Alzheimer’s Disease And Gene Therapy
The clinical symptomatology of Alzheimer’s disease (AD) is considered to be the result of an extensive destruction or disorganization of the cerebral cortex, as the patient’s cognitive functions become impaired. Late onset Alzheimer’s disease affects 5-10% of people over the age of 65 years old and while the case for this disease has not yet been fully understood, it is believed that a combination of genetic, environmental and lifestyle factors affects the risk for developing the disease. Researchers have not yet found a specific gene directly linked to sporadic AD however, patients with the Apolipoprotein E (APOE) specifically the E4 allele, located on chromosome 19 are twelve times more likely to develop the disease according to the Alzheimer’s Drug Discovery Foundation.
The neurodegenerative disease is pathologically characterised by failure of the normal protein synthetic machinery of the cell, with consequent abnormal post-translational processing of the amyloid precursor protein (Pearson and Powell, 1989). Therefore, leading to the extracellular deposition of Aβ into toxic plaques and intraneuronal accumulation of abnormal tau protein forming together creating neurofibrillary tangles (NFT). Early onset familial Alzheimer’s disease (FAD) is inherited as an autosomal dominant trait and accounts for 10% of AD cases. Genetic linkage studies have mapped the formation of abnormal amyloid precursor protein (APP), presenilin 1 (PSEN 1) and presenilin 2 (PSEN 2) genotype mutations on chromosomes 21,14 and 1. FAD progresses more rapidly, eliciting beta-amyloid peptide (Aβ) aggregation in earlier years, diagnosis can be as early as 20-30 years of age in this case. The APP mutation is located within the proximity of cleavage sites for β- secretases and y- secretases increasing production of Amyloid peptide, excessive amounts of this toxic protein leads to the death of nerve cells. Comment by Briana Hindemith: Proteins being synthesised by ribosomes translating mRNA into polypeptide chains – abnormal therefore indicating failure of this process Comment by Briana Hindemith: Integral membrane protein expressed in many tissues and concentrated in the synapses of neurons – generates Beta Amyloid (AB) polypeptide that is the primary form of Amyloid plaques found in AD brain Comment by Briana Hindemith: The formation of AB in large clusters at a progressively earlier rate
In the mid-1970s the first neurochemical that underlined dementing symptoms was discovered from the observation of neurons synthesising and releasing acetylcholine. While observations continued it became apparent that there was significant decrease in degradative enzymes and acetylcholinesterase in the limbic and cerebral cortices (Selkoe, 2001). This discovery lead to pharmacological research focused on attempting to enhance the acetylcholine levels primarily by inhibiting degradative enzymes. Since this past discovery pharmacological drugs such as Acetylcholinesterase inhibitors – donepezil, rivastigmine and galantamine are prescribed to patients with mild AD to temporarily ameliorate symptoms but unfortunately do not stop the progression of the disease. Currently in present day, there still is no modifying treatment available to patients suffering from AD however, gene therapy has been identified as a possible treatment for the Neurodegenerative disease. Studies conducted on the nerve growth factor (NGF) prove to exert pharmacological effects on particular cholinergic neurons known to atrophy in AD. NGF production is synthesised in the hippocampus and the cerebral cortex before being secreted to axon terminals in the basal forebrain cortical neurons. The aim of this treatment is to maintain the physiological concentration of NGF to support the growth and maintenance of Cholinergic neurons that help aid with the reduction of AB levels within the basal forebrain. This treatment can be approached using either ex-vivo or in-vivo methods. By treating the disease with an ex-vivo approach fibroblasts are transduce with retroviral vectors and injected into the nucleus basalis of patients, in an attempt to improve cognitive functions without adverse effects (Nilsson et al., 2010).
However early-stage clinical trials testing in vivo methods as an approach to treating Alzheimer’s disease have shown significant advantages. Alternative viral vectors such as recombinant adeno-associated (rAAV) have been developed to replicate genetic information to form double-stranded DNA which is then transcribed to produce the gene of interest. These vectors proceed to infect non-dividing neural cells with extensive studies showing for the virus to be non-toxic and weakly immunoreactive. Clinical research has been conducted on Aβ- degradation enzymes such as β- secretases and y- secretases inhibitors that could act as in-vivo treatments within the cortical neurons to decrease both intra and extra cellular levels of Aβ. However, due to the lengthy procedures required for ex-vivo gene delivery the in-vivo approaches are more likely to be favoured for treatment in the future. In the case of FAD patients, studies have indicated that individuals carrying the E2 allele within the APOE genotype reduce their risk of developing AD by 40%. As the APOE genotype performs neuroprotective and neurotrophic functions within the normal aging brain, the E2 allele binds to Aβ with greater affinity allowing for isoforms to form and regulate Aβ clearance through neurons, microglia or delivery to the blood-brain barrier (BBB) (Rebeck, Kindy and LaDu, 2002). Clinical tests have begun with an injection of a virus containing the APOE 2 gene into patients with FAD, aim of the treatment is to bath the brain in gene replacement therapy by relying on this virus to send instructions to re-code DNA. However, this treatment would be administered during the pre-symptomatic period aiming to stop the disease before it begins. While there are currently many treatments being investigated and researched there is still unfortunately no specific treatment for the prevention of AD.
AD remains a looming health crisis despite the efforts and research surrounding the neutron dysfunction and neurodegeneration that accompanies AD. Moving forward with future technology and the opportunity of gene therapy possibly preventing or curing AD there are multiple ethical issues surrounding the future treatment of this disease. It is easy to imagine situations where by adding what is presumed to be the beneficial gene or by removing the mutated gene that there is high controversy surrounding the topic. Speaking on behalf of a religious perspective 58% of individuals polled by CNN believe that by altering human genes is against the will of God (Ndsu.edu, 2019). Its an interesting issue to be raised as God has distinctively designed each and every human on this earth with a specific plan and purpose, he was holy and wise when doing so and by conducting treatments such as gene therapy we scientifically would be changing his divine creation. However, a world free from suffering and disease is an ideal for humanity, with AD currently increasing as one of the 21st Century’s greater medical issues. Currently over 5.4 million Alzheimer’s patients are receiving medical care incurring at a cost as high as $200 billion a year. Pharmacoeconomics studies the costs and benefits of therapies and technologies like gene therapy and evaluate the importance of them in regard to the global economic pressures (Issa and Keyserlingk, 2000). Ethical reviews on gene therapy and AD patients increase addressing the issue of future treatment availability and the costs/outcomes on medical care. With the possibility for the expenses of the treatment creating a larger economical separation between upper- and lower-class communities. Finally the ethical dilemma of DNA banking arises, as genotyping often involves the long-term storage of DNA for future analysis. Related issues of autonomy, privacy and informed consent ascends specifically due to the insurance industry’s interest in genetic information as it had the potential to predict future healthcare risks.
Furthermore, when deciding whether gene therapy would be appropriate and beneficial to fund as a treatment for AD the potential benefits need to outweigh the risks. Personally I believe if monitored by the government and medical society gene therapy has the opportunity to produced exceptional results and success specifically when treating AD.
ABSTRACT Alzheimer’s Disease has been around for over 100 years and has no cure. It is a neurogenerative disease that leads to dementia in patients, where the episodic memory is impaired, along with a decline in cognitive skills. A report in the 2019 Alzheimer’s Disease Facts and Figures consisted a graph and table which indicated the number of annual Alzheimer’s Disease death rates in the United States per 100,000 people by age and year. The death rates increased as the...
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