Samir El Andaloussi

To date, there are no curative treatments for most neurodegenerative disorders, including synucleinopathies of the central nervous system (CNS) such as Parkinsons disease (PD). The greatest challenges in treating these are currently insufficient penetration of drugs to the parenchyma of the brain and achieving stable reduction of α-synuclein (SNCA) protein aggregation, the most significant hallmark of PD pathology. Therefore, it is imperative to find new solutions to these unmet medical needs. Recently, we have harnessed nature’s own nanoparticles, extracellular vesicles (EVs), for targeted delivery of biotherpeutics, with focus on Cas9-based gene editors. Here, we will establish a novel CNS delivery platform exploiting these engineered EVs for CRISPR/Cas9-mediated silencing of SNCA gene expression and prevention of α-synuclein aggregation. After optimization of EV engineering components focusing on enhanced cargo loading, gene editing, and EV delivery to deep brain parenchyma, we will demonstrate their therapeutic effect in models of PD by local injection into the brain of mice using osmotic pumps. If successful, this will open an entirely new avenue to treat PD and other synucleinopathies. Importantly, the modular nature of the EV engineering platform permits further adaptation to deliver other gene editors or drug modalities, thereby opening innovative possibilities to treat a range of CNS diseases.

Genome-targeted therapies, e.g., CRISPR-Cas9, use genetic sequence to target their actions to specific genes, bringing unrivalled specificity. This specificity will revolutionise healthcare, bringing therapies to previously untreatable rare disorders and precision gene- and cell-specific approaches to common disorders. By simply modifying the target sequence, a therapy can be retargeted to treat a new disorder. Our challenge is to unlock this potential, by developing 'Therapeutic Genomics' (TG), a genome-led, patient-centred, data-driven vision to bring genome-targeted therapies to the clinic, at scale. To achieve this challenge, our research aims to answer five major questions. First, which variants and which patients can be treated? We will develop computational and experimental methods to identify tractable genetic variants with different genome-targeted therapies. Applying these to genome sequencing data collected nationwide by researchers and the NHS, we will identify patients with correctable variants and symptoms appropriate to experimental therapies. Second, how can Therapeutic Platforms be developed and retargeted at scale to treat numerous genetic disorders? In collaboration with the laboratory that discovered CRISPR-Cas9 (UC Berkeley), we will develop exemplar Therapeutic Platforms and then retarget these to develop numerous therapies for other variants and disorders. Working with our industry partners, including Intellia and Danaher, we will develop high-throughput parallelized methods for measuring potency and safety in scalable cellular models, reducing the reliance on animal testing. Subsequent generations of Therapeutic Platforms and retargeting will extend therapies to more disorders. Third, how can Therapeutic Platform therapies be delivered effectively? At present, we lack a suitable vector for targeting neurons throughout the brain, a hurdle complicated by the inaccessibility of mature human neurons. Using cutting-edge technology to maintain human neuronal viability post-mortem, we will use directed evolution to develop brain-wide and cell-type-specific delivery systems, including viral, non-viral, and hybrid approaches. Fourth, how can insights from one therapy be used to improve the next therapy? By collecting data throughout our CoRE's research, we will apply artificial intelligence to refine our therapeutic and delivery technologies, ultimately developing safer and more effective therapies that treat an ever-expanding list of disorders. The data and algorithms from this work will be shared publicly to help design suitable therapies for all patients who need them. Fifth, how can we foster the research culture and clinical ecosystem to bring therapies to the clinic? Our research aims can only be achieved through a positive, inclusive research culture (e.g., openness, collaboration, teamwork, integrity, and diversity), and an interdisciplinary team. The MRC CoRE in TG will build on institutional initiatives to support culture change, embracing opportunities to enhance mentorship, teamwork, and communication. Key principles of Equality, Diversity, and Inclusion (EDI) and inclusive Public Patient Involvement and Engagement (PPIE) will be fully integrated into, and will enrich, the planning and execution of the CoRE's activities and governance. The MRC CoRE in TG will prime the clinical landscape required to bring genome-targeted therapies to the clinic, in collaboration with stakeholders and patients. Our team has the experience and facilities to secure additional funding and conduct first-in-human clinical trials. We will enlist UK infrastructure and industrial collaboration to reduce manufacturing costs and engage with the UK and other regulatory agencies to define workable standards for assessing Therapeutic Platforms. By developing urgently needed therapies for multiple rare disorders today, we will develop the expertise and capacity to better treat all rare and common disorders in the future.