Named after Dr. Alois Alzheimer who discovered the disease in 1906, Alzheimer’s disease is the progressive deterioration of the brain that slowly destroys cognitive function. While some treatments exist to alleviate the symptoms of Alzheimer’s disease, there is no cure.
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Considering that researchers have studied the disease for over 100 years, making steps toward finding a cure is urgent. With evidence for the potential risk and protective factors of Alzheimer’s disease, dementia, and cognitive decline, researchers are now looking at gene editing as a solution. The CRISPR-Cas9 system, is an inexpensive, yet powerful, tool used by researchers to alter DNA sequences and gene function that has already shown promise in other neurological disorders. Through gene editing, the CRISPR-Cas9 system would go beyond the temporary lessening of Alzheimer’s disease’s symptoms and potentially prevent or stop the depreciation of the brain by targeting associated genes and correcting genetic defects. When examining the applications of CRISPR-Cas9, however, it is important to factor in both the ethical concerns of using this biotechnology, including the extent to which CRISPR should be permitted and who should have access to this technology, and concerns of not using it. While the system presents many ethical concerns and lingering questions, CRISPR-Cas9 provides a revolutionary and much-needed potential solution to Alzheimer’s disease.
In researching potential treatments for Alzheimer’s disease, it is necessary to examine both types: early onset and late onset.1 Early-onset Alzheimer’s disease, also called familial Alzheimer’s disease (FAD), occurs in people between the ages of 30 and 60 and represents less than 10% of all cases. FAD has a strong genetic component caused by mutations on chromosomes 1, 14, and 21.6 Mutations on chromosome 1 lead to the formation of amyloid precursor protein (APP), and those on 14 and 21 lead to the formation of abnormal presenilin 1 (PSEN1) and abnormal presenilin 2 (PSEN2) respectively. Late onset Alzheimer’s disease occurs in patients over the age of 60 and represents over 90% of all Alzheimer’s cases. In addition to genetic factors, lifestyle and environmental factors such heart and metabolic conditions also contribute to this type of Alzheimer’s disease. The apolipoprotein E (APOE) gene, particularly the APOE e4 allele is associated with increased risk of developing Alzheimer’s. Therefore, in order to cure Alzheimer’s disease, these genes should be targeted specifically, yet there is no guarantee this will be a solution given the impact of environmental factors.
Plaques and tangles are the two neurobiological markers of Alzheimer’s disease as opposed to dementia. Plaques are clumps of amyloid beta protein, which is derived from APP cleaved by beta secretase and gamma secretase, that breakdown brain cells by disrupting cell communication. Brain cells use an internal support and transport system that transports essential nutrients and materials. This system requires the normal structuring and function of a protein, tau. In Alzheimer’s Disorder, tau protein threads tangle abnormally inside brain cells, damage the transport system, and contribute to the death of brain cells. The problem, however, is that the presence of plaques and tangles, to confirm Alzheimer’s disease, can only be observed in an autopsy after death. Despite this, the accumulation of the Amyloid Beta protein can now be seen in PET scans as early as 15-20 years before symptoms are present, leaving a large potential therapeutic window.4 In order to properly treat the neurobiological markers of Alzheimer’s, and take advantage of preventative and disease reversal treatment, the ability to diagnose plaques and tangles is essential.
Symptomatic treatment drugs are divided into two main categories: cholinesterase inhibitors and NMADA receptor antagonists. The first mechanism is used in classical drugs called cholinesterase inhibitors, prescribed for mild to moderate cases, that attempt to slow down the Alzheimer’s disease by inhibiting the enzyme that breaks down acetylcholine. Donepezil, galantamine, and rivastigmine are three cholinesterase inhibitors.8 The drug Memantine is a NMDA (N-methyl-D-asparte) receptor antagonist and is used for moderate to severe cases. Memantine protects brain cells against excess glutamate, a chemical messenger released by damaged Alzheimer’s cells that usually attaches to NMDA receptors and results in a cell-damaging over-exposure of calcium. Despite much research and efforts, there remain no options for the prevention and treatment of Alzheimer’s disease.
There are currently three common gene editing tools available, including Zinc Finger Nucleases (ZFNs), transcription activator-like effectors nucleases (TALENs), and the clustered regularly interspaced short palindromic repeats (CRISPR). In particular, CRISPR-associated nuclease 9 (CRISPR/Cas9) is the most attractive option because it is faster, cheaper, more accurate, and more efficient than any other existing methods.
CRISPR technology is adapted from naturally occurring defense mechanisms of bacteria and archaea. Organisms use CRISPR derived RNA and Cas proteins like Cas9 to stop the attacks of invader viruses by chopping up their DNA. These components are then transferred into another organism to perform gene editing by cutting DNA and tricking a cell’s natural DNA repair mechanisms to complete a desired change. In particular, Cas9 is directed to cut a region of DNA, fusing crRNA, that is specific to the DNA target, and tracRNA to create a single guide RNA that consists of a small pre-designed RNA sequence. The cells natural repair mechanisms introduce changes in the genome and repair the Cas9 induced double strand breaks. Insertions and deletions (INDELS) may be introduced to disrupt gene function.
Science is now turning towards using CRISPR-Cas9 for Alzheimer’s disease after successful trials for Huntington’s disease, a different neurological disorder. Researchers were able to successfully edit out the faulty region of the mutant HTT gene in an in vivo mice model using cells derived from patient samples using the technique. There is clear potential for the use of CRISPR-Cas9 in correcting the autosomal-dominant mutations of PSEN1 and PSEN2 in early-onset Alzheimer’s disease models. This is supported by the fact that CRISPR-Cas9 was recently used to correct the PSEN2 autosomal mutations in iPSC-derived neurons. In addition, CRISPR/Cas-9 was used to knock out the Swedish APP mutation in patients.
There is also evidence that CRISPR/Cas9 is a useful technology in treating late-onset Alzheimer’s. A recent, although not formally published study, shows proof that CRISP/Cas9 can be used to control the amyloid pathway attenuating cleavage and A production, while up-regulating the neuroprotective a- cleavage. This APP editing, by targeting the C-terminus region, was proven to be effective in various human neurons and mouse cells. Lastly, research shows that CRISP/Cas9 can be used to convert the APOe4 allele, which is associated with an increased risk of developing Alzheimer’s disease, to an APOe3 allele to lower this risk.
Ethical and social issues regarding the use of CRISPR in people are centered around philosophical and safety dilemmas. The philosophical arguments question whether or not CRISPR should be used to alter germ-line cells, in human embryos, that would be passed on to the next generation. In addition, there is a fear that this technology will lead to the creation of designer babies. Recently in a 2015 Napa Valley meeting, a leading group of CRISPR-Cas9 developers, scientists, and ethicists met to discuss the ethical limits of CRISPR systems. Shortly after, a multidisciplinary committee of the National Academies of Sciences, Engineering, and Medicine published a report that favored somatic genome editing, but not for any kind of enhancement. In terms of safety, CRISPR is a relatively new technology and much of its effects continue to be unknown. Some are worried that the technology could still be more accurate and that unknown genetic changes could be occurring with unforeseen consequences. For example, it is important to ensure that the disruptions of the DNA occur in the mutant gene and not in the wild-type allele. While accuracy could be considered an issue, CRISPR technology is advances at such a rapid pace that technical limitations should be of minimal concern. The consequence of editing a gene in germline may be unclear and unpredictable because the interaction of genetic information and biological phenotypes is not clear, however. And, considering that Alzheimer’s has many environmental factors adds to this concern.
Another moral and ethical consideration, however, is not engaging in genome editing considering the tremendous social and economic cost of Alzheimer’s. Alzheimer’s disease currently affects 5.5 million Americans and this number is expected to triple by 2050 due to a growing and aging population. In addition, it is the third leading cause of death among Americans only trailing heart disease and cancer. $259 billion are going towards managing Alzheimer’s in the United States today, and this cost is expected to reach $1.2 trillion in 2050 which would bankrupt the entire health care system. Therefore, Alzheimer’s disease not only affects a large portion of the population due to the large number of those diagnosed, but is an economic burden to everyone. As a result, some may consider not using CRISPR unethical because continuing without a solution is detrimental to everyone’s health.
In addition to Alzheimer’s as a social challenge due to economic cost, the progression of symptoms presents a social challenge to both those diagnosed and those around them. Mild Alzheimer’s disease is characterized with symptoms such as wandering and getting lost, trouble managing expenses, repeating questions, taking a longer time to complete everyday tasks, and personality changes. Moderate Alzheimer’s disease damages areas of the brain that control language, reasoning, sensory processing, memory, and conscious thought, causes patients to have hallucinations, delusions, and paranoia, and makes them unable to recognize friends and family.1 Patients with severe Alzheimer’s cannot communicate with others and are completely dependent another person as their bodies completely shut down.1 These changes may frustrate the patient and be hard to comprehend for others. Tasks that were always handled by the diagnosed, will now have to be taken care of by someone else. The slow deterioration of bodily function can be difficult to watch especially when so much assistance is required, causes emotional pain, and tension from economic burden making any solution worth it.
The CRISPR/Cas9 system has the ability to target just about any gene and can do so more efficiently and effectively than any other current gene-editing mechanism. In doing so, however, there needs to be both clear cut guidelines reflecting the ethical use of CRISPR/Cas9 as well assufficient research regarding a disease in order to ensure that gene-mutation has an effective outcome. In the case of Alzheimer’s disease, there needs to be an accurate method of diagnosis, considering that a significant number of diagnosis are mistaken as Alzheimer’s disease instead oftreatable conditions such as depression, vitamin deficiencies, and hypothyroidism.3 In addition, the particular genetic risks leading to both early and late onset Alzheimer’s disease need to be made clear.Regulations need to be put in place protecting the life-saving aspect of CRISPR, rather than its cosmetic potential, and should require deep reasoning especially when consideringgremlins gene editing. Despite risks, urgency must also take precedent. Whether CRISPR-Cas9 gene editing realizes itself as a therapeutic tool in treating Alzheimer’s is in the hands of researchers, this kind of treatment, with sufficient regulation, will prove revolutionary as these symptoms not only impair the person with the disease, but also disable the lives of their family and friends.
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