Uridine

• (Nasdaq: PRQR) (ProQR), a company dedicated to changing lives through transformative RNA therapies based on its proprietary Axiomer™ RNA editing technology platform, today reported its financial and operating results for the year ended December 31, 2023, and provided a business update.
• At December 31, 2023, ProQR held cash and cash equivalents of €118.9 million, compared to €94.8 million at December 31, 2022.
• The Company experienced a net positive cash flow from operating activities in 2023 primarily due to the receipt of the Lilly up-front payment of $60 million in February 2023.
• For further financial information for the period ended December 31, 2023, please refer to our 2023 Annual Report on Form 20-F and our Statutory Annual Report which will be available on our website, www.

• Until the COVID-19 pandemic, however, vaccine development was still a long and idiosyncratic process.
• But the COVID-19 mRNA vaccines brought a new approach to vaccine development that has far-reaching implications for how researchers make drugs to treat many other diseases.

Some basics of mRNA drugs

• An mRNA drug comprises two essential components: mRNA molecules, which code for desired proteins, and the lipid molecules – such as phospholipids and cholesterol – that encapsulate them.
• From a drug development perspective, mRNA drugs offer significant advantages over traditional drugs because they are easily programmable.
• More importantly, different mRNA drugs produced by the same set of methods will have similar properties.
• This predictability significantly reduces the development risks and financial costs of developing mRNA drugs.

Self vs. nonself

• This may sound paradoxical – after all, your cells already contain large amounts of mRNAs.
• How does your immune system distinguish between self and nonself mRNAs?
• Therapeutic mRNAs enter cells using endosomes – sacs made of the cell’s membrane that take in materials from the cell’s environment.

• The 2023 Nobel Prize in physiology or medicine was awarded to the scientists who made this breakthrough discovery.
• RNA viruses also form double-stranded RNA when they replicate, and exposing cells to double-stranded RNA can lead to a strong immune response.
• Fortuitously, for mRNA vaccines, the residual amount of double-stranded RNA can stimulate the immune system to enhance antibody responses.

Moving beyond vaccines

• One promising example in development is using mRNA that encodes CRISPR-Cas9 gene-editing proteins to knock out genes that cause specific diseases.
• This disease is an ideal target for mRNA-based CRISPR gene therapy because the target protein is produced by the liver.

• Notable new developments in these areas include using computational algorithms to optimize mRNA sequences in ways that enhance their stability and engineering RNA polymerases that introduce fewer side products that may cause an immune response.
• Further advancements have the potential to enable a new generation of safe, durable and effective mRNA therapeutics for applications beyond vaccines.

Li Li receives funding from NIH.

• The rapid development of these vaccines changed the course of the pandemic, providing protection against the SARS-CoV-2 virus.
• Their discovery was not only integral to COVID-19 vaccine development, but may also lead to the development of many other therapies – such as vaccines for cancer.

Life’s work

• It’s made in the body from our very own DNA in a process called translation.
• DNA is our special encoded handbook of instructions for manufacturing proteins, which are the building blocks for material in the body.
• The cells then make whatever protein they’ve been instructed to, such as haemoglobin for helping red blood cells carry oxygen around the body.
• The researchers faced two major challenges as they began their work.
• Karikó and Weissman’s research had successfully eliminated the obstacles that had previously stood in the way of using mRNA clinically.

COVID vaccines

• Researchers had already been working on developing mRNA vaccines before the pandemic, such as a vaccine for Ebola that didn’t receive much commercial interest.
• This produced a harmless COVID particle which our cells then replicated, allowing our bodies to protect us from severe COVID infections when it encountered the real virus.
• Studies have also shown mRNA vaccines might be useful in treating certain types of cancer.

• Data presented at ESMO describe NUC-3373 plus leucovorin in combination with either oxaliplatin (NUFOX) or irinotecan (NUFIRI) in the dose-finding part of the study.
• The disease control rates for the NUFOX and NUFIRI regimens were 80% and 55%, respectively.
• With these data, NuCana has established the recommended Phase 2 dose for NUC-3373 as part of NUFOX and NUFIRI regimens.
• TS is required to convert uridine (specifically dUMP) to thymidine (specifically dTMP), one of the four nucleotides that comprise DNA.