Table 1.
Potential genes targeted in AD-associated gene therapy
| Target | Role in AD | Type of subjects | Type of gene delivery | Gene therapy outcome | Limitations | References |
|---|---|---|---|---|---|---|
| Transgenic mice | Lentiviral vector delivery of BACE1 siRNA | Reduced Aβ accumulation | Since the active site of BACE1 is hydrophilic and accessible compared to other proteases, its action must be eliminated. However, the focus of this research was on lowering BACE1 activity. | Singer et al., 2005 | ||
| BACE1 | Aβ generation | AppNL-G-F mice | AAV-based vector delivery of Single domain antibodies (VHHs) | Outcomes favorably influence amyloid burden, neuroinflammation, synapse and cognitive function. | – | Rincon et al., 2019 |
| Neurotrophic effect and Aβ initiation | Adult rats | AAV vector system | Mice were shielded against cognitive impairment caused by aging. | – | Klein et al., 2000 | |
| NGF | Eight individuals with mild Alzheimer’s disease | Ex vivo gene delivery | Caused the activation of degenerating neurons and cell hypertrophy | It is difficult to deliver NGF to the brain safely. | Malkki et al., 2015 | |
| Neurotrophic effect | Amyloid-transgenic mice | Entorhinal cortex BDNF delivery | Recovers cognition, partly restores abnormal gene expression, enhances cell signaling, and repairs synaptic loss. | – | Nagahara et al., 2009 | |
| BDNF | APP transgenic mouse line J20 | Lentiviral-mediated BDNF gene delivery | Increased synaptic protein levels, boosted learning and memory, and reduced neurodegeneration. | The alterations in BDNF levels and its mRNA were inconsistent. | Narisawa-Saito et al., 1996 | |
| hAPP mice | Lentiviral-based cathepsin B delivery | Roles in neuroprotection and anti-amyloidogenicity | – | Mueller-Steiner et al., 2006 | ||
| Cathepsin B | Aβ degradation | Human wild-type APP (hAPPwt) mice | Gene knockout | Decreased Aβ40, Aβ42, and CTFβ by a large amount, which is expressed in most AD patients. | This study does not agree with the previous study, which demonstrated that eliminating the cathepsin B gene in hAPP mice did not affect brain Aβ or CTFβ. | Hook et al., 2009 |
| A novel mouse model with overexpression of a mutant form of APP in the hippocampus, using a lentiviral vector (LV-APPSw) | HSV (siRNA) delivery | Down-regulation of APP | The findings did not address whether the model would replicate more extensive pathological alterations similar to those seen in AD if LV-APPSw or the microtubule-associated protein Tau were expressed over a longer period. | Hong et al., 2006 | ||
| APP | Aβ generation | PDAPP transgenic mice | Gene delivery of lentiviral vectors expressing APOE isoforms | Reduced hippocampal Aβ level | In this investigation, neither lenti-apoE3 nor lenti-apoE4 significantly reduced the brain Aβ load. | Dodart et al., 2005 |
| APOE2 | Aβ burden | Chlorocebus aethiops sabaeus nonhuman primates. | AAVrh.10-mediated APOE2 gene delivery | Stimulates localized APOE2 expression | – | Rosenberg et al., 2018 |
| Cultured cells | Herpes simplex virus vector-mediated neprilysin expression. | Reduced Aβ burden by degrading Aβ40 | The study did not address the long-term consequences of overexpression of neprilysin in vivo in transgenic mouse models of AD. | Hong et al., 2006 | ||
| Neuroprotection and improved memory function | A mutant form of human presenilin-1 (DeltaE9) mice, a mutant form of the chimeric mouse/human amyloid precursor protein (APP695) and wild-type (C57BL/6) mice | Lentiviral vector delivery of neprilysin | Decreased the level of total Aβ peptide and abatement of Aβ plaque formation | There has not been any discussion of the impact of increased expression of NEP lentiviral in the brain before Aβ plaque formation. | El-Amouri et al., 2008 | |
| Neprilysin | hAPP transgenic mice | entiviral vector expressing human neprilysin (Lenti-Nep) | Modulates Aβ deposition by splitting fibrils | The oligomer content might rise due to the probable fibril splitting, which would be detrimental. The study did not address this problem. | Marr et al., 2003 |
AAV: Adeno-associated virus; AD: Alzheimer’s disease; APOE: apolipoprotein E; APP: amyloid precursor protein; Aβ: amyloid-β; BACE1: beta-site amyloid precursor protein cleaving enzyme 1; BDNF: brain-derived neurotrophic factor; CTF: carboxyl-terminal fragment; hAPP: human amyloid precursor protein; HSV: herpes simplex virus; NEP: neprilysin; NGF: nerve growth factor; PDAPP: a transgenic Alzheimer’s disease mouse model.