Overview

Parkinson's disease is a brain disorder characterized by symptoms like shaking, slowed movements, and stiffness, caused by the progressive loss of dopamine-producing nerve cells in the brain. While some cases are inherited due to specific genes, for most people, Parkinson's occurs without any clear reason, believed to result from a combination of genetic and environmental factors.

The disease affects nearly 6 million people globally¹, making it the second most common brain disorder worldwide, following Alzheimer’s. It predominantly affects more men than women and often manifests in individuals over 60 years of age.

While current treatments focus on symptom management, gene therapy has emerged as a promising avenue for addressing the underlying causes of Parkinson's. This therapy involves introducing genetic material into specific brain cells to correct dysfunctional genes, potentially restoring normal cellular function and alleviating symptoms.

In this article explore the various gene therapy strategies implemented, including those aimed at increasing dopamine production, restoring nerve cell activity, and using growth factors to modify the disease's progression. Also, evaluate the safety and effectiveness of these approaches using clinical trials and ongoing research. They offer hope for improved treatment outcomes and the possibility of halting the progression of Parkinson's disease.

What is Parkinson's disease? 

Parkinson's disease is a nervous system disorder characterised by a range of symptoms, including unintended or uncontrollable movements like shaking or tremors, slowed movements, stiffness, loss of coordination, and difficulty with balance. 

These symptoms arise gradually and become worse over time. The underlying cause of Parkinson's disease involves the progressive deterioration or death of nerve cells, particularly those responsible for producing dopamine, a neurotransmitter crucial for regulating movement. 

In addition to motor symptoms, individuals with Parkinson's disease may experience challenges with memory, sleep, mental health, pain, and other health issues. 

Biological mechanisms of Parkinson's disease

Parkinson's disease occurs when specific brain cells responsible for controlling movement start to deteriorate. These cells produce dopamine, a chemical crucial for smooth muscle movements. As these cells die off, dopamine levels decrease, resulting in symptoms like tremors, stiffness, and difficulty moving.

This loss of dopamine-producing cells can also affect other brain functions, leading to non-motor symptoms such as cognitive impairment, mood changes, and sleep disturbances.

Contributing factors to Parkinson's disease

Researchers are exploring various factors for their correlation with Parkinson’s disease. These include:

Genetic factors

Certain genetic mutations are linked to an increased risk of developing Parkinson's disease, accounting for about 10 to 15% of all Parkinson's cases.

Environmental factors

Exposure to pesticides and other toxins is associated with a higher risk of Parkinson's disease. Other environmental factors, such as head injury and place of residence, may also play a role.

Lewy bodies

The presence of abnormal protein deposits called Lewy bodies in the brain is a hallmark of Parkinson's disease.

Mitochondrial dysfunction

The impaired function of mitochondria, the energy-producing components in cells, may contribute to the development of Parkinson's disease by releasing free radicals and resulting in oxidative stress.

Current treatments

The condition isn’t curable, but various treatments and management strategies are available to help manage the symptoms and improve quality of life. These treatments are personalised based on specific symptoms and the effectiveness of the treatments.

Medications

Treatment for Parkinson's disease through medication primarily focuses on: 

• Increasing dopamine levels in the brain
• Influencing neurotransmitters, the brain's messenger chemicals
• Helping control non-movement symptoms

Common medications used for Parkinson's disease include dopamine agonists, levodopa, MAO-B inhibitors, COMT inhibitors, anticholinergics, and amantadine.

Deep brain stimulation (DBS)

DBS involves inserting electrodes into the brain to administer a gentle electrical stimulation to a specific area of your brain.

Physical & occupational therapy

These programs concentrate on exercises designed to improve flexibility, balance, and overall mobility through muscle strengthening and coordination enhancement. Additionally, these therapies offer strategies to manage motor symptoms, aiding in the adaptation to daily activities.

Challenges in Parkinson’s treatment approaches

The above treatment methods for Parkinson’s disease, while helpful, present several limitations. 

• Medications used for symptom control often come with side effects such as nausea, dizziness, hallucinations, and dyskinesia² (involuntary movements)
• Prolonged use of these drugs can lead to tolerance, resulting in fluctuations in symptom control. 
• Deep Brain Stimulation (DBS), while offering relief for some, has diminishing effects over time and carries risks such as brain infection, damage, or bleeding from surgery
• Additionally, access to physical and occupational therapies may be limited by location, cost, and availability, creating barriers for individuals seeking comprehensive care

Gene therapy

Initially conceptualized in 1972 to replace faulty DNA with functional ones, gene therapy involves introducing genetic material into cells to rectify or complement defective genes, thereby correcting underlying genetic abnormalities. This groundbreaking approach in medicine promises long-lasting and curative effects, representing a significant advancement in the treatment of various diseases.

Although still in the experimental phase, ongoing research and clinical trials are paving the way for the development of safe and effective gene therapy approaches, bringing renewed hope to Parkinson's patients.

Gene therapy and Parkinson’s disease

Gene therapy is emerging as a potential treatment for Parkinson's disease, targeting specific genetic mutations responsible for the condition. By introducing genetic material into specific brain cells to correct dysfunctional genes, gene therapy addresses the disease's root causes at the genetic level, potentially restoring normal cellular function and alleviating symptoms.

Early-onset Parkinson's has been linked to hereditary factors, with ongoing research seeking to identify additional genetic risk factors. Recent studies, such as one conducted by Northwestern Medicine ³, show that gene therapy focused on a brain region called the substantia nigra can enhance the effects of levodopa, a common Parkinson's medication.

Moreover, gene therapy offers the possibility of personalised treatment, tailored to individuals based on their unique genetic makeup and disease characteristics.

Genes that are linked to Parkinson's 

Several genes have been identified as being linked to Parkinson's disease. Key genes associated with Parkinson's include.⁴ 

Alpha-synuclein (SNCA)

Changes in this gene lead to abnormal alpha-synuclein protein buildup in the brain, linked to Parkinson's.

LRRK2 (Leucine-rich repeat kinase 2)

Alterations in this gene are a common cause of Parkinson's, affecting nerve cell function, especially in certain populations.

Parkin (PARK2)

Changes in the Parkin gene disrupt protein recycling, causing a buildup of damaged proteins and contributing to Parkinson's.

PINK1 (PTEN-induced kinase 1)

Changes in the PINK1 gene are linked to early-onset Parkinson's, affecting cell energy use and survival, potentially leading to nerve cell death.

DJ-1 (PARK7)

Changes in the DJ-1 gene are associated with early-onset Parkinson's, potentially impairing the cell's ability to handle stress.

GBA (glucocerebrosidase-beta)

Changes in GBA raise Parkinson's risk by disrupting waste protein removal, leading to Lewy Body buildup in the brain, a key feature of the disease.

Types of gene therapy strategies for Parkinson’s disease

Gene therapy holds promise as a potential treatment for Parkinson's disease, with researchers exploring various methods to alleviate symptoms and modify the progression of the disease itself.

Two primary approaches are being pursued in gene therapy research for Parkinson’s: 

Symptomatic relief

Symptomatic relief strategies⁵ are currently under clinical investigation, aiming to alleviate the immediate symptoms of Parkinson's disease. These approaches utilize gene therapy techniques such as silencing faulty genes, replacing them with healthy ones, or fixing genetic abnormalities. 

Non-disease-modifying treatments fall under the category of symptomatic relief. They aim to ease Parkinson's symptoms by normalizing abnormal activity in specific brain regions responsible for movement control. This is achieved through the modulation of enzymes related to dopamine or GABA, neurotransmitters crucial for motor function.

Disease modification

On the other hand, disease-modifying strategies⁵ are still in development, focusing on halting cell death caused by Parkinson's disease and potentially regenerating lost neurons. These strategies target the underlying pathological processes of the disease, aiming for long-term benefits beyond symptom management.

Research is currently underway to deliver specific genes directly into brain neurons affected by Parkinson's disease, with several major clinical trials evaluating the effectiveness of this therapy. Three primary types of gene therapy approaches being tested are: 

Increasing dopamine production

Trials aim to instruct healthy brain cells to produce dopamine, thereby replacing lost dopamine neurons. This approach holds the potential to reduce or eliminate the need for dopamine-replacement medication. 

Restoring nerve cell activity

Certain trials are focussed on boosting the activity of enzymes responsible for producing GABA to regulate overactive nerve cells seen in Parkinson’s disease. Although initial results were not promising, researchers are now exploring innovative methods, such as employing light-responsive genes, to overcome this challenge. 

Using growth factors

Research is exploring how genes acting as growth factors can aid in the regeneration of the dopamine system or the preservation of dying cells and neurons, offering a potential path toward disease modification. Although significant results have not been observed yet, trials have tested growth factors to protect and rejuvenate neurons. Researchers are refining these trials to improve outcomes.

Clinical trials and research findings

Several gene therapy programs focused on glial cell line-derived neurotrophic factor (GDNF), a protein that supports neurons, and its potential to regrow dopamine nerve cells. Although initial clinical trials showed promise, the effectiveness of GDNF therapy remains unclear.⁵

These trials emphasized the need for earlier intervention in Parkinson's disease progression when dopamine fibres are still functional. 

Another approach involves infecting non-nerve brain cells to produce dopamine. While studies using lentiviruses to introduce synthetic dopamine pathways showed some benefit, few trials faced setbacks, while others had to be halted due to safety concerns.

Currently, a gene therapy trial targeting individuals with a mutated GBA gene is underway. This trial aims to assess long-term safety, immunosuppression requirements, immune response, and preliminary effectiveness indicators. While gene therapy for Parkinson's disease holds promise, further research is needed to determine its efficacy and safety.

Summary

Parkinson's disease affects millions worldwide, presenting as a complex interplay of motor and non-motor symptoms. A neurological disorder, Parkinson’s presents a multifaceted challenge characterized by motor and non-motor symptoms. 

While current treatments aim to manage symptoms, gene therapy emerges as a promising avenue for addressing the root causes of the disease. Through innovative genetic interventions, gene therapy offers both immediate relief and long-term modification of Parkinson's progression. Ongoing research explores diverse strategies, including symptomatic relief and disease modification, with the potential for personalised treatment tailored to individual genetic profiles. 

Gene therapy's ability to provide lasting effects with minimal administration heralds a new era in Parkinson's therapy, promising improved outcomes and quality of life for patients.