Despite decades of clinical efforts in the quest for a cure, Alzheimer’s disease (AD) and other dementias continue to be the most common neurodegenerative diseases in the elderly, affecting approximately 50 million living people worldwide (WHO, 2020). Hundreds of clinical trials have failed and no drug treatments are currently available to stop the disease progression. As the world’s population ages, there is a greater demand for alternate therapeutic strategies.
Recently, thanks to the discovery of CRISPR, scientists are now believing that gene editing technology can help enlighten possible therapeutic targets of the disease and may cast a new hope for AD treatment.
What Causes Alzheimer’s? An Urgent but Long-standing Question
Alzheimer’s disease was first reported by a German doctor named Alois Alzheimer in 1906. He described a 50-year-old woman patient who suffered from memory loss, disorientation, hallucinations, and other worsening psychological changes.
Ever since the first report of AD, scientists have strived to find the cause that makes a brain waste away. After performing autopsy of the first documented AD patient in 1906, Alzheimer found two abnormal structures within the brain cells, the plaque and the twisted fiber bands (later known as neurofibrillary tangles). Advances in brain imaging technologies have allowed modern researchers to determine that memory loss is exactly caused by plagues and tangles. This leads to two main hypotheses of AD pathogenesis: the amyloid hypothesis and the tau hypothesis (Front. Neurosci., 2018).
(Image source: The Lancet)
In 1984, researchers discovered that “a novel cerebrovascular amyloid protein”, named amyloid-beta, is the major component of AD brain plagues and may initiate nerve cell degeneration. According to the amyloid hypothesis, the production of amyloid-beta in the brain triggers a series of events causing the clinical syndrome of dementia. Two years later, tau protein was also found as the chief component of tangles and another prime suspect in nerve cell damage. The tau hypothesis states that the hyperphosphorylation of tau is the main cause of neurodegeneration in AD. When tau is hyperphosphorylated, it dissociates from microtubules and aggregates into neurofibrillary tangles contributing to neural damage.
Moreover, genes encoding four main proteins have been identified so far in association with Alzheimer’s, amyloid precursor protein (APP), presenilin 1 (PSEN1), presenilin 2 (PSEN2), and apolipoprotein E (APOE). The first three gene mutations are considered to be primary risk factors in early-onset (familial) AD, whereas the fourth one has been linked to the late-onset of the disease.
How to Find a Cure? Gene Editing for Alzheimer’s Disease
Although research has been ongoing for decades, a cure for AD has not found yet. Most of the current treatments can only address symptoms, which is not enough to reverse functional deficits in the brain. Recent years, gene editing has shown great potential for the treatment of familial AD and other diseases caused by genetic mutations (Nature Neuroscience, 2019). However, there are still some obstacles to the clinical development and application of gene editing technology, such as the lack of effective and non-invasive methods to transport gene editing tools to the brain.
An international research team led by scientists from the Hong Kong University of Science and Technology recently stated their way to overcome this problem. Their paper is titled, “Brain-wide Cas9-mediated cleavage of a gene causing familial Alzheimer’s disease alleviates amyloid-related pathologies in mice.” (Nature Biomedical Engineering, 2021)
For their reported study, the team used a modified adeno-associated virus (AAV) vector to intravenously introduce CRISPR-Cas9 construct targeting APP mutation into the hippocampus of transgenic mouse model. As mentioned above, APP is one of the risk factor in familial AD. Dysregulated processing of APP leads to the accumulation of amyloid-beta, consequently activating nerve cell degeneration in hippocampus.
Their data indicated that the amyloid plaques in mouse brains causing neurodegenerative disease remained low level for at least 6 months after the treatment, proving that a single injection of AAV-Cas9 vector could maintain long-term curative effect. Moreover, the neuroprotective effects come with no obvious side effects for the mice. Further experiments confirmed that systemic AAV delivery targeting a disease-causing mutation at the adult stage resulted in efficient brain-wide genome editing, consequently alleviating disease phenotypes throughout the brain.
As concluded by the authors, “the AAV-mediated, single-dose, non-invasive CRISPR–Cas9 system represents a promising approach to address the lack of therapeutic options for familial AD, as well as for other forms of brain disease that are caused by dominant mutations that affect multiple brain regions”.
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