Periodic Reporting for period 1 - PHOTOTHERAPORT (LUMINESCENT IMPLANTS AS PORTS FOR LIGHT-BASED THERAPIES)
Okres sprawozdawczy: 2024-01-01 do 2024-12-31
A major difficulty in developing clinically useful treatments is to deliver therapeutic action with spatiotemporal precision and pharmacological specificity. This unmet need is exemplified in (1) neuropathic pain, which is due to abnormal inflammation and/or excitability of localized somatosensory nerves, sometimes resembling sudden stabbings or electric shocks, and in (2) epilepsy. Inflammation can be treated with photobiomodulation (PBM) but requires localized delivery of light. These conditions can be also treated with neuroinhibitory drugs (e.g. inhibitors of sodium channels, potentiators of GABAa receptors) but their systemic adverse
side effects pose limitations to their safety and efficacy, and once administered, their activity cannot be controlled. To address this issue, we will use locally emitted light, which delivers anti-inflammatory action by PBM. It also allows turning on and off the pharmacological action of photoswitchable drugs locally and on demand. To illuminate the target sites in the body, we will develop PhotoTheraPorts, light-emitting implants based on upconverting nanoparticles. Their visible light emission can be controlled with infrared light applied externally through the tissue and bone. Their encapsulation offers high efficacy and long-term tolerability. We will also develop suitable photoswitchable drugs with anti-inflammatory and neuroinhibitory activity, and we will preclinically test the efficacy and safety of both devices and drugs. We will demonstrate preclinically a novel treatment modality to reduce inflammation and neuroinhibition locally and on demand, in well-established animal models of inflammatory and neuropathic pain and epilepsy, producing a deep impact in the management of these conditions.
side effects pose limitations to their safety and efficacy, and once administered, their activity cannot be controlled. To address this issue, we will use locally emitted light, which delivers anti-inflammatory action by PBM. It also allows turning on and off the pharmacological action of photoswitchable drugs locally and on demand. To illuminate the target sites in the body, we will develop PhotoTheraPorts, light-emitting implants based on upconverting nanoparticles. Their visible light emission can be controlled with infrared light applied externally through the tissue and bone. Their encapsulation offers high efficacy and long-term tolerability. We will also develop suitable photoswitchable drugs with anti-inflammatory and neuroinhibitory activity, and we will preclinically test the efficacy and safety of both devices and drugs. We will demonstrate preclinically a novel treatment modality to reduce inflammation and neuroinhibition locally and on demand, in well-established animal models of inflammatory and neuropathic pain and epilepsy, producing a deep impact in the management of these conditions.
The first PhotoTheraPort implants have been produced, testing different materials, geometries and embeddings. These devices have already been sent to partners that run experiments with photoswitchable drugs and in vivo implantation. Different classes of photoswitchable compounds are being tested for their analgesic potential, neuroinhibition, and antiepileptic capacity. The partners responsible for animal experiments and brain tissue testing have successfully carried out important administrative tasks and control experiments. Some of them already obtained preliminary results on analgesia by photobiomodulation (PBM) in rodents and neuroinhibition in brain tissues by photopharmacological modulation (PPM).
(Objective O1) Developing the technologies required to build custom-assembled PhotoTheraPort biophotonic implants that emit light matching the requirements of PBM and PPM, have a patient-friendly design, and have a promising safety profile in accordance with regulatory standards - The partners TAU and LIOS have conducted an extended analysis of the state survey regarding the types of implants. They have designed phototheraport implants based on upconverting crystals and explored different geometry and class of materials. The first implants have already been sent to partners responsible to test them in vivo. Overall, the first 12 months of the project have shown significant progress towards the achievement of this goal. During our M12 consortium meeting, all partners agreed that TAU and LIOS have done an excellent work in producing the first phototheraports and proposed actions to go forward and improve some aspects of the implants (embedding matrix, dimension, color of light emitted, manipulation techniques of certain geometries).
(Objective O2) Developing photoswitchable neuroinhibitory drugs that display high efficacy and a promising safety profile, amenable to PhotoTheraPortsmediated photocontrol - Two classes of photoswitchable neuroinhibitory drugs have been developed at IBEC during the first year of the project: blockers of voltage-gated sodium channels and agonist potentiators of GABAA receptors. Using a model photoswitchable drug, IBEC could test the coupling of analgesic compounds and phototheraports, thus better defining the necessary characteristics of the latter.
Lastly, another important step towards the achievement of objective goal was the definition of detailed design considerations of photoswitchable neuroinhibitory drugs against pain and epileptic seizueres, which are also crucial for Objectives 3 and 4.
(Objective O3) Demonstrate and validate the usefulness of PhotoTheraPort-mediated PBM and PPM to produce analgesia by interrupting pain signals at the peripheral and spinal cord levels - The first important step made by UCA to achieve this goal was to obtain the license required to conduct in vivo experiments on rodents using the implants and drugs developed by the partners. Following the project timeline, UCA already implanted the first phototheraports obtained by partners in rodents (peripheral and spinal configurations). Preliminary results already showed analgesic effects of infrared light application to phototheraports in the peripheral configuration, while the illumination of spinal cord implants still needs to be optimized. These first-year achievements led to a stimulating discussion among the partners on improvements for both implants and compounds, safety issues and data collection to keep into account also regarding Objectives 5 and 6.
(Objective O4) Demonstrate the usefulness of PhotoTheraPort-mediated PPM to interrupt pain signals and epileptic focal seizures in the brain, including in human brain slices ex vivo for therapeutic validation - The work carried out by partners TECHNION and RSU in the first year of the project laid the ground for future testing of phototheraports mediated PPM. After a long administrative process, RSU formalized an agreement with the Netherlands Bio Bank to have access to human brain tissues suitable for therapeutic validation in the project. RSU already has the first samples available for testing drugs and phototheraports. On the other hand, TECHNION has set up the slice preparation to test the anti-epileptic effect of photoswitchable drugs and carried out important control study with compounds received from IBEC. These will allow to proceed efficiently towards the completion of Objective 4.
(Objective O5) Elaboration and execution of a clear regulatory roadmap and a viable commercialization plan to exploit our technologies from their early-stage validations by the end of the project (and beyond the project duration) -The partners have developed an initial strategy of exploitation of the results. The results of the project are promising but still preliminary, so the partners are committed to keep updating the exploitation strategy as the project progresses and more work is done on the Key Exploitable Results. In our M12 Consortium Meeting the partners also discussed best practices to collect as much data as possible on efficacy and safety of PhotoTheraPorts from in vivo experiments.
(Objective O2) Developing photoswitchable neuroinhibitory drugs that display high efficacy and a promising safety profile, amenable to PhotoTheraPortsmediated photocontrol - Two classes of photoswitchable neuroinhibitory drugs have been developed at IBEC during the first year of the project: blockers of voltage-gated sodium channels and agonist potentiators of GABAA receptors. Using a model photoswitchable drug, IBEC could test the coupling of analgesic compounds and phototheraports, thus better defining the necessary characteristics of the latter.
Lastly, another important step towards the achievement of objective goal was the definition of detailed design considerations of photoswitchable neuroinhibitory drugs against pain and epileptic seizueres, which are also crucial for Objectives 3 and 4.
(Objective O3) Demonstrate and validate the usefulness of PhotoTheraPort-mediated PBM and PPM to produce analgesia by interrupting pain signals at the peripheral and spinal cord levels - The first important step made by UCA to achieve this goal was to obtain the license required to conduct in vivo experiments on rodents using the implants and drugs developed by the partners. Following the project timeline, UCA already implanted the first phototheraports obtained by partners in rodents (peripheral and spinal configurations). Preliminary results already showed analgesic effects of infrared light application to phototheraports in the peripheral configuration, while the illumination of spinal cord implants still needs to be optimized. These first-year achievements led to a stimulating discussion among the partners on improvements for both implants and compounds, safety issues and data collection to keep into account also regarding Objectives 5 and 6.
(Objective O4) Demonstrate the usefulness of PhotoTheraPort-mediated PPM to interrupt pain signals and epileptic focal seizures in the brain, including in human brain slices ex vivo for therapeutic validation - The work carried out by partners TECHNION and RSU in the first year of the project laid the ground for future testing of phototheraports mediated PPM. After a long administrative process, RSU formalized an agreement with the Netherlands Bio Bank to have access to human brain tissues suitable for therapeutic validation in the project. RSU already has the first samples available for testing drugs and phototheraports. On the other hand, TECHNION has set up the slice preparation to test the anti-epileptic effect of photoswitchable drugs and carried out important control study with compounds received from IBEC. These will allow to proceed efficiently towards the completion of Objective 4.
(Objective O5) Elaboration and execution of a clear regulatory roadmap and a viable commercialization plan to exploit our technologies from their early-stage validations by the end of the project (and beyond the project duration) -The partners have developed an initial strategy of exploitation of the results. The results of the project are promising but still preliminary, so the partners are committed to keep updating the exploitation strategy as the project progresses and more work is done on the Key Exploitable Results. In our M12 Consortium Meeting the partners also discussed best practices to collect as much data as possible on efficacy and safety of PhotoTheraPorts from in vivo experiments.