Gene Therapy in Neurodegenerative Diseases: A Path Toward Treating Multiple Sclerosis (MS)

Introduction to Multiple Sclerosis (MS)

Imagine waking up one morning unable to feel your legs, struggling to see clearly, and finding that even the simplest tasks take up all of your effort. For millions living with multiple sclerosis (MS), this is not just a bad day, it’s a lifelong reality. But what if there was something that could change that? Gene therapy has emerged as an innovative approach to treat complex diseases that uses genetic mechanisms to correct underlying abnormalities.This article explores how gene therapy is revolutionizing the management and treatment of multiple sclerosis by targeting the genetic and cellular causes of the disease. It also examines the genetic mechanisms underlying MS and highlights advanced technologies like CRISPR being used to repair myelin, regulate immune responses, and improve patients quality of life.

MS is a chronic autoimmune condition of the central nervous system (CNS) that affects approximately 2.8 million people worldwide [1]. MS patients experience symptoms such as fatigue, muscle weakness, compromised motor coordination, and cognitive impairment, all of which progressively worsen over time [2]. The pervasive range of these symptoms partially accounts for why MS is such a prevalent cause of disability, as it severely disrupts patients' quality of life. 

MS imposes a heavy economic burden, costing $85.4 billion annually in the U.S., with over $65,000 in excess medical costs per patient and more than half spent on disease-modifying therapies [3]. These high costs highlight the need for more effective, long-term solutions like gene therapy that target the disease at its source.

At the cellular level, MS occurs when the body’s immune system attacks myelin, the protective sheath that insulates nerve axons and is essential for efficient signal transduction [1]. This attack leads to demyelination, which disrupts signal transmission, damages the axons, and contributes to relentless neuroinflammation [1]. Oligodendrocytes, the support cells responsible for producing the protective myelin sheath, struggle to repair the damage due to inflammation and ongoing immune attacks that impair their ability to regenerate myelin. As a result, neurons are damaged or undergo degeneration and lesions form in the brain and spinal cord [1].

Neurobiology and Genetic Basis of MS

In MS, the body’s B and T cells attack the myelin sheath. B cells produce antibodies that promote an inflammatory response and activate immune cells to eliminate foreign and infectious agents. On the other hand, T cells coordinate immune responses by directly killing infected cells or by influencing the activity of other immune cells [4]. In MS, however, this immune response is disrupted by a mix of genetic predisposition and environmental stimuli, leading to a breakdown of immune tolerance—where the immune system normally avoids attacking the body’s own tissues for myelin [1,5].

This autoimmune misfire causes B cells to erroneously produce antibodies that establish myelin as an immune target [2], while T cells launch an inflammatory response that leads to direct damage of the cells containing myelin. While both contribute to demyelination, B cells primarily tag myelin for destruction through antibody production, whereas T cells execute the attack through cytotoxic and inflammatory mechanisms. Some subgroups of T cells, referred to as Th1 and Th17, produce pro-inflammatory cytokines. These cytokines are small proteins that enable immune cells to communicate with each other. In this case, cytokines such as interferon-gamma (IFN-γ) and interleukin-17 (IL-17) induce inflammation of the CNS [2].

Additionally, microglia, a type of macrophage play an important role in the persistence of neuroinflammation in MS. Peripheral macrophages help clear cellular debris and infiltrate the CNS in response to injury or immune activation, allowing microglia to become chronically activated in the disease environment. These activated microglia release pro-inflammatory cytokines, which lead to an increase in reactive oxygen species (ROS), along with other neurotoxic factors that contribute to axonal damage and neuronal loss [1,6]. At the same time, the pathological activity of chronically activated microglia disrupts oligodendrocyte function and interferes with their maturation, thereby inhibiting the regeneration of myelin and tissue repair [7,8]. Although microglia are capable of protective and reparative responses under healthy conditions, in MS their sustained activation skews toward a pro-inflammatory phenotype, which further exacerbates disease pathology [2,6].

The course of disease in MS is under strong genetic control. The strongest known genetic risk factor is a mutation in HLA-DRB1, a gene that allows the immune system to differentiate between bodily proteins and foreign proteins [1]. In addition, more than 200 chromosome regions  are involved in immune regulation, particularly in T cell differentiation and antigen presentation, and carry variants that may increase susceptibility to MS [1, 4]. However, genetic susceptibility alone does not guarantee the onset of MS. Environmental factors like lack of vitamin D, Epstein-Barr virus infection, and smoking exacerbate the genetic risk factors that influence disease onset and severity [5,9,10].

Limitations of Current Therapy

For many individuals with MS, treatment is not simple, as currently available therapies all have various shortcomings. For example, treatment often focuses on either symptom management or slowing disease progression, rather than reversing existing damage. Additionally, these treatments often come with challenges such as persistent inflammation, high costs, and restricted therapeutic effectiveness. 

One of the first issues is that they fail to stop or undo the effects of MS. Some of the therapies include immune regulator drugs that help to slow the disease, such as interferon-beta and natalizumab, which help to slow the disease [2]. These drugs work by suppressing the immune system and reducing inflammation. However, this is a lifelong treatment that must be continued throughout the patient's life and carries its own risks, including increased susceptibility to infections, organ toxicity, or even organ failure [1]. 

As for symptom management, strategies often rely on steroids and muscle relaxants that are primarily used for palliative care. Other therapies like mitoxantrone–a chemotherapy drug, work by inhibiting DNA replication and RNA synthesis of genes associated with inflammation [2,5]. This inhibition helps suppress immune system activity and limits damage to myelin in MS. However, like the immune regulator drugs, these therapies only slow the progression of the disease and are associated with significant side effects, including heart and liver damage [5].

One of the primary disadvantages of current MS medications is their cost and limited access, especially in the US, where the cost of treatment exceeds $90,000 annually despite the availability of generic brands [3]. The medications primarily aim to delay disease progression  through the control of immune reactions rather than attacking the core genetic causes [2]. Conversely, gene therapy targets faulty DNA and RNA to cure the disease at its source. However, it is largely inaccessible due to its experimental nature, production cost, and price levels that are typically above $1 million per patient [5,11]

Cutting-Edge Gene Therapy Technologies

New therapeutic avenues for complicated neurological conditions like multiple sclerosis (MS) have been created by recent developments in genetic engineering. Among the most promising technologies is CRISPR-Cas9, a precise and highly efficient gene-editing process taken  from the immune system of bacteria. CRISPR works by using a guide RNA to locate a specific DNA sequence and an enzyme Cas9 to cut the DNA at that location, allowing scientists to remove, replace, or modify the genetic code. With CRISPR, scientists can harvest, cut, and edit specific sections of DNA, potentially reversing genetic mutations at their origin [11]. In MS, it may be used to alter the function of immune-associated genes such as HLA-DRB1 by either silencing harmful variants, correcting mutations, or inserting protective versions to reduce the immune system's misdirected attack against myelin.

Non-viral gene transfer methods are increasingly becoming the gap filler with regard to viral methods for gene therapy. Unlike viral vectors that rely on the use of engineered viruses to deliver genetic material into cells, non-viral methods use physical or chemical means. These include nanoparticle-based systems or, in experimental or localized settings, electroporation to transfer genes with reduced risks of toxicity and immune response. These methods are being explored for the delivery of gene therapy to oligodendrocytes and neural stem cells, both of which play critical roles in re-myelinating injured myelin [7]. These developments are enhancing the safety, specificity, and promise of gene therapy as a treatment for MS.

Gene Therapy as a Treatment Modality 

Gene therapy represents a new frontier in the management of MS by not just stopping the disease, but helping the brain to repair itself. One promising approach is the repair of the myelin sheath by boosting the activity of oligodendrocytes, the cells that produce myelin. This happens by using genetic methods to introduce and or activate repair mechanisms that slow down with age[8,12]. There have been encouraging results in animal models, particularly in aged mice, where researchers demonstrated that small molecule induced epigenetic rejuvenation can enhance oligodendrocyte differentiation, it could also promote remyelination and improve neural repair in demyelinated regions of the CNS [8]. 

Another central goal is preventing the immune system from damaging the nervous system. Scientists are examining gene therapy as a method of restoring balance by essentially delivering genes that enhance the function of specific immune cells, called regulatory T cells (Tregs). These play a soothing role on destructive, inflammatory responses and suppress the immune system, specifically the overactive components driving the autoimmune attack [2]. Scientists are also working on ways of protecting these cells so they can carry on their function.

Another hopeful avenue is the restoration of small molecules like microRNA-23b that are involved in controlling inflammation in the body, with methods such as gene therapy to reintroduce these regulatory elements. [5,13]. Tuning into these important members of the immune system, scientists hope to silence the root cause of MS and to change the trajectory of the disease.

Challenges and Ethical Considerations

While its revolutionary potential to redirect the course of disease treatment for conditions like MS is real, gene therapy remains plagued with a range of challenges that cross technical, ethical, and social domains. One major concern is the potential for off-target effects, where technologies like CRISPR can unintentionally alter DNA regions and cause negative consequences. Continued uncertainty about the long-term safety, persistence, and reversibility of these treatments over a patient's lifetime represent far reaching ethical questions. Additionally, the prohibitively high costs and limited availability of these treatments risk exacerbating current health inequities and raise complex questions, including how to distribute the limited quantity of advanced treatments care. Obtaining informed consent becomes more complicated when patients must weigh the risks and uncertainties of producing irreversible modifications to their genetic code in hopes of long-term benefit [11,14].

Conclusion

Gene therapy is a powerful and promising area of research in the fight against multiple sclerosis. By treating the disease at its genetic roots to repair damaged myelin, re-balance the immune system, and trigger regeneration in the central nervous system, it has the potential not only to cure the disease but to alter the course of MS itself. Whereas other treatments mainly aim to halt or reverse progression and reduce inflammation, gene therapy promises lasting repairs that actually target the disease's cause. However,  this novel approach is not without its challenges. Technical challenges, ethical issues, and issues of access need to be addressed carefully if gene therapy is to be a safe, equitable, and effective.With studies in progress, gene therapy can transform the lives of millions with MS with a new life, for the promise of healing and a future beyond the limits of existing treatments.

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