Periodic Reporting for period 1 - PROTO (PROTO - Advanced PeRsOnalized Therapies for Osteoarthritis – TACKLING INFLAMMATION TO IMPROVE PATIENT OUTCOMES)
Période du rapport: 2023-01-01 au 2024-06-30
Osteoarthritis (OA) is a chronic progressive joint disorder, characterized by inflammation causing pain, stiffness, swelling and gradual loss of joint function.
OA affects over 16% of the global adult population, and it is the most common and rapidly growing form of arthritis, leading to reduced mobility and chronic disability and is associated with cardiovascular and metabolic co-morbidities. OA is mostly triggered by micro- and macro-injuries to affected joints, where repair processes initiate proinflammatory immune cascades that eventually lead to progressive joint destruction. This vicious cycle results in cartilage degradation, subchondral bone remodelling and low-grade joint inflammation. To date there are no disease modifying treatments that can prevent or slow down OA.
Within PROTO we have joined forces to address the key feature of OA progression – inflammation.
We intend to do this in a two-pronged approach addressing different early inflammatory disease stages.
(i) We will use an innovative anti-inflammatory allogeneic placental (PLX-PAD) cell therapy to treat patients with early-stage knee OA as a direct approach to reduce inflammation and degeneration.
(ii) We will train patients following anterior cruciate ligament reconstruction (ACLR) a few months after surgery, to restore normal biomechanics and alleviate mechanically induced inflammation within the joint. This group will serve as a pre-stage knee OA group, as in previous work we have shown that pathological gait patterns in persons after ACLR or with knee OA are associated with progressive cartilage loss and persistent inflammation.
OA affects over 16% of the global adult population, and it is the most common and rapidly growing form of arthritis, leading to reduced mobility and chronic disability and is associated with cardiovascular and metabolic co-morbidities. OA is mostly triggered by micro- and macro-injuries to affected joints, where repair processes initiate proinflammatory immune cascades that eventually lead to progressive joint destruction. This vicious cycle results in cartilage degradation, subchondral bone remodelling and low-grade joint inflammation. To date there are no disease modifying treatments that can prevent or slow down OA.
Within PROTO we have joined forces to address the key feature of OA progression – inflammation.
We intend to do this in a two-pronged approach addressing different early inflammatory disease stages.
(i) We will use an innovative anti-inflammatory allogeneic placental (PLX-PAD) cell therapy to treat patients with early-stage knee OA as a direct approach to reduce inflammation and degeneration.
(ii) We will train patients following anterior cruciate ligament reconstruction (ACLR) a few months after surgery, to restore normal biomechanics and alleviate mechanically induced inflammation within the joint. This group will serve as a pre-stage knee OA group, as in previous work we have shown that pathological gait patterns in persons after ACLR or with knee OA are associated with progressive cartilage loss and persistent inflammation.
During the first 18 months of the project we characterized, evaluated, and selected clinical batches of PLX-PAD cells, which will be released following clinical study approval (WP2). We provided in-house preclinical data on the safety and efficacy of intraarticular injections of PLX-PAD cells and submitted a CTA via CTIS. The national competent authorities (NCA) requested a Phase I study before the Phase IIa. We held a second Scientific Advice Meeting and are preparing the Phase I protocol for submission in Q4 2024 (WP3).
We developed and validated a biomechanical gait index to identify patients with pathological gait patterns after ACLR and created a personalized physical training program, implemented in the re.flex app. We also completed ethics applications and recruitment materials, and validated our treatment approach through data analyses from a previous study (WP4).
Significant progress was made in deep immunophenotyping of inflammatory cells and molecular profiling of cytokines in OA patient samples, identifying differences between blood and synovial fluid and detecting inflammation markers, laying the groundwork for future clinical studies (WP5).
In WP6, we developed and validated deep-learning software to detect Hoffa synovitis, Figure 1 shows the segmentation process, and completed the imaging protocol for clinical trials, now ready for use. This protocol has been published in Osteoarthritis & Cartilage Open.
We also established advanced co-culture systems of hCH organoids with PLX-PAD to test anti-inflammatory and regenerative effects, identifying key signaling components and developing microfluidic cultures for detailed analysis (see organoids in Figure 2 (WP7). Finally, PROTO consortium results have been disseminated on our website (Figure 3), at multiple conferences and in publications (WP8). While the project is still in its early phase, 12 papers have been published and the consortium has started to raise awareness within patient communities and other health care providers.
We developed and validated a biomechanical gait index to identify patients with pathological gait patterns after ACLR and created a personalized physical training program, implemented in the re.flex app. We also completed ethics applications and recruitment materials, and validated our treatment approach through data analyses from a previous study (WP4).
Significant progress was made in deep immunophenotyping of inflammatory cells and molecular profiling of cytokines in OA patient samples, identifying differences between blood and synovial fluid and detecting inflammation markers, laying the groundwork for future clinical studies (WP5).
In WP6, we developed and validated deep-learning software to detect Hoffa synovitis, Figure 1 shows the segmentation process, and completed the imaging protocol for clinical trials, now ready for use. This protocol has been published in Osteoarthritis & Cartilage Open.
We also established advanced co-culture systems of hCH organoids with PLX-PAD to test anti-inflammatory and regenerative effects, identifying key signaling components and developing microfluidic cultures for detailed analysis (see organoids in Figure 2 (WP7). Finally, PROTO consortium results have been disseminated on our website (Figure 3), at multiple conferences and in publications (WP8). While the project is still in its early phase, 12 papers have been published and the consortium has started to raise awareness within patient communities and other health care providers.
The ambitious programme of PROTO aims to halt and partially reverse the structural and functional changes caused by inflammatory processes in OA.
Our ambitious goal is to introduce: (i) the highly innovative anti-inflammatory local placental derived cell therapy in early-stage OA patients and (ii) a personalized sensor-based training intervention intended to prevent inflammation and OA onset during a crucially important ‘window of opportunity’ by correcting pathological movement patterns in pre-stage OA patients. A vast array of mechanistic side studies are conducted within PROTO and have already revealed important mechanisms, which support the clinical anti-inflammatory treatment approach.
Our ambitious goal is to introduce: (i) the highly innovative anti-inflammatory local placental derived cell therapy in early-stage OA patients and (ii) a personalized sensor-based training intervention intended to prevent inflammation and OA onset during a crucially important ‘window of opportunity’ by correcting pathological movement patterns in pre-stage OA patients. A vast array of mechanistic side studies are conducted within PROTO and have already revealed important mechanisms, which support the clinical anti-inflammatory treatment approach.