A novel, first-in-its-kind, aptamer-based LYTACs to address the unmet clinical need of diabetic wounds.

Introduction

Diabetic foot ulcers (DFUs), a major complication of diabetes, occur in approximately 25% of patients, with a five-year recurrence rate of around 65%. DFUs often lead to hospitalization, with limb amputations occurring in up to 60% of cases. DFU-related mortality is 5% within twelve months, rising to 42% after five years. Despite their high prevalence and significant impact on quality of life, no effective treatment has been approved, leaving DFUs as a highly unmet clinical condition.

Project Objective

APTADEGRAD aims to obtain in vivo proof-of-concept for a novel, first-in-class therapy using aptamer-based Lysosome Targeted Chimeras (LYTACs) to heal diabetic foot ulcers (DFUs).

Mechanism of Action

These LYTACs will target:

• IL-1β
• Its receptor IL-1R1
• MMP-9 for degradation

These proteins are known to play a key role in impaired healing in diabetic wounds. Our hypothesis is that:

a) Aptamer-based LYTACs' mechanism of action may offer the potential to deliver a controlled, dose-dependent reduction of MMP-9, IL-1β, and its receptor IL-1R1. This would moderate the excessive DFU inflammatory response while maintaining biologically beneficial levels of these proteins to promote healing and prevent infection.

b) The simultaneous targeting of these relevant proteins will produce a synergistic effect in the inflammation cascade, providing superior efficacy outcomes.

Expected Outcomes

Should the main objective of the project be achieved (i.e., showing efficacy in animal models of DFU), we would demonstrate for the first time a potential therapy based on LYTACs in the context of diabetic ulcers, with potential applications in other types of chronic wounds or immune pathologies.

Additional Knowledge Gathering

In addition to efficacy data, we will gather essential knowledge about LYTACs, including:

1. Toxicity
2. Efficacy
3. Mechanism of action
4. Differences with other approaches such as blocking or inhibition

This knowledge is essential for the successful future translation of the novel concept of LYTACs in pharmaceutical development to clinical trials.