Nucleic Acid Aptamers as Novel Class of Therapeutics to Mitigate Alzheimer’s Disease Pathology

Tannenberg, R. K.; Shamaileh, Hadi Al; Lauridsen, Lasse Holm; Kanwar, Jagat R.; Dodd, Peter R.; Veedu, Rakesh N.

doi:10.2174/1567205011310040009

Cited by 17 publications

(10 citation statements)

References 44 publications

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“…The potential for aptamers to mitigate AD pathology has been extensively reviewed elsewhere [13,72]. Much of the aptamer research with respect to AD has focused on developing aptamers that selectively bind to monomeric or oligomeric forms of Ab peptides for the purpose of understanding and preventing aggregation.…”

Section: Aptamers For Alzheimer's Disease Treatmentmentioning

confidence: 99%

Aptamers as Promising Molecular Recognition Elements for Diagnostics and Therapeutics in the Central Nervous System

McConnell

Holahan

DeRosa

2014

Nucleic Acid Therapeutics

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Oligonucleotide aptamers are short, synthetic, single-stranded DNA or RNA able to recognize and bind to a multitude of targets ranging from small molecules to cells. Aptamers have emerged as valuable tools for fundamental research, clinical diagnosis, and therapy. Due to their small size, strong target affinity, lack of immunogenicity, and ease of chemical modification, aptamers are an attractive alternative to other molecular recognition elements, such as antibodies. Although it is a challenging environment, the central nervous system and related molecular targets present an exciting potential area for aptamer research. Aptamers hold promise for targeted drug delivery, diagnostics, and therapeutics. Here we review recent advances in aptamer research for neurotransmitter and neurotoxin targets, demyelinating disease and spinal cord injury, cerebrovascular disorders, pathologies related to protein aggregation (Alzheimer's, Parkinson's, and prions), brain cancer (glioblastomas and gliomas), and regulation of receptor function. Challenges and limitations posed by the blood brain barrier are described. Future perspectives for the application of aptamers to the central nervous system are also discussed.

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Section: Aptamers For Alzheimer's Disease Treatmentmentioning

confidence: 99%

Aptamers as Promising Molecular Recognition Elements for Diagnostics and Therapeutics in the Central Nervous System

McConnell

Holahan

DeRosa

2014

Nucleic Acid Therapeutics

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“…The development of aptamers for treatment of brain cancers and neurological conditions is not a new concept. There have been numerous reports of aptamers for development of treatments for glioblastoma and brain disease [49][50][51]. However, these aptamers have mainly been suggested for use in diagnostic applications as they lack therapeutic effect.…”

Section: Discussionmentioning

confidence: 99%

Bifunctional Aptamer–Doxorubicin Conjugate Crosses the Blood–Brain Barrier and Selectively Delivers Its Payload to EpCAM-Positive Tumor Cells

Macdonald

Denoyer

Henri

et al. 2020

Nucleic Acid Therapeutics

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The prognosis for breast cancer patients diagnosed with brain metastases is poor, with survival time measured merely in months. This can largely be attributed to the limited treatment options capable of reaching the tumor as a result of the highly restrictive blood-brain barrier (BBB). While methods of overcoming this barrier have been developed and employed with current treatment options, the majority are highly invasive and nonspecific, leading to severe neurotoxic side effects. A novel approach to address these issues is the development of therapeutics targeting receptor-mediated transport mechanisms on the BBB endothelial cell membranes. Using this approach, we intercalated doxorubicin (DOX) into a bifunctional aptamer targeting the transferrin receptor on the BBB and epithelial cell adhesion molecule (EpCAM) on metastatic cancer cells. The ability of the DOXloaded aptamer to transcytose the BBB and selectively deliver the payload to EpCAM-positive tumors was evaluated in an in vitro model and confirmed for the first time in vivo using the MDA-MB-231 breast cancer metastasis model (MDA-MB-231Br). We show that colocalized aptamer and DOX are clearly detectable within the brain lesions 75 min postadministration. Collectively, results from this study demonstrate that through intercalation of a cytotoxic drug into the bifunctional aptamer, a therapeutic delivery vehicle can be developed for specific targeting of EpCAM-positive brain metastases.

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“…In the past 5 years, aptamers targeting proteins, DNA, and RNA have been developed for treating AD [188–191] . In 2020, an RNA aptamer with high affinity for toxic Aβ42 dimers developed [192] (Figure 4b).…”

Section: Drugs Targeting Famentioning

confidence: 99%

Formaldehyde‐Crosslinked Nontoxic Aβ Monomers to Form Toxic Aβ Dimers and Aggregates: Pathogenicity and Therapeutic Perspectives

2021

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Alzheimer's disease (AD) is characterized by the presence of senile plaques in the brain. However, medicines targeting amyloid‐beta (Aβ) have not achieved the expected clinical effects. This review focuses on the formation mechanism of the Aβ dimer (the basic unit of oligomers and fibrils) and its tremendous potential as a drug target. Recently, age‐associated formaldehyde and Aβ‐derived formaldehyde have been found to crosslink the nontoxic Aβ monomer to form the toxic dimers, oligomers and fibrils. Particularly, Aβ‐induced formaldehyde accumulation and formaldehyde‐promoted Aβ aggregation form a vicious cycle. Subsequently, formaldehyde initiates Aβ toxicity in both the early‐and late‐onset AD. These facts also explain why AD drugs targeting only Aβ do not have the desired therapeutic effects. Development of the nanoparticle‐based medicines targeting both formaldehyde and Aβ dimer is a promising strategy for improving the drug efficacy by penetrating blood‐brain barrier and extracellular space into the cortical neurons in AD patients.

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Nucleic Acid Aptamers as Novel Class of Therapeutics to Mitigate Alzheimer’s Disease Pathology

Cited by 17 publications

References 44 publications

Aptamers as Promising Molecular Recognition Elements for Diagnostics and Therapeutics in the Central Nervous System

Aptamers as Promising Molecular Recognition Elements for Diagnostics and Therapeutics in the Central Nervous System

Bifunctional Aptamer–Doxorubicin Conjugate Crosses the Blood–Brain Barrier and Selectively Delivers Its Payload to EpCAM-Positive Tumor Cells

Formaldehyde‐Crosslinked Nontoxic Aβ Monomers to Form Toxic Aβ Dimers and Aggregates: Pathogenicity and Therapeutic Perspectives

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