Periodic Reporting for period 1 - geneTIGA (Gene-edited T cells combating IgA Nephropathy. A blueprint approach for safe & efficient genome editing of T cells to sustainably combat several immune diseases and cancers related to B-cell pathology)
Período documentado: 2022-07-01 hasta 2023-12-31
The prevalence of chronic diseases stemming from dysregulated immune responses is on the rise, affecting over 10% of the population and imposing a substantial burden on both individuals and society at large. Patients grappling with these conditions endure persistent health challenges, organ dysfunction, premature mortality, and a marked decline in their overall well-being. Societal costs in the EU alone surpass 100 billion euros annually, underscoring the urgency for effective interventions. Regrettably, current treatments often fall short in restoring immune homeostasis over the long term.
Our principal objective is to pioneer a safe and potent cell therapy utilizing genome-edited T cells. Specifically tailored to combat IgA nephropathy (IgAN), the most prevalent primary glomerulonephritis and a major contributor to end-stage renal disease lacking adequate treatment options. Our innovative approach holds promise for addressing other diseases associated with IgA, including IgA myeloma, IgA-lymphoma, and various autoimmune conditions like rheumatoid arthritis and systemic lupus erythematosus. Moreover, our methodology could serve as a blueprint for tackling disorders linked to other immunoglobulin types, such as IgG4.
While genetically modified T cell therapies have revolutionized the management of advanced hematological malignancies, their potential in severe autoimmune disease treatment is also emerging. Yet, existing gene transfer techniques relying on retroviral vectors pose risks of insertional mutagenesis and subsequent malignancy. Additionally, their complex manufacturing processes inflate costs in cell therapy production. Leveraging genome editing facilitates precise gene targeting, potentially mitigating oncogenic hazards and enhancing the long-term safety profile of genetically modified T cell products. Non-viral genome editing presents a cost-effective avenue for cell therapy manufacture. Within the geneTIGA project, we will meticulously assess and compare genome editing strategies for T cell redirection using synthetic antigen receptors, ensuring both efficacy and safety. Our overarching goal is to establish robust and reproducible techniques applicable not only to T cell products but also to broader gene therapy endeavors.
Ultimately, our aim is to engineer a "living drug" capable of providing a singular therapeutic intervention for IgAN and related conditions, ready for clinical evaluation. Furthermore, our initiative provides tools and technologies poised to accelerate the advancement of next-generation gene and cell therapies across diverse medical fronts.
Our principal objective is to pioneer a safe and potent cell therapy utilizing genome-edited T cells. Specifically tailored to combat IgA nephropathy (IgAN), the most prevalent primary glomerulonephritis and a major contributor to end-stage renal disease lacking adequate treatment options. Our innovative approach holds promise for addressing other diseases associated with IgA, including IgA myeloma, IgA-lymphoma, and various autoimmune conditions like rheumatoid arthritis and systemic lupus erythematosus. Moreover, our methodology could serve as a blueprint for tackling disorders linked to other immunoglobulin types, such as IgG4.
While genetically modified T cell therapies have revolutionized the management of advanced hematological malignancies, their potential in severe autoimmune disease treatment is also emerging. Yet, existing gene transfer techniques relying on retroviral vectors pose risks of insertional mutagenesis and subsequent malignancy. Additionally, their complex manufacturing processes inflate costs in cell therapy production. Leveraging genome editing facilitates precise gene targeting, potentially mitigating oncogenic hazards and enhancing the long-term safety profile of genetically modified T cell products. Non-viral genome editing presents a cost-effective avenue for cell therapy manufacture. Within the geneTIGA project, we will meticulously assess and compare genome editing strategies for T cell redirection using synthetic antigen receptors, ensuring both efficacy and safety. Our overarching goal is to establish robust and reproducible techniques applicable not only to T cell products but also to broader gene therapy endeavors.
Ultimately, our aim is to engineer a "living drug" capable of providing a singular therapeutic intervention for IgAN and related conditions, ready for clinical evaluation. Furthermore, our initiative provides tools and technologies poised to accelerate the advancement of next-generation gene and cell therapies across diverse medical fronts.
The partners within geneTIGA have initiated the work and begun to identify potential lead candidates for the targeting of IgA and optimized genome editing methodologies. The international and highly interdisciplinary team has identified putative bottlenecks in the development of genome edited T cell products and existing models of IgA nephropathy, generating an interconnected working program to enable the successful developments from preclinical stage up to future clinical trials. Early contact between discovery teams and GMP experts has facilitated the identification of reagents suitable for future clinical translation of the geneTIGA project. The partners have assembled joint-teams to address the tasks of the consortium and shared their respective expertise, protocols, and reagents to achieve the objectives and cross-validate each other’s first findings. Involvement of senior and young researchers enables the development of highly skilled workforce. Dissemination of the results has begun within the scientific community at congresses and other educational events. While the project is still in its early phase, first publications have been released or are under revision. Through the patient representative’s organization, the geneTIGA consortium has started to raise awareness within patient communities and other health care providers.
The ambitious work program of the geneTIGA consortium aims to develop first-in-class Advanced Therapy Medicinal Products (ATMPs) for IgA-nephropathy and other diseases with significant unmet clinical needs. GeneTIGA partners are dedicated to establishing and comparing the most promising genome editing technologies for their efficacy, safety, and suitability for manufacturing clinical T cell products. These developments are of increasing interest in the community, because long-term observations of virally transduced T cell products: The main US regulatory authority for drug development (FDA) has recently raised concerns regarding the long-term safety of traditional gene transfer modalities in T cell products. While the rate of secondary-malignancy in virus-transduced T cell products is still very low, the notion to establish genome editing as a safer gene transfer alternative has therefore been strengthened. The work of geneTIGA may contribute to changing the future of clinical manufacturing of T cell products redirected with synthetic antigen receptors.
Further, novel models and methods are developed to characterize the T cell products potency and safety, both using humanized animal models, but also advanced in vitro models. Herein, geneTIGA also contributes and adheres to the principles of Replacement, Reduction, and Refinement (3Rs). Upon completion of this work, the results will not only provide a blueprint for the specific ATMPs developed within geneTIGA but also offer a roadmap for applying genome editing in the creation and putative regulatory pathways of genome-edited therapies for both malignant and non-malignant diseases.
Further, novel models and methods are developed to characterize the T cell products potency and safety, both using humanized animal models, but also advanced in vitro models. Herein, geneTIGA also contributes and adheres to the principles of Replacement, Reduction, and Refinement (3Rs). Upon completion of this work, the results will not only provide a blueprint for the specific ATMPs developed within geneTIGA but also offer a roadmap for applying genome editing in the creation and putative regulatory pathways of genome-edited therapies for both malignant and non-malignant diseases.