer. More than half of the few drugs that enter the phase of human trials, do not get approval for commercial use, with all the effort related to that going to waste. Quantum computing is a new type of supercomputer that works differently than current computers. Based on the exotic properties of quantum mechanics, they will be able to solve very complicated problems, that are currently unsolvable in a short amount of time; modelling the properties of drugs is one of these problems. Quantum computers can help scientists select and study more and better substances in order to deliver faster more efficient drugs for the benefit of all. In this project, we will develop a quantum computer and use it alongside a classical supercomputer to solve problems that are of real value to the pharmaceutical companies. SeeQC and Riverlane, two of the most successful UK-based companies developing quantum hardware and software respectively will join forces to develop a useful quantum machine. SeeQC will work with the Oxford Instruments to improve the quantum hardware, while Riverlane will develop the software to operate the quantum machine and the quantum algorithms to be used for the calculations. With the help of Merck, a global pharmaceutical company, the University of Oxford and the Medicines Discovery Catapult we will identify some of the pain points of the drug discovery process where quantum computers can help. We will solve them by interleaving our quantum machine with a very powerful supercomputer, that belongs to the Science and Technology funding Council. In this way, the most demanding part of the calculations will be solved on the quantum machine. This trick will deliver more accurate results ten times faster than standard computers. The UK is a world leader in the pharmaceutical sector and a pioneer in developing the quantum technology industry. This project is of real national value as it will boost the development of quantum computers, while showing how useful they can be in solving major problems of a very important industry.

SMi Drug Discovery, a developer of optical devices capable of unprecedented levels of resolution, has designed an automated diagnostic device that will enable the detection of both past and present COVID-19 infections. Unlike other tests, SMi's technology directly observes single molecules to provide irrefutable evidence of their existence. The device produces highly accurate results at unprecedented speed, and is highly scalable. It is capable of screening a handful of samples in less than 2 minutes, and up to 1,000 samples in less than 20 minutes - a theoretical capacity of up to 72,000 samples per day, per machine. SMi's technology also allows the simultaneous screening of multiple disease types, allowing COVID-19 to be distinguished from diseases with similar symptoms such as other coronaviruses or influenza - especially beneficial during winter flu seasons. The device is compact, portable, can be operated by non-specialists and does not require specialised laboratory conditions. Here are two examples of how it might be used for COVID-19: * Workplace: The device's speed means that employees can be tested as they arrive at work, and receive results within minutes. Infected persons can therefore be identified very quickly, significantly reducing the risk of transmission. This capability could be especially critical in healthcare settings such as hospitals and care homes. * Population: The device's portability and ease of use by non-specialists means that routine mass testing can be undertaken at testing centres and population pinch-points; for example, at public transport terminals such as airports, at supermarkets or via mobile testing vans. Providing near-instant results and the ability to conduct testing outside of a clinical environment fundamentally distinguishes this technology from others. Because the SMi device is able to analyse single molecules, it requires only tiny quantities of reagents (dramatically lower than the amounts currently used in a single COVID-19 diagnostic testing kit) and small patient samples. This mitigates the risk of reagent shortages, and dramatically reduces operational costs. Portability, its ability to work outside of specialist laboratories and reduced material waste provide additional environmental benefits. Together with its high throughput, these features would facilitate the monitoring of entire populations - a transformational leap for the management of the global pandemic. SMi's technology provides the diagnostic capabilities necessary to get people back to work and economies moving again in a safe and controlled manner.

Alchemab Therapeutics has a new way of approaching drug discovery by focussing on what keeps people well, sometimes against the odds. All of us produce a vast repertoire of different antibodies as part of our usual immune responses to fend off pathogens and to help the body maintain its health status. We believe that some individuals are able to use this mechanism to protect themselves against diseases to which they are pre-disposed. Huntington's disease (HD) is a devastating neurodegenerative disease, without any current medicines to slow or stop its progress. It has a genetic cause that is screened for in members of HD high-risk families. Surprisingly, some rare individuals with known genetic HD risk factors have far out-lived the age at which they would be expected to develop clear symptoms, and the underlying reason is not fully understood. Alchemab analysed B cells (which produce antibodies) of some of these resilient patients and identified antibodies common to those individuals resisting disease and not present in those patients who are showing symptoms. This grant will fund work to determine what the molecular target of these antibodies is (what they bind to), and whether they can protect against pathological mechanisms of HD. Our aim is to develop and test these antibodies as therapies to help other individuals living with a HD diagnosis that may not have been so lucky as to develop a protective antibody response themselves, which could be transformative in slowing the course of the disease. To do this, we intend to work with UK experts in complex cellular models of neurodegeneration, including those at the Medicines Discovery Catapult. Accessing human brain cells for neurodegeneration research is difficult, and so methods have been developed to reprogramme, in the lab, cells taken from skin into the cell types found in the brain. This can also be done with cells taken from Huntington's disease patients. We will use these human cell-based systems to find out how our antibodies change the biology that is different between healthy and HD. By using these cells for our studies, we are able to stay as close to the human biology of patients which led us to the discovery of these antibody candidates as possible, and this may give us a better chance of success in clinical trials. We hope this will help us to bring much needed therapies to Huntington's Disease patients faster than traditional drug discovery.

Although great progress has been made in the treatment of some common cancers there remain many indications where there has been little improvement in care over decades. The most difficult tumours tend to be inoperable with treatment options limited to chemotherapy and radiotherapy. Chemotherapy is administered systemically and a balance between toxicity and tumour dose is hard to achieve. Radiotherapy is more effective as it can be targeted to the tumour. However, it relies on the presence of oxygen to generate cell killing free radicals, meaning that aggressive oxygen deficient (hypoxic) tumours cannot be treated without unacceptable off-target toxicity. Recently, nanoparticles have begun use as radiosensitisers to enhance the efficacy of radiotherapy treatment. Direct intratumoural injection is currently under active investigation as a method of reducing systemic toxicity but presents a threefold challenge for clinicians. Firstly, direct real-time imaging of the needle tip into the tumour is difficult, particularly for deep tumours in, for example, the pancreas. Secondly, it is not known how far from the needle tip the active ingredient disperses into the tumour. Thirdly, conventional injection provides little control of the distribution of the nanoparticles within the tumour. Consequently, it is very difficult for the clinician to devise an effective clinical intervention strategy for intratumoural injection. This project brings together collaborators with broad and deep skills in the area of nanoparticle development, fluid delivery and medical imaging. This programme will develop the basis of a clinical intervention strategy for cancer treatment of human patients using intratumoural injection.

TARGET aims to preclinically validate Sixfold's Programmable Oligonucleotide Delivery System (PODS) for delivery of short interfering RNA (siRNA) gene silencing cargo to specific cells. By taking advantage of the interdisciplinary and complementary expertise of the partners --Sixfold and Medicine Discovery Catapult (MDC)-- the project allows for rapid scientific and commercial progress. Compared to small molecule or antibody-based drugs, siRNAs can act on virtually unrestricted choice of --otherwise "undruggable"-- therapeutic targets, with high specificity and potency; while their easy manufacturing allows for rapid lead optimization \[1\]. As such, siRNAs have the potential to provide effective treatment options for a variety of diseases including cancer. The first regulatory approvals of Alnylam's siRNA therapies for liver disorders in 2018-19 \[1-2\] have validated the clinical and commercial opportunity for such therapies. However, the major limiting factor for their further success remains the lack of safe and effective systems for systemic delivery of siRNAs to specific diseased cells \[4\]. Current approaches, primarily GalNAc-conjugates, lipid nanoparticles and viral vectors, are sub-optimal given their limited cell targeting specificity, cargo loading capacity, high toxicity, and complex/expensive manufacturing that limit the type and number of addressable disease indications. PODS can address this drug delivery challenge given their modular design based on a central nanoscaffold, which can be functionalised with therapeutics and targeting molecules that recognise biomarkers on cancer -but not healthy- cells. Sixfold's first-generation PODS demonstrated promising results. TARGET expands PODS utility and creates an intelligent and versatile delivery system that goes beyond the limitations of current standards. As such, PODS represent an attractive opportunity to capture a significant portion of the thriving gene therapy delivery market and could accelerate other Advanced Therapy Medicinal Products (ATMP), through improved safety, efficacy and reduced cost of goods, especially compared to viral technologies. By bringing MDC's unique expertise in advanced preclinical imaging, TARGET allows for completion of a comprehensive preclinical datapack to pharmaceutical industry standards, for rapid commercialization and clinical advancement. Sixfold's broad IP portfolio and business strategy engage the entire biopharmaceutical supply chain, providing diverse benefits to the wider UK life sciences sector. \[1\]Lam\_J.K.W\_et\_al.\_Mol\_Ther\_Nucleic\_Acids\_2015\_4(9):e252.\[2\]Alnylam\_Press\_release\_10\_August\_2018\[3\]Alnylam\_Press\_release\_20\_November\_2019.\[4\]Payne\_D\_Nature\_574\_S1\_2019\.

The IMPACTT project will study the immune profiles of 3,000 patients infected with SARS-CoV-2 in order to understand our immune responses to the virus. This project will generate five outputs: 1\. Generation of a panel of immune related biomarkers that are predictive of response to treatment, including adverse events 2\. Understanding why some patients have very mild symptoms, yet others have severe reactions that result in ventilation and even loss of life; 3\. Identification of novel therapeutic targets; 4\. Publicly available database of the immune profiles of 3,000 patients; 5\. Creation of a biorepository of 3,000 patient samples to support further research into the SARS-CoV-2 virus.

Diagnostic testing for SARS-CoV2 is at the centre of the public health response to the COVID-19 pandemic, facilitating the isolation of asymptomatic cases thereby suppressing community transmission. COVID-19 testing is becoming ever more widespread as economic and recreational activities resume, for example, a negative test result is now required to travel to many international destinations. Two methods account for almost all SARS-CoV-2 diagnostic tests: RT-PCR and lateral flow antigen tests. RT-PCR tests provide high sensitivity but are performed in centralised facilities that depend on complex delivery networks, take several hours to process and have slow turnaround times (~24 h). Lateral flow tests are performed by the patient so the result is returned quickly (30 min), however, the test is less sensitive, catching only 60% of cases that were positive by RT-PCR (Cochrane review, 2021). RT-PCR and lateral flow tests require a nasopharyngeal swab, which is uncomfortable to perform and can give inconsistent results if not collected by a trained professional. ONI is developing a novel method to detect SARS-CoV-2 and other respiratory viruses in under 10 minutes by removing time-consuming and costly sample preparation steps, using widely available reagents and making sample analysis automated, faster and safer. Our single-step virus detection assay will allow direct detection and differentiation of SARS-CoV-2 and other viruses in saliva without the need for a nasopharyngeal swab. The assay will run on ONI's new imaging device, with a unique desktop-format and easy-to-use workflow designed specifically for this assay. Together with partners at Imperial College London we will perform side-by-side validation with existing tests on COVID-19 clinical swab samples and assess its ease of use through the London IVD Cooperative. We will then optimise the instrument’s usability with partners at Medicines Discovery Catapult (MDC)-Lighthouse Labs so that the device can be easily operated by non-specialists. Our test will remove the need for high-containment facilities and specialised personnel with automated assay operation, facilitating its use in de-centralised clinical and non-clinical settings. We will engage regulatory bodies to support testing at airports and companies, where our compact and rapid platform will allow detection of SARS-CoV-2 and other respiratory viruses in asymptomatic carriers in a few minutes, helping reduce infection spread, minimising further economic losses and allowing control of future emerging viruses. The ONI-VirusDx assay has the potential to allow rapid, de-centralised single-step virus testing UK-wide.

Several prominent researchers in fibrosis have estimated that 1:2 deaths are caused by complications associated with fibrosis. The prototype fibrotic disease is Idiopathic Pulmonary Fibrosis (IPF): characterised by altered lung architecture and loss of respiratory surface area leading to increased deposition of extracellular matrix in the lung interstitium. Current treatments are primarily to limit progression and treat symptoms rather than treat the disease or underlying causes. Pharmaceutical therapies (Esbriet, Ofev) have significant side-effects and only act to slow disease progression. The need for new anti-fibrotic medication is therefore of paramount importance in sustaining human health and preventing premature deaths. If left ignored the combination of a growing aged population and diseases, such as fibrosis, will become a crippling public health crisis. Successful project delivery will improve quality of life and enable those affected to continue to work, thereby improving social and economic outcomes (productivity and healthcare costs).

Current treatments for patients who have a risk of forming blood clots are effective but carry a significant increase in the risk of bleeding. Anticoagulants taken by mouth include vitamin-K dependent antagonists (e.g. warfarin), direct thrombin inhibitors and FXa inhibitors [Non-vitamin K Oral Anticoagulants (NOACs)]. Studies have shown that NOACs significant reductions in stroke, bleeding in the brain, and death than warfarin but there is increased bleeding in the gut with a similar numbers of patients having major bleeding events (of which 1 in 8 result in death) compared with warfarin[Lancet.2014:15;383(9921):955-62]. Furthermore, because of the risk of bleeding, it is not possible to completely stop clots from forming in patients on treatment. As a result, patients on the new anticlotting treatment (NOACs) are still having blood clots (2.2-3.8%) and bleeding (3.6-20.7%) events with some resulting in death(Nat Rev Cardiol.2014,11(12):693-703).The objective of this proposal is to develop highly specific compounds which block an activated clotting enzyme, Factor XII (FXIIa) and for which there is strong evidence that inhibition will not increase the risk of bleeding. This exciting development will allow patients to be treated more safely, without the need for monitoring and enable safe dose escalation in high risk patients, unlike current medicines that have a small window between beneficial effects and undesirable bleeding events. The aim is to produce an orally administered once or twice daily treatment.The team at Lunac Therapeutics Limited, working with a UK based contract research organisation (sub-contractor), have generated a quality lead series of potent and highly selective agents which block the effects of FXIIa. These agents produce a high level of protection against clotting without the risk of bleeding in comparison with current medicines when tested in our experimental systems with very good anti-clotting effects. Thus, these compounds validate the idea that blocking the effects of FXIIa will deliver high protection against clotting in the absence of a significant bleeding risk, "the holy grail" of anticoagulant treatment. This project will work in collaboration with the University of Leeds and the Medicines Discovery Catapult using sub-contractors to generate a drug that will be ready for preclinical testing (Preclinical Development) to ensure it is safe to use in man. The deliverable of the award will be selection of a preclinical candidate (drug ready for preclinical development) with carefully designed experiments to improve the chances of success in the next stage of Preclinical Development.

"Chief.AI provides full-service AI brokerage and marketplace that aims to become the pre-eminent access point for artificial intelligence as a service (AIAAS) globally. It achieves this by brokering global AI resources, channeling them on demand for metered consumption in a simple to use but secure and private marketplace environment. Chief.AI enables Plug-and-Play retail of global AI back-ends, served to business consumers across a RESTful API on a PAYG model. Suppliers can readily connect AI services to Chief, which enables easy discovery, comparison and purchase of services. Businesses can search for the most appropriate service, purchasing it programmatically and consuming it as and when needed. Services are organised by industrial sector, enabling sectoral businesses to discover and consume industry-relevant AI services with ease. Consumption, benchmarking, and real-time service feedback mechanisms enrich the AI experience across metrics such as algorithm effectiveness, efficiency and AI ethics scores. Revenue is derived from transparent two-sided commission on service usage. This is a paradigm changing way of introducing the businesses and developers to AI, from the current deployment heavy implementation via an easy to use and stable API."

Integrated through Optibrium's existing software offering (StarDrop(tm)), DeepADMET is a next-generation project that will develop and apply novel deep learning methods to extend and improve predictive models of important Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) endpoints to guide more efficient design and selection of high quality drug candidates. Data for important ADMET endpoints that are not readily accessible will be curated as the basis for building models for these endpoints, which are not currently available, and extend and improve the accuracy of the current state-of-the-art models. The successful delivery of project objectives will enhance Optibrium's foothold in the Computational Drug Discovery market through the commercialisation of the software licences through our existing sales force or, where appropriate, by partnership with organisations specialising in that sector or region. DeepADMET forms a key part of Optibrium's Augmented Chemistry(tm) strategy, moving beyond 'tools' to support chemistry optimisation. Intellegens is a spin-out from the University of Cambridge that has developed a unique Artificial Intelligence (AI) method for training neural networks from incomplete data sets. The MDC has a wide variety of partners drawn from: UK biotech and enables it to meet its core strategic objectives as a catalyst for enabling innovation within the sector. Specifically, the project utilizes key and rare expertise in information extraction and curation strategies and tools, the further development and validation planned here will be applicable in future translational life science sectors.

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