Periodic Reporting for period 1 - BEndTarG (Brain Endothelium - TARgeted Gene therapy to improve Aβ clearance in Alzheimer’s Disease)
Reporting period: 2022-09-01 to 2024-08-31
Alzheimer's disease (AD) is a progressive neurodegenerative disorder with no cure and limited treatment options. It is the most common cause of dementia, and its prevalence is expected to double in Europe by 2050 due to the ageing population. Despite significant research efforts, current therapies are limited in their ability to halt disease progression. To tackle this pressing problem, researchers have focused on grasping the pathogenesis of Alzheimer's disease (AD) and creating novel therapies aimed at enhancing the brain's protective systems, such as the blood-brain barrier, while also diminishing the buildup of amyloid-beta (Aβ) proteins. To tackle this pressing problem, the present project has been focused on developing an innovative gene therapy approach aimed at targeting and modulating the blood-brain barrier (BBB) to enhance the overall clearance of Aβ. The proposed Aβ lowering intervention relies on re-establishing proper expression levels of a novel key intervenient in the process of Aβ clearance across the brain endothelium. By delivering such therapeutic genes specifically to the brain endothelium, one aims to: i) restore target gene expression at BBB and enhance brain endothelial cells clearance function; ii) modulate Aβ accumulation within the brain, a key contributor to AD pathology; and iii) promote neuroprotection from Aβ-associated damage and death, thereby slowing cognitive decline.
This project consisted of three main research activities: i) establish a gene therapy approach capable of up-regulate the target gene in the brain endothelium; ii) develop a super-selective brain-endothelium nanocarrier to allow the specific targeting of brain endothelial cells and increase the potency of the nanocarrier to deliver the therapeutic gene into these cells; iii) use of state-of-the-art BBB in vitro models to perform a fast screening of nanocarriers for the brain endothelium binding and uptake. The project has generated a CRISPR-based gene therapy approach with a confirmed ability to up-regulate the target gene in a BBB in vitro model. This up-regulation was associated with increased co-localisation of Aβ aggregation forms with the upregulated receptor, suggesting improved clearance across the BBB. Moreover, in this project, different BBB-targeting nanocarriers were developed and characterised in vitro based on their potential to target and cross the BBB. These outcomes allowed the selection of the most promising brain endothelium super-selective formulations that can now be tested in an in vivo AD scenario. Final experiments and data analyses are currently being performed so that the results are predicted to be published as peer-reviewed scientific articles by the end of 2024/beginning of 2025.
The BEndTarG project has significantly contributed to the scientific advancement of AD research while also rendering gene therapy approaches more accessible to diverse audiences, including those with non-scientific backgrounds (via outreach activities). Finding a treatment for AD requires a comprehensive understanding of the early cellular and molecular mechanisms underpinning the structural and functional alterations associated with the disease. This project establishes the foundational knowledge about the target gene's role in Aß clearance and introduces a biocompatible super-selective nanocarrier designed for efficient gene delivery, which will be vital for future translational therapeutic advancements. This project’s tangible socioeconomic effects will take time to materialise. However, once we know more about the potential impact of this therapeutic strategy in vivo, a prospective clinical therapy may be formulated to prevent AD progression and enhance healthy life expectancy and quality of life. For peers in my field and those in related areas, the benefits are clear, as this project introduces novel and potential therapeutic avenues for AD research.