New CRISPR-based strategies for Alzheimer disease

Kiani, Lisa

doi:10.1038/s41582-023-00856-5

Cited by 2 publications

(2 citation statements)

References 2 publications

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“…Researchers saw that the amount of fat in the blood of the animals went down. [13][14][15] GFP Tagged Cas9 Lentivirus Cells Infection CRISPR-Cas9 parts tagged Green Fluorescence Protein (GFP) infected the cells by lentivirus reporter in both pre-integration viral genomes and integrated proviruses. With CRISPR, which gets rid of only latently infected T-cell lines and the cells that house HIV (monocytes and macrophages), long-term defense against HIV-1 has also been achieved.…”

Section: Use Of Virtual Reality To Mimic Heart Diseasementioning

confidence: 99%

CRISPR-Cas Associated Cells and Animal Mediated Biomedical Modelling

Nazir,

A. Mirza,

Rao

2024

Preprint

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Gene editing is now easy to make new disease models through in-vivo and in vitro tests. It can potentially be used to make animals with single-gene or multiple-gene changes. The mutant strains with changed germlines are no longer needed with in vivo gene editing, which uses the CRISPR-Cas9 system to target cells of interest in their normal tissues. Whereas, the AAVs and other viral vectors have made it possible to change cells selectively. Gene editing hade made it possible to use human induced pluripotent stem cells (iPSC) to model diseases that run in families. Researchers can compare and contrast the human genomes of many different ethnic and racial groups using this method. Scientists may be able to make a disease in a lab dish using iPSCs from a patient. Using CRISPR, iPSCs made from patient cells can be fixed if they have certain problems. This shows that gene therapy is possible and shows what happens when cells aren't working right. The fact that CRISPR-Cas9 can change the DNA by just one nucleotide has had a huge effect on biological studies. CRISPR is becoming more and more popular, which shows how useful, easy, and effective it is. With the broad use of CRISPR-based apps, the tool is now used for much more than just changing genes. This method can be used to screen the whole genome, control the translation of genes based on their sequence, and edit several genes at the same time. Scientists can now model diseases in different species and learn more about how genes work because of these advances. Genome-wide association studies and genome-editing tools like CRISPR are giving us a good look at the future of personalized medicine.

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Section: Use Of Virtual Reality To Mimic Heart Diseasementioning

confidence: 99%

CRISPR-Cas Associated Cells and Animal Mediated Biomedical Modelling

Nazir,

A. Mirza,

Rao

2024

Preprint

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“…CRISPR base editing technology, including CBE 32,44,45 and other CRISPR modalities 32,44 are being used to edit genes involved in a wide range of human diseases, including AD. 32,35,44,46–51 The first CRISPR based therapy, CASGEVY TM , was recently approved by the U.S. Food and Drug Administration (FDA) for sickle cell disease, 52 and clinical trials of gene editing for many diseases are underway, 53,54,56 , with promising phase 1 results for the liver disease transthyretin amyloidosis. 55…”

Section: Introductionmentioning

confidence: 99%

Successful Gene Editing of Apolipoprotein E4 to E3 in Brain of Alzheimer Model Mice After a Single IV Dose of Synthetic Exosome-Delivered CRISPR

Teter,

Campagna,

Zhu

et al. 2024

Preprint

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Background. The gene for apolipoprotein E4 (ApoE4 E4) confers an increased risk for development and lowers the age of onset of Alzheimers disease (AD). It is a highly suitable target for CRISPR-based editing because ApoE4 differs from ApoE3 by a single nucleotide polymorphism in the codon for residue 112 that codes for arginine (CGC) in E4 and cysteine (TGC) in E3. Editing of E4 to E3 could lower the risk of AD or ameliorate E4-related AD phenotypes. For AD, in order to deliver CRISPR components across the blood-brain barrier to the brain, we have developed a delivery platform termed Synthetic Exosomes (SEs) microfluidically-synthesized deformable nanovesicles approximately the size of natural exosomes that have the ability to cross the BBB and deliver cargo to the brain. Here, we describe our use of SEs carrying CRISPR to successfully edit E4 to E3 in brain tissue of an E4-expressing mouse model. Methods. Several CRISPR guide RNAs (gRNA) and Cytosine Base Editor (CBE) mRNAs were synthesized by chemical and in vitro transcription syntheses, respectively. Four combinations of gRNA and CBE mRNA were tested in vitro for their relative activity to edit the E4 (cytosine) to E3 (thymine) in E4-expressing neuroblastoma (E4-N2A) and human Kelly-neuroblastoma cells, to assess which combination produced the highest E4 to E3 base editing efficiency. The CRISPR RNA combination with the highest efficiency was encapsulated in SEs and injected intravenously (IV) via the tail vein into an AD model E4-expressing (E4-5XFAD) transgenic mouse; as a negative control, an E4-5XFAD mouse was injected with empty SEs. Five days after injection, mice were euthanized and brain, liver, and buffy coat (white blood cells (WBC)) collected to determine the editing of E4 to E3 measured by Next Generation Sequencing. In addition, E3 mRNA was measured in the brain and liver and compared to the %E3 gene editing. Results. The highest gRNA+CBE mRNA editing efficiency was ~50% in E4-N2A cells and the same gRNA+CBE combination delivered in SEs to Kelly neuroblastoma cells showed 6.5% editing efficiency. In the E4-5XFAD mouse in vivo, five days after IV delivery of a single dose of the highest-activity SE-CRISPR gRNA+CBE mRNA, the percent of E4 edited to E3 was 0.14% in brain, 0.8% in liver, and 0.36 % in WBCs. As evidence of functional editing, SE-CRISPR-treated mice had 0.03% E3 mRNA in brain and 0.09% E3 mRNA in liver. Conclusions. While this level of ApoE4 to E3 editing achieved five days after a single IV injection of SE-CRISPR is small, it provides initial in vivo proof-of-concept that the ApoE4 gene can be successfully edited and editing results in functional expression of ApoE3 mRNA. The findings presented herein supports further optimization of the SE-CRISPR approach to increase the level of editing in brain as part of clinical development of SE-CRISPR as a powerful novel therapeutic approach for AD.

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New CRISPR-based strategies for Alzheimer disease

Cited by 2 publications

References 2 publications

CRISPR-Cas Associated Cells and Animal Mediated Biomedical Modelling

CRISPR-Cas Associated Cells and Animal Mediated Biomedical Modelling

Successful Gene Editing of Apolipoprotein E4 to E3 in Brain of Alzheimer Model Mice After a Single IV Dose of Synthetic Exosome-Delivered CRISPR

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