In Vivo CRISPR-Based Nanoplatform for Gene Editing: A New Disruptive Avenue for Non-Invasive Treatment of Genetic Brain Diseases

Descripción del proyecto

Nanotecnología de edición génica para una terapia encefálica personalizada

La revolucionaria tecnología de modificación del genoma CRISPR/Cas tiene un gran potencial para tratar muchas enfermedades genéticas. Con todo, la administración de la maquinaria CRISPR/Cas a las células enfermas del encéfalo constituye uno de los mayores retos actuales de la medicina. El equipo del proyecto de investigación BrainCRISPR, financiado con fondos europeos, desarrollará una plataforma nanométrica «inteligente» de oro para transportar de forma segura y eficiente la maquinaria CRISPR/Cas a través de la impenetrable barrera hematoencefálica, hasta las regiones profundas del encéfalo y las neuronas enfermas, con el fin de realizar una modificación del genoma eficaz. La innovadora nanoplataforma de BrainCRISPR puede tener un impacto revolucionario en el tratamiento de encefalopatías genéticas asoladoras para dar esperanza a enfermos y familias con pocas opciones.

Objetivo

Genetic brain diseases are among the most devastating and fatal diseases, typically having only palliative treatments and no cure. The revolutionary CRISPR/Cas gene editing technology provides a new horizon and enormous potential for treating such diseases. However, efficient and safe delivery of CRISPR machinery to diseased cells within the brain is one of the greatest challenges in medicine today. Here, I plan to expand far beyond the state-of-the-art, and propose a game-changer approach for this unmet need: A breakthrough nanoplatform, which will transform CRISPR into a clinically-relevant, non-invasive technology, enabling therapeutic genome editing in the brain. Our proof-of-concept results serve as the baseline of this pioneering research project, revealing the exceptional capabilities of insulin as a key to overcoming formidable brain and cell barriers. We will harness these unique abilities within the novel nanoplatform, and shuttle CRISPR machinery across the blood-brain barrier, transport it into deep brain regions, and mediate its successful entry into specific diseased brain cells, leading to highly effective gene editing. The nanoplatform will be designed to meet key criteria for non-invasive, safe and efficient delivery of CRISPR to the brain, while conferring a high degree of modularity and compositional heterogeneity - thus providing both universal and patient-specific components. The nanoplatform will be thoroughly investigated in primary brain cells, 3D organoids, and case-studies of monogenic brain disease models. This comprehensive research will culminate with a universal and modular BrainCRISPR nanoplatform, and delineate design principles for its precise tailoring to specific needs of different brain diseases. Overall, this research will provide in-depth fundamental knowledge and have a transformative effect on applying CRISPR in brain, whilst opening a wide array of possibilities with broader impact on genetic brain therapy and beyond.