Development of hybrid nanoparticles for brain delivery of siRNA targeting RAGE aimed at the treatment of neurodegenerative diseases

• Grant number: 24/09788-4
• Support Opportunities: Regular Research Grants
• Start date: November 01, 2024
• End date: October 31, 2026
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Luciane Carla Alberici
• Grantee: Luciane Carla Alberici
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Adriano Silva Sebollela ; Renata Fonseca Vianna Lopez

Abstract

Neurodegenerative diseases are among the greatest strategic challenges associated with increased life expectancy and changes in the demographic profile worldwide. Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most frequent neurodegenerative diseases, affecting 13% of the population over 65 years old. In Brazil, the Ministry of Health projects that by 2050 this percentage will quadruple, significantly increasing the current annual expenditure of R$ 80 billion.Most cases of AD and PD (over 90%) are idiopathic, and since no single specific cause has been identified for these diseases, the vast majority of available treatments focus on symptomatology, lasting a lifetime. Drugs to replenish dopamine and acetylcholine levels are still the main therapeutic agents used, which can be combined with other multidisciplinary approaches. In recent years, biotechnological inputs (monoclonal antibodies) targeting molecular targets - fibrillar aggregates of beta-amyloid peptide (A²) in amyloid plaques in AD and ±-synuclein in Lewy bodies in PD - have been designed, but they have shown high cost and varied efficacy, being largely unavailable to the vast majority of patients. Despite the known formation of fibrillar aggregates in these diseases, there is also the predominance of other factors in the neurodegenerative process, such as mitochondrial dysfunction and a history of pro-inflammatory stimuli.It is known that A² and fibrillar forms of ±-synuclein bind and activate the receptor for advanced glycation end products (RAGE) in AD and PD, respectively. Activated RAGE contributes to the progression of neuronal loss in various animal models, as this receptor keeps different transcription factors active that promote the activation of pro-inflammatory genes, such as NF-kB, EGR-1, AP-1, and STAT, which maintain high RAGE expression. Disrupting this signaling axis, formed by the accumulation of A² in AD or ±-synuclein in PD, which end up activating RAGE and maintaining a chronic pro-inflammatory state in specific CNS locations, could help alleviate the neurodegenerative process in the brain structures affected by these diseases, and this will be the working hypothesis of this proposal. In fact, preliminary data from our group show that in a model of cognitive impairment induced by polymicrobial sepsis, the administration of anti-RAGE antibodies via hippocampal cannula was able to inhibit the increase of A² levels, P-Tau, and neuroinflammation markers, in addition to recovering the cognitive performance of the animals. These data, together with observations showing that RAGE silencing in the CNS via lentiviral vector injection for siRNA reduces neuroinflammation and protects against parkinsonism, indicate that targeted inhibition of RAGE, if performed through a specific delivery mechanism to the CNS, is a promising strategy for inhibiting neuroinflammation and controlling neurodegeneration in the clinical context of AD and PD.To achieve this, we intend to use the intranasal route to deliver small interfering RNA (siRNA) sequences directly to the areas affected by neurodegeneration. For this, we propose to develop an emulsion of hybrid lipid-polymeric nanoparticles (NLP) for encapsulating RAGE siRNA, to ensure its delivery and absorption in the hippocampus and nigrostriatal axis through intranasal administration. This product will be developed and tested in different experimental cellular and preclinical models to test its efficacy in inhibiting RAGE, neurodegeneration, and neuroinflammation parameters, as well as preclinical safety and toxicity parameters. In this context, the central objective of this proposal is the preclinical development and characterization of hybrid nanoparticles for the cerebral delivery of interfering RNA targeting RAGE for the treatment of neurodegenerative diseases. (AU)