Periodic Reporting for period 4 - CardioReGenix (CardioReGenix: Development of Next-Generation Gene Therapies for Cardiovascular Disease)
Reporting period: 2023-07-01 to 2024-06-30
WHO estimates 17.7 million people die each year from cardiovascular disease (CVD), an estimated 31% of all deaths worldwide. While progress with conventional treatments is making incremental gains, there remains a need to develop innovative therapeutic approaches. Gene therapy has gained significant momentum, mainly for treatment of rare monogenetic diseases. Marketing authorization for gene therapy products has not impacted diseases such as CVD. A recent, deeper understanding of the molecular/cellular mechanisms of CVD and technology associated with more efficient and safer gene therapy vectors has allowed new opportunities for development of next-generation ATMPs for CVD.
CardioReGenix focused on technological innovations for the treatment of CVD, in particular heart failure and myocardial ischemia. We aim to overcome bottlenecks in gene therapy for CVD by:
i) maximizing cardiac-specific gene expression;
ii) maximizing cardiac-specific gene delivery;
iii) reducing adverse immune responses;
iv) optimizing manufacturing for research and clinical-grade ATMPs;
v) validate new promising targets using in vitro and preclinical models;
vi) preparing for first-in-man studies;
vii) developing and implementing an exploitation and valorization strategy
CardioReGenix will
i) strengthen Europe's competitive position in gene therapy development for CVD;
ii) improve the prospect of successfully treating patients suffering from CVD by gene therapy and
iii) develop and refine the latest gene therapy platforms that go significantly beyond the state of the art.
CardioReGenix focused on technological innovations for the treatment of CVD, in particular heart failure and myocardial ischemia. We aim to overcome bottlenecks in gene therapy for CVD by:
i) maximizing cardiac-specific gene expression;
ii) maximizing cardiac-specific gene delivery;
iii) reducing adverse immune responses;
iv) optimizing manufacturing for research and clinical-grade ATMPs;
v) validate new promising targets using in vitro and preclinical models;
vi) preparing for first-in-man studies;
vii) developing and implementing an exploitation and valorization strategy
CardioReGenix will
i) strengthen Europe's competitive position in gene therapy development for CVD;
ii) improve the prospect of successfully treating patients suffering from CVD by gene therapy and
iii) develop and refine the latest gene therapy platforms that go significantly beyond the state of the art.
RPA1:
Work to date with respect to WP1 has been associated with the development of strategies to maximize cardiac-specific gene expression. The in vivo performance of the redesigned vectors is being examined. WP2 has been investigating methodologies for the delivery of cardiac-targeted therapeutics. Specific tissue tropism of AAV and HAdV vectors is being investigated. Currently, a selection of AAV vectors has been investigated for potential use in cardiac targeting. Furthermore, work has commenced on the use of liver-detargeted novel adenoviral vectors as an alternative delivery system. Finally, initial studies have commenced on the targeting of ncRNAs to cardiac cells and methods to enhance their therapeutic potential. Work within work package 3 has commenced with the investigations of strategies to reduce any immune reaction to the AAVs or AAV transduced cells.
RPA2:
WP1 was completed while WP2 continued to show promising data with the development of cardiac-targeting of vectors. Partner UEDIN began investigating their novel adenovirus which has shown greater cardiotropic activity. WP3 has progressed with the investigations of strategies to reduce the immune responses to vectors. Partner UEF indicated that the selection of AAV for clinical trial development had caused adverse inflammatory effects within their model for preclinical assessment. A Grant Agreement amendment was approved and the clinical trial has been removed. Preclinical studies have progressed and a range novel vectors are being investigated. The regulatory pathway (WP7) associated with the development of the necessary regulatory dossiers is being developed.
REPA3:
Prototype CRE-vectors containing therapeutic non-coding shRNA1212 were validated in vitro and in vivo. Progress with AAV5 and AAV9 peptide display library resulted in identification of variants for investigations. UEF partner has continued a concentrated study of AAV and shRNA1212. Partner MHH is working on a new design of dendrimer/polymer-based nanoparticles while partner Cardior worked on the structural optimization of the antisense oligonucleotide inhibitors. Partner CAU engineered immunogenic candidate regions of AAV5 and developed mutated variants that resulted in reduced humoral immune responses. Partner VUB has generated AAV “stealth” vectors based on genetic fusions between AAV cap proteins and proteasome inhibitor polypeptides. Partner Cardior successfully finished an in vitro test system and validated it in the scope of the miR-21 oligonucleotide inhibitor optimization. Partner ASP has revised the documentation required to develop the necessary preclinical dossiers to support a future Phase I study.
REPA4:
The final activities associated with the project were completed with deliverables being submitted. The Cardioregenix project has resulted in more than 50 publications arising from the research activities. Partners UEDIN and BBS have continued work on the patented novel Ad vector showing greater cardiotropism. Partner CAU and VUB completed work developing processes to achieve stealth modifications to reduce immune responses to the vectors being utilised. Partner UEF completed the in vivo studies for AAV6 shRNA1212 which in partnership with Partner ASP has developed the regulatory route for the next phase of development. Partner Cardior has been acquired by Novo Nordic and continued their developments of novel vector directed delivery to cardiovascular tissues in collaboration with Partner MHH.
Work to date with respect to WP1 has been associated with the development of strategies to maximize cardiac-specific gene expression. The in vivo performance of the redesigned vectors is being examined. WP2 has been investigating methodologies for the delivery of cardiac-targeted therapeutics. Specific tissue tropism of AAV and HAdV vectors is being investigated. Currently, a selection of AAV vectors has been investigated for potential use in cardiac targeting. Furthermore, work has commenced on the use of liver-detargeted novel adenoviral vectors as an alternative delivery system. Finally, initial studies have commenced on the targeting of ncRNAs to cardiac cells and methods to enhance their therapeutic potential. Work within work package 3 has commenced with the investigations of strategies to reduce any immune reaction to the AAVs or AAV transduced cells.
RPA2:
WP1 was completed while WP2 continued to show promising data with the development of cardiac-targeting of vectors. Partner UEDIN began investigating their novel adenovirus which has shown greater cardiotropic activity. WP3 has progressed with the investigations of strategies to reduce the immune responses to vectors. Partner UEF indicated that the selection of AAV for clinical trial development had caused adverse inflammatory effects within their model for preclinical assessment. A Grant Agreement amendment was approved and the clinical trial has been removed. Preclinical studies have progressed and a range novel vectors are being investigated. The regulatory pathway (WP7) associated with the development of the necessary regulatory dossiers is being developed.
REPA3:
Prototype CRE-vectors containing therapeutic non-coding shRNA1212 were validated in vitro and in vivo. Progress with AAV5 and AAV9 peptide display library resulted in identification of variants for investigations. UEF partner has continued a concentrated study of AAV and shRNA1212. Partner MHH is working on a new design of dendrimer/polymer-based nanoparticles while partner Cardior worked on the structural optimization of the antisense oligonucleotide inhibitors. Partner CAU engineered immunogenic candidate regions of AAV5 and developed mutated variants that resulted in reduced humoral immune responses. Partner VUB has generated AAV “stealth” vectors based on genetic fusions between AAV cap proteins and proteasome inhibitor polypeptides. Partner Cardior successfully finished an in vitro test system and validated it in the scope of the miR-21 oligonucleotide inhibitor optimization. Partner ASP has revised the documentation required to develop the necessary preclinical dossiers to support a future Phase I study.
REPA4:
The final activities associated with the project were completed with deliverables being submitted. The Cardioregenix project has resulted in more than 50 publications arising from the research activities. Partners UEDIN and BBS have continued work on the patented novel Ad vector showing greater cardiotropism. Partner CAU and VUB completed work developing processes to achieve stealth modifications to reduce immune responses to the vectors being utilised. Partner UEF completed the in vivo studies for AAV6 shRNA1212 which in partnership with Partner ASP has developed the regulatory route for the next phase of development. Partner Cardior has been acquired by Novo Nordic and continued their developments of novel vector directed delivery to cardiovascular tissues in collaboration with Partner MHH.
The CardioReGenix project, investigating a range of innovative ncRNA-based therapeutic strategies for patients with severe cardiovascular diseases (CVD), particularly coronary heart disease (CHD) and heart failure (HF), was designed to deliver impact through introducing highly novel gene therapy approaches to overcome the current clinical problems associated with tissue targeting, uptake, and unwanted side effects including untoward immune responses. Our novel approaches will be tested in the clinic in a patient population as future development to reduce the burden of CHD on healthcare and social care systems. Our belief is that the impact of the CardioReGenix project will be to reduce patients’ symptoms, morbidity, inability to work and potential mortality and thereby improve the patients’ quality of life and reduce health care costs and welfare payments throughout Europe. An additional impact of the successful completion of the CardioReGenix project is the creation of a range of new platform technologies for biotech companies in Europe. Hence, the social and indirect economic impact of CardioReGenix will be noticeable at different levels of society: (i) at the level of a single human being by improving the quality of life (QoL), health and survival; (ii) at the level of a family by improving the QoL of affected families through a decreased need for family or relatives to take care of the affected person; (iii) at the level of society increased QoL and autonomy of patients (and their families) will lead to an overall decreased social costs associated with home or hospital care. Once cured, the patients will be able to lead active professional lives. The social and indirect economic impact will in the first instance relate to the primary disease targets of CardioReGenix (i.e. CHD and HF) but since the technology platform developed within CardioReGenix has broad implications beyond CVD, it will ultimately have a broader impact on patients and their families suffering from other cardiac disorders. Finally, CardioReGenix will foster the improvement of medical knowledge and competitiveness of Europe in the field of gene therapy technologies.