Saudi Cultural Missions Theses & Dissertations
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Item Restricted Benchmarking Gene Therapies for Sickle Cell Disease in Saudi Arabia Using Mendelow’ s Stakeholders Matrix(University College London, 2024-08-28) Alajmi, Reem; Nieroda, MarzenaAim and Methods: This paper explores the potential of GTs for SCD in KSA, addressing their applicability, accessibility, and comparison with traditional treatments. It aims to benchmark GTs in KSA by analysing advancements in R&D, developing equitable distribution strategies, and comparing real-world data. A scoping review was conducted using major academic databases, with 29 relevant articles selected to assess the effectiveness and implementation of SCD GTs in KSA and globally. Findings: Traditional treatments for SCD have long relied on blood transfusions and pharmacologic options like HU, approved by the FDA in 1998. While these treatments have been essential, their limitations have led to the development of new therapies, including GTs. GT offers a curative approach by targeting the genetic root of SCD. Recently, FDA-approved gene therapies, such as Casgevy and Lyfgenia, have marked a significant advancement. These therapies use innovative genome editing techniques to replace defective cells. Although promising, the adoption of GT is tempered by concerns about cost, accessibility, and long-term efficacy compared to traditional treatments, which remain widely used due to their established effectiveness and broader availability. Practical Implications: GT has the potential to revolutionize SCD management, but challenges like accessibility, affordability, and infrastructure readiness, particularly in Saudi Arabia, require comprehensive policy reforms and supportive systems for successful implementation.46 0Item Restricted Chimeric antigen receptors cells targeting T cell malignancies(University College London, 2024-05-02) Aldahshan, Hala; Qasim, Waseem; Georgiadis, Christos; Preece, RolandT cell leukaemias are characterised by the abnormal growth and dysfunction of T cells at various stages of development. Novel treatments for T cell malignancies, including adoptive cell transfer and chimeric antigen receptor (CAR) therapies, are being investigated. CAR-T cell therapy introduces a CAR transgene into T cells using viral or non-viral methods and redirects them against malignant cells. CAR-T cells have shown promise against B cell malignancies but face challenges in treating T cell malignancies due to fratricide during production and the risk of T cell aplasia post-administration. Genome editing allows for mitigating these challenges. Trials are underway testing base edited CAR7-T cells, targeting T cell receptor beta (β) chain (TRBC), CD7 and CD52, for elimination of graft-versus-host disease (GVHD), fratricide resistance and protection from serotherapy. This project investigated alternative base editor (BE) platforms incorporating rat or human cytidine deaminases that allow targeted C•G>T•A conversions in the genome independent of DNA breaks. These were tested for the multiplexed disruption of the TCRαβ and CD7 loci in combination with lentiviral transduction strategies for expression of CAR7. All editors achieved on-target conversion with undetectable chromosomal translocations and no ectopic RNA aberrations. Optimal delivery timing for each BE mRNA was next investigated with respect to lentiviral CAR7 transduction to ensure orderly removal of shared antigens. Finally, site-specific ‘knock-in’ of a CAR transgene using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) was investigated as it may favour more physiological levels of CAR expression and disruption of endogenous TCRαβ. A virus-free manufacturing timeline for anti-CD7 CAR-T cells was established using Streptococcus pyogenes (Sp) Cas9 ribonucleoproteins (RNPs) with single guide RNA (sgRNA) guides in combination with double-stranded (ds) DNA CAR templates flanked by regions of homology to T cell receptor alpha (α) chain (TRAC), CD3ζ or CD7. Phenotypic profiling revealed CAR7+ expression and molecular analysis confirmed site-specific integration of CAR7 into CD3ζ, CD7, but not TRAC. CD3ζ-CAR7 effector cells exhibited potent cytotoxicity against CD7+ targets, comparable to lentivector expressed CAR7, warranting further investigation.12 0