APOE: The New Frontier in the Development of a Therapeutic Target towards Precision Medicine in Late-Onset Alzheimer’s

Yang, Anna; Kantor, Boris; Chiba‐Falek, Ornit

doi:10.3390/ijms22031244

Cited by 32 publications

(24 citation statements)

References 98 publications

(134 reference statements)

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“…As pointed out above, one of the most notable things about CRISPR/Cas-based gene therapy is how rapidly it has evolved. But as exciting as this development, experts in fields ranging from science, medicine to bioethics, including our group, have cautioned that the progress in the clinical applications related to the technology, should not overtake the associated shortcomings related to research and ethical complications that arise ( Yang et al, 2021 ; Angrist et al, 2020 ; MacDougall et al, 2021 ). In fact, the ethical issues related to the CRISPR/Cas technology have made headlines most recently.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic modulation of gene expression in the disease state: Treatment strategies and approaches for the development of next-generation of the epigenetic drugs

Rittiner

Cumaran

Malhotra

et al. 2022

Front. Bioeng. Biotechnol.

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Epigenetic dysregulation is an important determinant of many pathological conditions and diseases. Designer molecules that can specifically target endogenous DNA sequences provide a means to therapeutically modulate gene function. The prokaryote-derived CRISPR/Cas editing systems have transformed our ability to manipulate the expression program of genes through specific DNA and RNA targeting in living cells and tissues. The simplicity, utility, and robustness of this technology have revolutionized epigenome editing for research and translational medicine. Initial success has inspired efforts to discover new systems for targeting and manipulating nucleic acids on the epigenetic level. The evolution of nuclease-inactive and RNA-targeting Cas proteins fused to a plethora of effector proteins to regulate gene expression, epigenetic modifications and chromatin interactions opened up an unprecedented level of possibilities for the development of “next-generation” gene therapy therapeutics. The rational design and construction of different types of designer molecules paired with viral-mediated gene-to-cell transfers, specifically using lentiviral vectors (LVs) and adeno-associated vectors (AAVs) are reviewed in this paper. Furthermore, we explore and discuss the potential of these molecules as therapeutic modulators of endogenous gene function, focusing on modulation by stable gene modification and by regulation of gene transcription. Notwithstanding the speedy progress of CRISPR/Cas-based gene therapy products, multiple challenges outlined by undesirable off-target effects, oncogenicity and other virus-induced toxicities could derail the successful translation of these new modalities. Here, we review how CRISPR/Cas—based gene therapy is translated from research-grade technological system to therapeutic modality, paying particular attention to the therapeutic flow from engineering sophisticated genome and epigenome-editing transgenes to delivery vehicles throughout efficient and safe manufacturing and administration of the gene therapy regimens. In addition, the potential solutions to some of the obstacles facing successful CRISPR/Cas utility in the clinical research are discussed in this review. We believe, that circumventing these challenges will be essential for advancing CRISPR/Cas-based tools towards clinical use in gene and cell therapies.

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Section: Discussionmentioning

confidence: 99%

Therapeutic modulation of gene expression in the disease state: Treatment strategies and approaches for the development of next-generation of the epigenetic drugs

Rittiner

Cumaran

Malhotra

et al. 2022

Front. Bioeng. Biotechnol.

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“…A few cases have Mendelian inheritance trends, which often result in the early onset of symptoms through altered metabolism of Aβ, 7 but for most patients, the genetic predisposition is more complex. 8 The most common genetic risk factor is variants of the APOE gene, 9 which is believed to mainly increase the risk for AD through modulating the accumulation of Aβ. 10 In addition, genome-wide association studies (GWASs) have identified additional single-nucleotide polymorphisms (SNPs) with risk effects for AD dementia.…”

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confidence: 99%

β-Amyloid–Dependent and –Independent Genetic Pathways Regulating CSF Tau Biomarkers in Alzheimer Disease

et al. 2022

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Background:Abnormal metabolism of amyloid-β (Aβ) and soluble P-tau, as well as neurodegeneration, are key components of Alzheimer’s disease (AD), but it is unclear how these different processes are related to genetic risk factors for AD.METHOD:In the Swedish BioFINDER study, we tested associations between a priori defined polygenic risk scores (PRSs) for AD (excluding Single Nucleotide Polymorphism [SNPs] within the apolipoprotein E [APOE] region in the main analysis) and biomarkers in cerebrospinal fluid (CSF) (Total tau [T-tau] and Phosphorylated tau181 [P-tau181], Aβ1-38, Aβ1-40, Aβ1-42 and Aβ1-42/1-40, neurofilament light [NfL]) in Cognitively Unimpaired (CU) individuals (n=751), and in Mild Cognitive Impairment (MCI) (n=212), and AD dementia (n=150) patients. Results were validated in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset with 777 individuals (AD=119, MCI=442, and CU=216).Result:A PRS with SNPs significant at P<5e-03 (∼1742 variants) were associated with higher CSF P-tau181 (beta=0.13, P=5.6e-05) and T-tau (beta=0.12, P=4.3e-04). The associations between PRS and tau measures were partly attenuated but remained significant after adjusting for Aβ status. Aβ pathology mediated 37% of the effect of this PRS on tau levels. Aβ-dependent and independent subsets of the PRS were identified and characterized. There were also associations between PRSs and CSF Aβ biomarkers with nominal significance, but not when corrected for multiple comparisons. There were no associations between PRSs and CSF NfL.Conclusion:Genetic pathways implicated in causing AD are related to altered levels of soluble tau through both Aβ-dependent and Aβ-independent mechanisms, which may have relevance for anti-tau drug development.

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“…Mechanistic insights gained from these studies may be harnessed to optimize treatment strategies for subjects with a high risk of cardiometabolic and neurological diseases due to APOE gene polymorphism. Several approaches, such as the use of apoE mimetic peptides [ 180 ], apoE4 structural correctors [ 179 ], modulators of apoE trafficking pathways [ 181 ], apoE antisense oligonucleotides [ 182 ] and APOE gene therapy [ 183 ] have been proposed and tested in preclinical models with various efficacies. The challenge of these approaches is the specific targeting to appropriate tissues and cell types, where their effectiveness can be optimized without any adverse effects.…”

Section: Conclusion and Perspectivementioning

confidence: 99%

Apolipoprotein E in Cardiometabolic and Neurological Health and Diseases

Alagarsamy

Jaeschke

Hui

2022

IJMS

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A preponderance of evidence obtained from genetically modified mice and human population studies reveals the association of apolipoprotein E (apoE) deficiency and polymorphisms with pathogenesis of numerous chronic diseases, including atherosclerosis, obesity/diabetes, and Alzheimer’s disease. The human APOE gene is polymorphic with three major alleles, ε2, ε3 and ε4, encoding apoE2, apoE3, and apoE4, respectively. The APOE gene is expressed in many cell types, including hepatocytes, adipocytes, immune cells of the myeloid lineage, vascular smooth muscle cells, and in the brain. ApoE is present in subclasses of plasma lipoproteins, and it mediates the clearance of atherogenic lipoproteins from plasma circulation via its interaction with LDL receptor family proteins and heparan sulfate proteoglycans. Extracellular apoE also interacts with cell surface receptors and confers signaling events for cell regulation, while apoE expressed endogenously in various cell types regulates cell functions via autocrine and paracrine mechanisms. This review article focuses on lipoprotein transport-dependent and -independent mechanisms by which apoE deficiency or polymorphisms contribute to cardiovascular disease, metabolic disease, and neurological disorders.

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APOE: The New Frontier in the Development of a Therapeutic Target towards Precision Medicine in Late-Onset Alzheimer’s

Cited by 32 publications

References 98 publications

Therapeutic modulation of gene expression in the disease state: Treatment strategies and approaches for the development of next-generation of the epigenetic drugs

Therapeutic modulation of gene expression in the disease state: Treatment strategies and approaches for the development of next-generation of the epigenetic drugs

β-Amyloid–Dependent and –Independent Genetic Pathways Regulating CSF Tau Biomarkers in Alzheimer Disease

Apolipoprotein E in Cardiometabolic and Neurological Health and Diseases

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