Abstract
Alzheimer’s disease (AD) is the most common dementia disorder. While genetic mutations account for only 1% of AD cases, sporadic AD resulting from a combination of genetic and risk factors constitutes >90% of the cases. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-associated protein (Cas9) is an impactful gene editing tool which identifies a targeted gene sequence, creating a double-stranded break followed by gene inactivation or correction. Although CRISPR/Cas9 can be utilized to irreversibly inactivate or correct faulty genes in AD, a safe and effective delivery system stands as a challenge against the translation of CRISPR therapeutics from bench to bedside. While viral vectors are efficient in CRISPR/Cas9 delivery, they might introduce fatal side effects and immune responses. As non-viral vectors offer a better safety profile, cost-effectiveness and versatility, they can be promising for the in vivo delivery of CRISPR/Cas9 therapeutics. In this minireview, we present an overview of viral and non-viral vector based CRISPR/Cas9 therapeutic strategies that are being evaluated on pre-clinical AD models. Other promising non-viral vectors that can be used for genome editing in AD, such as nanoparticles, nanoclews and microvesicles, are also discussed. Finally, we list the formulation and technical aspects that must be considered in order to develop a successful non-viral CRISPR/Cas9 delivery vehicle.
Highlights
Alzheimer’s disease (AD) is the most common type of dementia, affecting millions of people worldwide
While this study provides a proof of concept that silencing Amyloid-precursor protein (APP) selectively decreases BACE1 activity without detectable off-target effects, investigations are needed in order to verify the efficiency and long-term effects of silencing BACE1 in AD models
An altered Aβ metabolism is commonly found in FAD and SAD, regardless of the genetic factors
Summary
Alzheimer’s disease (AD) is the most common type of dementia, affecting millions of people worldwide. AD brains exhibit neuropathological alterations which represent the disease hallmarks: extracellularly accumulated β-amyloid (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) comprising hyperphosphorylated tau protein [2]. The formation of NFTs in AD brains is explained by the tau hypothesis. In AD, it has been proposed that 3R and 4R tau might accumulate in a hyperphosphorylated form, resulting in NFTs or threads if present within neuronal cell bodies or axons, respectively. It has been reported that there could be a molecular link between NFT formation and Aβ deposition The latter has been found to initiate reduced neuroplasticity, neuronal viability and microtubule disassembly, and inhibit the transport of mitochondria along microtubules. It has been hypothesized that tau neurotoxicity could be an event downstream from Aβ accumulation [8] This hypothesis still needs to be experimentally verified. Of AlzheimAeIrC’sDd, Aismeaylsoei.d(pAre),cuArmsoryploroidteicnaIsnctaradceelhluylaproCt-hteersmisin. a(lBD)o, mTaauinh; AyPpPo,tahmeysliosi.dAprIeCcDur,sAormpryolteoiind; precursor protein IntAraβ,cebleltual-aamr yClo-tidermprointeainl;DGoSmK3a,inG;lyAcoPgPe,namSyyntlhoaisde pKriencausers3o; rNpFrTost,enineu; rAofβib,riblleatray-atamngylelos.id protein; GSK3, GlyRcoepgreinnteSdywnitthhamseinKorinmaosdeif3ic;aNtioFnTfsr,omneWureonfiebt raill.l,aJroyurtnaanlgolfeCs.onRteropllreidntReedleawsei,thpumblinshoerdmbyodification from Wen Eeltseavli.e,rJ,o2u01r9n[a9l].of Controlled Release, published by Elsevier, 2019 [9]
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