Periodic Reporting for period 1 - LightCure (LightCure - Light for double specificity and efficacy without burden)
Período documentado: 2024-01-01 hasta 2025-06-30
Congenital hyperinsulinism (CHI) is a group of rare diseases of newborns and infants with functionally defective nonneoplastic beta-cells that cause hypoglycemia and severe morbidity through oversecretion of insulin. CHI is a major cause of hypoglycemic brain injury with intellectual disability, epilepsy and cerebral palsy. As no registered causal therapy exists, management of CHI aims at increasing blood glucose levels causing severe side effects in all patients while life-threatening frequent hypoglycaemias remain. Removal of hyperfunctioning beta cells by pancreatectomy leads to insulin dependent diabetes mellitus and maldigestion of food. CHI also represents a major burden for families, because of disability but also as a result of continuous monitoring and correction of glucose levels for many years. Health problems and economic decline occur in most parents. A normal life is not feasible for families with babies with CHI. LightCure consortium partners have demonstrated the feasibility of selectively targeting beta cells using exendin 4 (EX) labelled with a photosensitizer (700DX) specifically binding to beta cells. This photosensitizer can be activated by light of a certain wavelength and will produce radical oxygen species leading to cell damage, a principle called targeted photodynamic therapy (tPDT). In this project we will build on existing cutting-edge technology exclusively available to the consortium partners and perform human proof of concept studies demonstrating safety and efficacy of tPDT with EX700DX. We will deliver the proof-of-concept that after injection of EX700DX, minimally invasive tPDT leads to normalization of blood glucose levels avoiding morbidity, enabling a normal life for babies with CHI and their families. The LightCure consortium will validate EX700DX in animal models. These data, together with toxicity data, clinical grade EX700DX and the required CE certified laser devices, are needed for preparation of proof-of-concept studies. Finally, the concept of EX700DX tPDT will be proven in humans. Furthermore, there is a lack of standards for measuring quality life and burden of disease in CHI to objectively assess the effects of tPDT. We will create questionnaires and tools for shared therapy decison-making for tPDT based on scientific evidence. n addition, we will create more awareness to this disease through campaigns, a documentary and project website.
For the first objective, we have set up protocols for the production of GMP-grade modified peptides. Efforts are currently focused on preparing non-GMP exendin-700DX photosensitizer variants for toxicity studies, preclinical validation, and future GMP production. Work to achieve the second objective is still ongoing, but significant progress has been made. We have implemented in vitro and ex vivo models and techniques to investigate the biological effect of tPDT and optimize the pharmacological and light dose. This will be investigated in more depth in vitro and in vivo in rat models. In addition, we are planning an in vivo study in rats to determine the dosimetric protocols when using radiolabeled EX as a companion diagnostic. Altogether, these findings will ultimately be translated to individually tailored PDT in human use (WP4/5).
The work of objective 3 is still ongoing. The biological effect of exendin tPDT is being investigated in relevant in vitro and ex vivo models These results will lead to tailored protocols for the in human proof-of-concept, and validation of these results will be done. Work on objective 4 has not been started yet as we need to await for the preclinical development in the other workpackages (WP2 and 3). However, contacts within the participating sites with supporting departments necessary for successful execution have been made. Furthermore, microscope analyses have been started as preparation in WP5.
Objective 5: there has been a significant investment in ensuring that the HI Global Registry (HIGR) can serve as the go-to international open-access registry for CHI research and data collection. Significant progress has been made to increase the quality and amount of data available in HIGR and to ensure that it is readily available to researchers interested in utilizing the data. In addition, ethics approval has been obtained for measuring quality of life and burden of disease in CHI. Patient and healthcare professional recruitment is currently ongoing and proceeding. The qualitative data collection is currently ongoing. Concurrently, the qualitative data analysis has been initiated. The initial transcripts are currently undergoing coding and thematic analysis as part of an iterative process.
Objective 6 is not fully achieved since it is still ongoing. We have contacted an international organisation to seek advice from experts in the field of pediatrics. They will provide input on the setup of toxicity studies and the related documentation required for EMA submission and subsequent phase II and III trials. We plan to include them in the LightCure consortium.
Significant progress have been achieved for objective 7. We actively launched glucose as a vital sign to raise awareness, to encourage early diagnosis and effective management of HI to reduce brain damage. We engaged in activities targeted at medical professionals and the public, including an international CHI awareness day, the CHI documentary film, participation at medical conferences, and began planning and drafting the letter-writing campaign for hospitals. We also created long-form and short form advocacy statements and a list of essentials for people with HI that are posted in 5 languages on our website. We upgraded and expanded materials targeted to CHI families for education and support. For objective 8, a patient advisory board is established and actively engaged in activities for exploitation and dissemination as well as attended in-person consortium meetings to provide feedback on the on-going advocacy and scientific aspects of the project.
Work is still ongoing for objective 9, but the final proposal for the laboratory testing is completed and will be reviewed soon by the medical ethical committee.
The work of objective 3 is still ongoing. The biological effect of exendin tPDT is being investigated in relevant in vitro and ex vivo models These results will lead to tailored protocols for the in human proof-of-concept, and validation of these results will be done. Work on objective 4 has not been started yet as we need to await for the preclinical development in the other workpackages (WP2 and 3). However, contacts within the participating sites with supporting departments necessary for successful execution have been made. Furthermore, microscope analyses have been started as preparation in WP5.
Objective 5: there has been a significant investment in ensuring that the HI Global Registry (HIGR) can serve as the go-to international open-access registry for CHI research and data collection. Significant progress has been made to increase the quality and amount of data available in HIGR and to ensure that it is readily available to researchers interested in utilizing the data. In addition, ethics approval has been obtained for measuring quality of life and burden of disease in CHI. Patient and healthcare professional recruitment is currently ongoing and proceeding. The qualitative data collection is currently ongoing. Concurrently, the qualitative data analysis has been initiated. The initial transcripts are currently undergoing coding and thematic analysis as part of an iterative process.
Objective 6 is not fully achieved since it is still ongoing. We have contacted an international organisation to seek advice from experts in the field of pediatrics. They will provide input on the setup of toxicity studies and the related documentation required for EMA submission and subsequent phase II and III trials. We plan to include them in the LightCure consortium.
Significant progress have been achieved for objective 7. We actively launched glucose as a vital sign to raise awareness, to encourage early diagnosis and effective management of HI to reduce brain damage. We engaged in activities targeted at medical professionals and the public, including an international CHI awareness day, the CHI documentary film, participation at medical conferences, and began planning and drafting the letter-writing campaign for hospitals. We also created long-form and short form advocacy statements and a list of essentials for people with HI that are posted in 5 languages on our website. We upgraded and expanded materials targeted to CHI families for education and support. For objective 8, a patient advisory board is established and actively engaged in activities for exploitation and dissemination as well as attended in-person consortium meetings to provide feedback on the on-going advocacy and scientific aspects of the project.
Work is still ongoing for objective 9, but the final proposal for the laboratory testing is completed and will be reviewed soon by the medical ethical committee.
This project is still ongoing. Until now, the project has results beyond the state of the art by introducing innovative methodologies and novel insight into targeted photodynamic therapy with exendin. In WP2 and 3, this innovative method will be developed and tested in in vitro and in vivo models. Significant impact has been achieved in these two workpackges as several Master students have completed their internships. Preliminary results of WP6 and 7 were presented at several congresses in Europe and US, which increased the visibility of the LightCure project. In addiiton, the work conducted under WP7 has an impact on the awareness, diagnosis, and management of hyperinsulinism. Enhancements to the CHII website and LightCure website and expanding educational, advocacy, and support materials have significantly increased patient engagement. More families now have access to reliable resources, empowering them with knowledge and support that improves their ability to navigate care pathways. This multifaceted approach to raising awareness of the condition enables a more effective way to reach people through various methods: meaningful graphics, social media, film, conference presentations, and online resources.