Author: Elena Mishina
Abstract
The Problem:
According to the United Nations report on Neurological disorders, by 2030, about 18,394 people over the age of 59 worldwide will be diagnosed with Alzheimer's every day. In 2018 alone, Alzheimer's accounted for over 122,000 deaths, making it the sixth leading cause of death in America and the fifth leading cause of death among Americans over 65. With this study, it is hoped to find a way to slow down or even stop the primary spread of Alzheimer's disease.
Intro to the Study:
Researchers observed high levels of a protein known as beta-amyloid (Aβ), or amyloid-beta peptides, which accumulates in the brain in the form of oligomers and amyloid plaques that damage neuronal synapses. This is what leads to the enormous amount of neuronal damage that causes the symptoms of Alzheimer's disease. In addition, this very peptide negatively affects the work of the microglia, which normally work as our brain's caretakers, cleansing it of debris and protecting it from pathogens. However, due to high concentrations of the amyloid-beta peptides, microglia become too active, damaging and killing healthy neurons, thus provoking the emergence and progression of Alzheimer's. By applying genetic engineering technology, namely base editing, we will be able to replace mutations in genes, thus stopping or at least slowing down the progression of the disease.
The entire process of cellular malfunctioning occurs through dysfunctional receptors on the surface of microglia known as TREM2. Using techniques such as whole-genome sequencing and genomic association, researchers have identified several rare TREM2 variants that have been linked to an increased risk of developing Alzheimer's. Thus, using CRISPR we can theoretically edit the genetic code of these cells to slow the progression of Alzheimer's Disease. The introduction of CRISPR-CAS9 technology will deactivate these enzymes, thereby stopping their uncontrolled growth. After binding to the target DNA site, base conjugation between the guide RNA (defining the editing site) and the DNA causes a small displaced segment of single-stranded DNA to loop, where the DNA bases are modified by the enzyme deaminase.
Using this approach, we can perform precise editing of individual letters at a time, allowing us to precisely correct single-nucleotide polymorphisms, including those responsible for dysfunctional TREM2 variants.
After working on the editing,adeno-associated virus (AAV) technology can be used to deliver the desired gene back into the body without disrupting cell life. The viral DNA is replaced with new DNA and it becomes a precisely coded vector and is no longer considered a virus, since most of the viral components have been replaced. The AAV vector is then used to deliver normal copies of genes to the right tissues or organs of the body, but it now delivers the therapy that has been built into it. In the case of Alzheimer's disease research, there are plans to use a variant of AAVs called AAV6, which has been developed specifically to affect microglial cells.
The Expected Results:
Provided the modified TREM2 gene is working right in the microglia and amyloid-beta peptides will no longer accumulate in the microglia, thereby not causing inflammation within the brain or triggering mutations within the microglia. In addition, the microglias will perform their functions normally, ridding neurons of debris and protecting them from harmful cancer cells. All this will facilitate brain function several times over and most likely slow down or even prevent the development of early-stage Alzheimer's.