The Advanced Therapies front of Pioneer Science brings together projects that explore innovative approaches for the development of new therapeutic strategies, focusing on complex and hard-to-treat diseases. Integrating biotechnology, gene editing, and advanced experimental models, the research aims to understand pathological mechanisms and also to intervene precisely in biological processes, expanding the possibilities of translating scientific knowledge into clinical applications.
The project investigates new non-viral strategies for delivering CRISPR/Cas9 gene editing systems, integrating cell-penetrating peptides, extracellular vesicles (EVs), and programmable cellular platforms. The goal is to understand and optimize intracellular transport mechanisms, endosomal escape, and cell specificity, aiming to increase the efficiency and safety of gene editing in complex biological models. Modular architectures will be developed and tested for the incorporation of CRISPR into EVs, conjugation of targeting peptides, and controlled release systems for genetic material. The project seeks to generate scalable in vivo delivery system prototypes that are compatible with regulatory requirements, contributing to making advanced therapies based on gene editing more accessible and applicable in hematological and neurological diseases.
The group led by Thyago Calvo researches the therapeutic potential of the superexpression of neuroprotective factors through epigenetic editing with CRISPR-Cas9 in Alzheimer’s disease.
Everything begins with the understanding that the aging of the Brazilian population is associated with an increase in neurodegenerative diseases, especially Alzheimer’s disease. Besides being very complex, the disease has limited treatments capable of modifying its progression, which are still restricted to patients in specific stages of the disease. An intriguing fact is that some individuals age cognitively healthy, even with the classic markers of the disease in the brain, such as beta-amyloid plaques and tau tangles.
What differentiates them? A hypothesis that motivates this project is that the brain has endogenous resilience mechanisms that compensate for or mitigate the impact of neuropathology. The group seeks to activate these neuronal resilience programs to obtain such benefits.
The project proposes to use epigenomic editing with CRISPR-Cas9 to elevate the levels of some key neuroprotective proteins in neuronal models relevant to the disease. Unlike traditional approaches, which insert exogenous genes or inhibit protein aggregates, this strategy acts on the regulation of endogenous gene expression, without modifying DNA, in a specific, potentially reversible, and safe manner.
The neuroprotective effects of this intervention are initially being studied in vitro, in models of beta-amyloid aggregates and in neurons exposed to neurotoxic agents. If successful, this modality will represent a relevant conceptual and therapeutic advance by exploring the potential of epigenomic editing with CRISPR to activate endogenous neuronal resilience programs. In addition to the strong translational potential, this new generation of advanced therapies could be useful for other complex diseases, whether neurodegenerative or not.
The group’s studies investigate the mechanisms associated with the persistence of symptoms in infections caused by arthritogenic alphaviruses, such as Chikungunya and Mayaro. Although the acute phase of these infections is well characterized, a significant portion of patients develops chronic arthralgia, with persistent inflammation in the joints that can last from weeks to years and significantly impact quality of life.
Using immunocompetent mouse models that reproduce the transition from the acute phase to the chronic phase, the research observes that, even in the absence of detectable viral particles, viral RNA remains present in muscle tissues. Based on this finding, the project seeks to understand the molecular mechanisms of the immune response, RNA regulation, and the role of possible viral persistence in maintaining the chronic inflammatory condition. By advancing the understanding of these processes, the research contributes to the identification of new therapeutic targets aimed at treating chronic complications associated with viral infections.
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