Introduction

Alzheimer’s disease is a common type of dementia, which causes reduced memory function and mental abilities, as the disease progresses. Symptoms like hallucination, loss of memory, sudden personality change, and loss of speech and language function develop with disease progression.¹

The exact cause of Alzheimer’s Disease is not clear, but it has multiple factors that increase the risk of developing it -genetic factors are one of them.¹ This gives rise to an opportunity to apply a type of treatment called gene therapy. Gene therapies are new strategies to treat genetic-associated disorders and involve delivering the correct genetic material into human cells to replace the disease-causing gene.² Gene therapy for Alzheimer’s Disease aims to target and alter the genes that contribute to the disease pathology.

Understanding alzheimer's disease

Amyloid beta (Aβ) plaques and tau tangles are the two widely known causes of Alzheimer’s Disease.³ Amyloid beta is the collective group of proteins with different lengths with the most common being Aβ38, Aβ40, Aβ42, and Aβ43.au tangles refer to abnormal interweaves of tau protein.

Recent studies have identified other factors that contribute to the disease development, such as neuroinflammation, lipid dysfunction, microglia response, and alterations in blood vessels. Relevant genes and their variants for these factors were identified through large genome-wide association studies and by using next-generation sequencing techniques.³ These further confirmed that Alzheimer’s Disease is often associated with genetic changes. Also, some of the important spotted genes and the genes’ products had functions in microglia, which shifted some focus onto microglial response in Alzheimer’s Disease.⁴

The rationale for gene therapies

Amyloid precursor proteins (APP) are processed by either alpha-secretase or beta-secretase and follow γ-secretase to produce p3 and Aβ peptides respectively.⁵ Aβ peptides can be broken down under normal circumstances but usually maintain a balance between production and elimination.⁶ However, when specific genetic mutations happen, such as those in the genes that code for amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2), they could contribute to the autosomal dominant form of Alzheimer’s.³

A mutated APP gene could result in mutated amyloid precursor proteins that then quickly accumulate. For example, E674Q (Shanghai APP mutant), an APP gene mutant was identified to code for Amyloid precursor proteins that attract interaction with beta-secretase hence producing more Aβ peptides.⁷ Presenilin-1 (PSEN1) and presenilin-2 (PSEN2) are two homologous forms of presenilin, a component of γ-secretase. PSEN mutations alter where γ-secretase cuts the amyloid precursor proteins, leading to longer and more toxic versions of amyloid beta protein.⁸

Types of gene therapies

Gene therapy is a typeof molecular medicine that inserts a piece of genetic material into the target cell and allows the cell to function by using it. The process of gene delivery and gene expression in the target cell is called transduction. To deliver the genetic material into the cells, efficient vehicles are needed. Vectors are one of the widely used vehicles for gene delivery.⁹ Vectors are eitherviral and non-viral. Viral vectors are from different virus systems, such asretroviruses, lentiviruses, adenoviruses, and adeno-associated viruses. The viruses are modified to eliminate their own toxicity while ensuring they still containing the target gene for delivery. Non-viral vectors can be the naked DNA itself, along with liposomes and nanoparticles.⁹ 

Gene delivery methods 

One strategy of gene therapy is to deliver the correct gene into the cell using vectors. The segment of the correct gene will be taken up by the cell and used to produce the correct functioning protein. This will then be delivered - thedelivery can be done in vivo orex vivo. Delivery through the in vivo methods is done by injecting the vector intravenously into the tissue whereit will then be taken up by cells. Ex vivo delivery involvesinitially extracting cells from patients, cultivating them in a laboratory setting where genetic materials are introduced, and subsequently reintroducing the modified cells back into the patient.⁹

Gene editing techniques

Gene editing is another form of gene therapy that involves precisely modifying the DNA within an individual's cells to treat or prevent genetic disorders. Unlike traditional gene therapies that involve the addition or replacement of genes, gene editing allows for the direct alteration of the existing genetic code. Gene editing makes use of the DNA repairmechanism in cells. When there is a break in our DNA strands, it automatically triggers the DNA break repair system. To edit the gene, scientists produce a double-strand break of our DNA using enzymes, and by providing correct genetic material, gene correction can take place through this repair mechanism.¹⁰

One of the most powerful and widely used gene editing techniques is the CRISPR-Cas9 system. The CRISPR-Cas9 system used today consists of two components, a single guide RNA (sgRNA) and CRISPR associated protein 9 (Cas9). The sgRNA acts as the detector that locates a DNA sequence in the target cell that is complementary to the sgRNA itself. The sgRNA can be designed and produced in labs, which gives a degree of freedom to manipulate the CRISPR-Cas9 system.The Cas9 identifies where to cut the gene and cuts it.¹¹

Specific genes targeted in gene therapies for alzheimer’s

Gene therapy is considered for Alzheimer’s disease because genetic factors are involved in its pathology.

The pathways for gene therapy specializing in Alzheimer's disease include: 

1. Maintain and increase neuron growth and synaptic activity:Neurotrophins like nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) are responsible for the maintenance of neurons hence these genes controlling neurotrophin expression are targeted. 
2. Target enzymes involved in amyloid-beta degradation:The degradation of amyloid-beta requires the involvement of numerous enzymes, and in patients with Alzheimer's Disease (AD), the expression of certain enzymes is diminished, leading to inadequate degradation of amyloid-beta.For instance, Endothelin-converting Enzyme-2 (ECE) and Cathepsin B.¹²
3. Target proteins involved in amyloid-beta production:The amyloid precursor protein and the enzyme β-secretase are two vital components in amyloid-beta production. A decreased expression of these genes may down-regulate expression of AD-associated proteins.¹² 
4. Target Aβ burden-associated factors (APOE):
   1. The Apolipoprotein E (APOE) gene itself was found to have a strong association especially APOE4, an allele of the apolipoprotein E (APOE) gene, but APOE3 is less toxic than APOE4. APOE's main function is to regulate cholesterol metabolism, and it has been observed that individuals with Alzheimer's Disease (AD) exhibit a reduction in brain cholesterol levels.APOE4 itself have been identified to take part in different pathways like Aβ production, Aβ clearance, Aβ fibrillization, tangle formation, and cholesterol homeostasis. This suggests that the POE and APOE receptors can be a potential target for gene therapy.^12,13

Clinical trials

There were a number of clinical trials going on in the past ten years relating to Alzheimer’s. In 2005, a phase 1 clinical trial was done of nerve growth factor gene therapy for Alzheimer disease. The gene therapy involved the injection of autologous fibroblasts that had been modified in the laboratory to express NGF into the forehead of eight patients diagnosed with mild Alzheimer's Disease (AD). The results with six remaining followed-up patients showed that this therapy slowed disease progression.¹⁴

Recently, another phase 1 clinical trial of gene therapy targeting Tau protein was led by Dr Catherine Mummery (UCL Queen Square Institute of Neurology & the National Hospital for Neurology and Neurosurgery) in 2023. The group used a drug called BIIB080 (/IONIS-MAPTRx) which aimed to silence the gene coding for tau protein. The trial results indicated an absence of severe adverse events among the participants, although mild to moderate adverse events were still present. The drug exhibited positive efficacy, with researchers noting a reduction of more than 50% in the total tau concentration within the central nervous system of patients 24 weeks after the final dose.¹⁵

Challenges and considerations

Gene therapy, while holding immense promise, faces several challenges and considerations that necessitate careful examination. Safety concerns in gene therapy for neurological disorders are paramount, given the intricate nature of the central nervous system. Ensuring that genetic modifications do not induce unintended consequences or adverse effects is a critical challenge. 

There are still challenges to develop effective and safe gene therapies for Alzheimer's disease. Whether it is developing an efficient and safe vehicle that is able to deliver the genes of interest to targeted cells in the brain, or to find a promising gene target specific to Alzheimer’s disease.

Ethical considerations play a significant role, particularly when manipulating the human genome. Questions of consent, equity, and the potential for unintended consequences raise ethical dilemmas that requirethoughtful resolution. 

Future perspectives

The drug BIIB080 (/IONIS-MAPTRx) is undergoing a phase 2 clinical trial and it is estimated to be completed by 2030.¹⁶ Genomic studies have now explored more genes related to Alzheimer’s disease and scientists will find suitable gene targets for gene therapy.  Potential advancements in gene therapies for Alzheimer’s diseasemay include the development of more precise and targeted gene-editing techniques, enhancing the efficacy of treatments and minimizing off-target effects.In the future, the more understanding we gain about Alzheimer’s disease, the higher possibility we have to develop new disease-modifying therapies.

Summary

This article discussed gene therapy for Alzheimer’s diseases. Gene therapies are treatments that alter human cells at a genetic level and are able to treat genetic diseases. The correct genes can be delivered into cells hence producing correct functioning proteins, also genes can be edited directly by gene editing techniques. 

Alzheimer’s disease is a neurodegenerative disease. More and more research shows that Alzheimer’s disease is heavily associated with genetic factors and this allows the application of gene therapy for Alzheimer’s disease. Even though there is no gene therapy that can cure Alzheimer’s disease, it can slow down disease progression and relieve symptoms.