Periodic Reporting for period 1 - APTADEGRAD (A novel, first-in-its-kind, aptamer-based LYTACs to address the unmet clinical need of diabetic wounds.)
Période du rapport: 2022-12-01 au 2023-11-30
The aim of APTADEGRAD project is to obtain an in vivo proof of concept for a novel, first-in-class therapy using Lysosome Targeting Chimeras (LYTACs) to heal diabetic foot ulcers (DFUs). Diabetic foot ulcers (DFUs), a major complication of diabetes, occur in ~25% of patients, with a five-year recurrence rate of ~65% . DFUs often end in hospitalization, with limb amputations in up to 60% of cases . DFU related mortality is 5% within twelve months, rising to 42% after five years. Across Europe the cost of treating DFUs is estimated to be >150Bn euros per year. DFU incidence is expected to increase 2% per year, together with healthcare related costs . Impaired wound healing in diabetes is multifactorial: Peripheral neuropathy and ischemia from peripheral vascular disease combine with risk factors such as high plantar pressures and obesity to contribute to DFU onset . Each phase of healing (hemostasis, inflammation, proliferation and remodeling) is negatively impacted resulting in a DFU, and a gate for chronic infection , . Despite high prevalence and its major impact on the quality of life, no effective treatment has been approved, so DFU remain a highly unmet clinical condition. Standard DFU treatments are limited to surgical debridement, dressings, vascular assessment, and glycemic control, among others. New early-stage preventative and long-term supportive therapies are essential to mitigate social and economic impact of DFUs. DFUs are characterized by imbalances in growth factors, cytokines and proteases. Our innovative targeted degradation solution will directly address this dysfunction, targeting persistent local inflammation and excessive protease activity3, .
By employing aptamer and antibody-based targeted degraders (LYTAMERs and mAb-LYTACs) we would target IL-1β, its receptor IL-1R1, and MMP-9 for degradation, which are known to play a key role in diabetic impaired wound healing. We hypothesize that the pathological inflammatory cascade can be addressed with a degrader approach to deliver a superior therapeutic outcome via: 1) the targeted protein degradation (TDP) mechanism of action (MoA) and 2) the synergistic effect of simultaneous degradation of key targets in this cascade. Our therapy would deliver a pro-healing environment while maintaining a balanced homeostasis of proinflammatory molecules necessary to prevent recurrent DFU associated infections. This technology offers a cost-effective, off-the-shelf, ready-to-use, scalable, chemical-like therapy which can be easily applied to diabetic (and other) wounds using an adapted hydrogel delivery system.
The purpose of APTADEGRAD project is to complete the preclinical development and evaluation of these degraders, using validated in vitro and in vivo models to assess their safety and efficacy when administered topically. Parallel MoA studies will compare degraders to antibody-mediated blocking/inhibition therapies. Finally, we will address regulatory and scale-up activities needed to prepare these candidates for first-in-man, clinical evaluation.
By employing aptamer and antibody-based targeted degraders (LYTAMERs and mAb-LYTACs) we would target IL-1β, its receptor IL-1R1, and MMP-9 for degradation, which are known to play a key role in diabetic impaired wound healing. We hypothesize that the pathological inflammatory cascade can be addressed with a degrader approach to deliver a superior therapeutic outcome via: 1) the targeted protein degradation (TDP) mechanism of action (MoA) and 2) the synergistic effect of simultaneous degradation of key targets in this cascade. Our therapy would deliver a pro-healing environment while maintaining a balanced homeostasis of proinflammatory molecules necessary to prevent recurrent DFU associated infections. This technology offers a cost-effective, off-the-shelf, ready-to-use, scalable, chemical-like therapy which can be easily applied to diabetic (and other) wounds using an adapted hydrogel delivery system.
The purpose of APTADEGRAD project is to complete the preclinical development and evaluation of these degraders, using validated in vitro and in vivo models to assess their safety and efficacy when administered topically. Parallel MoA studies will compare degraders to antibody-mediated blocking/inhibition therapies. Finally, we will address regulatory and scale-up activities needed to prepare these candidates for first-in-man, clinical evaluation.
An efficient degrading strategy that allows the targeted degradation of various targets at the lysosomal level has been set up. So far, the APTADEGRAD consortium has managed to demonstrate the in vitro efficiency of these degraders for the IL-1b and MMP-9 targets, as well as for other alternative targets that intervene in the inflammatory process. A patent protecting this degrading strategy has been filed. These degraders allow us to continue the development of the project and move towards the first in vivo proofs of concept while continuing to work on the development of the first lytamer candidates. Moreover, aptamers and antibodies against the targets of interest have been successfully discovered.
APTADEGRAD project is progressing towards the ultimate goal of obtaining relevant in vivo PoC on the safety and efficacy of a LYTAC-based therapy for DFU. In one year the project has been able to produce its first LYTACs candidates which are now undergoing relevant in vitro and in vivo assays. Moreover, these candidates demonstrated in vitro that they are able to bind the proteins of interest (IL1-beta and MMP-9) and sort these proteins to the lysosomal degradation. To our knowledge, this is the first attempt to degrade these extracellular proteins.
The work carried out during the first reporting period, allow us to be in an excellent position to study whether these candidates are able to address the challenges posed by DFUs.
The work carried out during the first reporting period, allow us to be in an excellent position to study whether these candidates are able to address the challenges posed by DFUs.