Apolipoprotein E targeted stem cell gene therapy for people with Alzheimer’s Disease

Abstract

Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder that involves the formation of amyloid-plaques and tau tangles. An increase in the aged population has resulted in AD being a major global health challenge however there are no long-term treatment strategies to combat the disease. More than 60% of AD cases have been associated with heritable genes with the Apolipoprotein E (APOE) having the strongest association to AD pathology. Polymorphism in the APOE gene gives rise to three allelic isoforms of which APOE ε4 has been recognised as the most significant genetic risk factor for developing late-onset AD. Carriers of APOE ε4 are more likely to develop AD whereas APOE ε2 and APOE ε3 offer protection against the disease. The use of gene therapy approaches can be used to the lessen the impact of APOE variation in contributing to AD.

Hematopoietic stem cells (HSCs) are multipotent precursor cells that can self-renew and differentiate into the cellular components of the hematopoietic system. HSC gene therapy (HSC-GT) approaches have been shown to prevent disease progression in patients with genetic diseases affecting the CNS and immune system. Blood-derived monocytes can migrate into different tissues and differentiate into blood-monocyte derived macrophages (BMDM) which carry out organ-specific homeostatic functions. In AD, these BMDM migrate into the brain and assist brain-derived microglia with the clearance of Aβ and tau.
This aim of this thesis was to investigate factors that affected ex vivo manipulation of isolated HSCs from human bone marrow samples once transduced with a lentivirus (LV) carrying a protective isoform of APOE. The HSCs carrying the LV were then differentiated into macrophages and the expression of LV was investigated.

The results show that HSCs maintain high levels of transduction with LVs however transgene expression is decreased when HSCs undergo lineage specific commitment into macrophages. This thesis also highlights that there are several factors that affect the transduction efficiency of HSCs and subsequent transgene stability, and that these factors must be optimised for efficient gene delivery into HSCs for clinical efficacy.

Date of Award	10 Dec 2024
Original language	English
Awarding Institution	University of Bristol
Supervisor	Kevin C Kemp (Supervisor), Patrick Gavin Kehoe (Supervisor) & James B Uney (Supervisor)