By Catherine Duan
Published 4:06 EST, Tues September 29th, 2021
Abstract
Parkinson’s disease (PD) is the second most common neurodegenerative disease, currently affecting nearly one million individuals throughout the United States alone1. Despite its pervasiveness, no treatments currently exist to ameliorate the underlying processes of neurodegeneration, with existing therapies focusing purely on symptom management2. The purpose of this review is to provide a panoramic discussion of the mechanisms utilized by four primary treatment options – 1) pharmacotherapy, 2) gene therapy, 3) deep brain stimulation, and 4) stem cell therapy; to examine research regarding the safety and efficacy of each; and to set forth an evidence-based recommendation for future research, investment, development, and treatment. After reviewing research regarding the safety, capability, and associated adverse events for each of the four therapies, I suggest that a combined administration of the drug L-dopa with a dopa-decarboxylase inhibitor and gene therapy exhibits the greatest potential for future development given results in human clinical trials and relatively low risk of adverse events.
Introduction
Parkinson’s disease is a chronic degenerative neurological disorder with early symptoms including bradykinesia, tremor, and freezing of gait3. Later stages of the disease manifest in frequent infection, Parkinson’s disease dementia, and even death4. While the causes of PD are unknown, major pathological markers include degeneration of midbrain dopaminergic neurons in the substantia nigra and an abundance of Lewy bodies in the remaining substantia nigra dopamine neurons5. PD is characterized largely by dopamine deficiency in its initial stages, which evolves to cause both motor and nonmotor symptoms as the disorder progresses. PD-induced death of substantia nigra dopamine neurons dysregulates the output of the entire basal ganglia circuit, a brain region important for motor control6. The globus pallidus internus (GPi) and substantia nigra pars reticulata (SNr) become hyperactive as a result of diminished striatal inhibition. This is further enhanced by heightened excitatory inputs from the subthalamic nucleus (STN) that result from decreased inhibitory control from the globus pallidus external (GPe)7 (Figure 1b). The dysregulation of basal ganglia output is considered to be the major cause behind the movement disorders associated with PD, and therefore is the site that most PD treatments are targeted. In this review, I focus on therapies aimed at treating the effects of motor deterioration, namely dyskinesia, following the decline of nigrostriatal dopamine neurons.
Although no disease-modifying treatment for PD currently exists, symptomatic therapies such as pharmacotherapy and deep brain stimulation have been employed to improve the quality of life for diagnosed individuals2. The drug L-dopa, often coadministered with dopa-decarboxylase inhibitors such as Carbidopa, works by increasing the diminished dopamine supply to the striatum (Figure 1b, I). It has been established as the gold standard of therapies and is now prescribed to nearly every PD patient upon diagnosis8. Another more recently established treatment is deep brain stimulation (DBS), which centers around the implantation of electrodes designed to regulate abnormal activity in the GPi and STN caused by irregular dopaminergic levels (Figure 1b, II).
While both of these treatments offer therapeutic value, each come with their own set of complications. L-dopa loses the ability to suppress Parkinsonian motor symptoms evenly throughout the day, which ultimately leads to frequent fluctuations in symptom presentation known as on and off states9; dopa-decarboxylase inhibitors (DDC-I) are often administered with L-Dopa to ameliorate off-state effects10. DBS also appears initially effective, but requires invasive neurosurgery with a high risk of severe adverse events11.
Given the issues with efficacy and side effects of pharmacotherapies and DBS, there exists a growing demand for other treatment options. Recent insights in treatment fields such as gene therapy and stem cell therapy also offer renewed hope for more effective therapeutic outcomes. Gene therapy (Figure 1b, III) targets the striatum in hopes of enhancing the expression of certain genes that can upregulate dopamine, therefore mitigating symptoms caused by decreased dopamine concentrations. Stem cell therapy (Figure 1b, IV) aims to implant adapted stem cells to replace damaged dopaminergic neurons, thereby offsetting the effects of dopamine deficiency.
In this review, outcomes are quantified through Section III of the Unified Parkinson’s Disease Rating Scale (UPDRS), a rating tool used in which higher scores correspond to greater severity of motor symptoms in disease progression12. Given their relatively high efficacy and low occurrence of adverse events, I recommend that a dual approach of gene therapy with the drugs L-dopa and Carbidopa be utilized as a baseline path for treatment and research.
Figure 1: Simplified schematic diagram of basal ganglia circuitry in normal (A) and parkinsonian (B) states. Perpendicular dashes represent inhibitory projections, while arrows represent excitatory projections, with the relative thickness of each line being indicative of the magnitude of effect. Gold circles indicate regions in which each respective treatment acts. The absence of dopamine neurons results in hyperactivity from the GPi and SNr along with decreased inhibitory control of the GPe.
Pharmacotherapy
Of the few existing treatments of PD, pharmacotherapy is considered the primary choice, administered either as a stand-alone treatment or as a baseline regiment upon which additional therapies are administered. The goal of most PD pharmaceutical treatments is to replenish diminishing dopamine concentrations in the striatum; however, dopamine itself is a water-soluble molecule and therefore incapable of penetrating the blood-brain barrier (BBB) if ingested orally. L-dopa, a dopamine precursor, is a commonly prescribed drug that can pass through the BBB, allowing for uptake by brain dopaminergic neurons and conversion to dopamine13. To further increase dopamine concentrations, dopa-decarboxylase inhibitors (DDC-I) such as Benserazide and Carbidopa are often simultaneously administered to decrease the peripheral breakdown of L-dopa by endogenous dopa-decarboxylase10.
Initial administration of L-dopa and DDC-Is is commonly characterized by substantial amelioration of parkinsonian symptoms and high tolerability. As a representative example, one randomized, double-blind procedure controlled study found that patients receiving 600 mg of daily L-dopa and Carbidopa scored an average of 9.2 points lower on the total UPDRS 42 weeks after treatment started compared to their baseline score before starting. Further, another trial studying effects at 102 weeks found a mean difference of 9.8 units14. Clinical data from this and other studies4,15,16 indicates that L-dopa and DDC-Is play a significant role in reducing Parkinson’s Disease symptoms.
While combined administration of L-dopa and DDC-Is has a long history of successful use in treating PD, pharmacological upregulation of dopamine has its limits. Given the simultaneous administration of a DDC-I, L-dopa has a half-life of only 1.5 to 2 hours. Thus, the duration of action starts at around 2 to 4 hours before decreasing due to the deterioration of dopaminergic neuronal storage abilities17. This rapid catabolism of dopamine leads to pulsatile stimulation and inconsistent delivery to receptors, which in turn results in a wide range of dyskinesias and increased motor complications in the off-state18. In the aforementioned trial, later results demonstrate a 40% chance of increased motor complications after a period of 4 to 6 years due in part to L-dopa’s pulsatile stimulation and also overall disease progression10. Strategies for reducing the off state and extending the effective length of treatment include increasing the dosage of dopaminergic medication, adding another dopaminergic medication, dose fractionation, or adding catechol-O-methyltransferase inhibitors (COMTIs) or monoamine oxidase type B inhibitors (MAOBIs) to inhibit the breakdown of L-dopa and dopamine and prolong their effects19.
Gene Therapy
In general, gene therapy employs therapeutic genes to treat disorders by correcting, replacing, or silencing defective genes20. In terms of the treatment of movement disorders like Parkinson’s, it typically offers selective restoration of dopamine concentration to the striatum through the upregulation of dopaminergic signaling21. While there are multiple ways to administer gene therapies, most make use of non-replicating viral vectors, such as a recombinant adeno-associated virus (AAV) and lentivirus, to deliver treatments to targeted areas22.
There are two gene therapies currently in consideration for the treatment of PD symptoms, both of which work to target similar molecular pathways in the brain. The first, Aromatic L-Amino Acid Decarboxylase (AADC) gene therapy, involves anatomically focal supplements of the AADC enzyme that enables an increased rate of conversion from L-dopa to dopamine in transduced cells21. Treatments target the post-commissural striatum, the target of the nigrostriatal dopamine neurons that die off during PD. The medium spiny neurons of the post-commissural striatum do not degenerate during Parkinson’s, and previous studies have exemplified the potential for these cells to express transgenes for extended periods of time23.
The second therapy employs a combined approach of AADC with the genes tyrosine hydroxylase (TH) and guanosine triphosphate cyclohydrolase I (GCH1). TH converts L-tyrosine to L-dopa, while GCH1 catalyzes the synthesis of the essential tyrosine hydroxylase cofactor, tetrahydrobiopterin. Unlike the AADC gene alone, collective transduction of TH-AADC-CH1 to the putamen allows dopamine to be synthesized in non-dopaminergic areas of the striatum without the use of L-dopa24.
Both therapies have shown success in treating PD symptoms. Initial administration of AADC gene therapy with L-dopa and DDC-Is in a phase I open-label safety study of intrastriatal infusion demonstrated at 6 months that all subjects showed improvement in total UPDRS scores. UPDRS motor scores decreased from 38.6 to 24.6 in the off-state and from 15.5 to 11.2 in the on-state. Postoperatively, results at 1 and 2 years showed continuing improvements in total mean UPDRS scores for the combined cohorts: off-state 37% at 1 year and 38% at 2 years, and on-state 32% at 1 year and 22% at 2 years25.
Similarly, therapies utilizing TH-AADC-CH1 also yielded positive results. In a multicenter phase ½ open-label trial with 12-month follow-up, significant improvements were demonstrated in average UPDRS motor scores off medication at 6 months, where the mean score decreased from 38 to 26, as well as at 12 months, where scores decreased from 38 to 2726.
The most common adverse events from AADC gene therapy were headaches and short-lived discomfort at the surgical site, while more serious effects included hemorrhaging in 2 of the 10 patients25. Similar results were observed at postoperative appointments for TH-AADC-CH1 trials, during which treatment-related adverse events included mild dyskinesias and on-off phenomena. No serious adverse events related to the study drug or surgical procedure were reported26. Given these promising results, further trials are in progress in order to provide greater insight into both forms of treatment.
Deep Brain Stimulation
While the status quo of PD management is mainly pharmacological, relying on L-dopa and dopamine agonists, deep brain stimulation (DBS) represents a commonly prescribed neurosurgical treatment11. Experimental data in nonhuman models of PD has established that neuronal activity in the subthalamic nucleus (STN) and globus pallidus pars interna (GPi) is strikingly exaggerated in the parkinsonian state, and lesions in these areas can lead to dramatic improvement of motor symptoms27. Thus, the goal of deep brain stimulation is to minimize the pathological influences of irregular activity from the STN and GPi caused by the loss of dopaminergic inputs to the dorsal striatum. DBS mimics the neuronal effect of lesions with reduced risk of permanent neurological deficit by stimulating implanted electrodes in the brain target. Despite its widespread use and success in treating PD, the actual therapeutic mechanisms by which DBS operates are still relatively obscure28.
Operations are frequently categorized into two divisions based on the region of implantation, usually in the GPi or STN, with studies showing that both are safe and effective for the management of symptoms29. The STN is generally considered to be the preferred target for practical and theoretical purposes30, but comparative studies are relatively limited and have not demonstrated significant clinical benefits to one location versus another31.
Four longitudinal studies reviewed the long-term consequences of both procedures at various times after surgical operation to juxtapose the effects of DBS in the GPi and STN given continued administration of L-dopa and DDC-Is. Three months after the procedures were performed, a series of double-blind, crossover evaluations determined that as compared to no stimulation, STN stimulation was correlated to a median improvement in the UPDRS motor score from 50 to 27, while GPi stimulation resulted in a median improvement from 44 to 28. In comparison to the base levels, there were significant improvements in the UPDRS motor scores at each visit with stimulation in both the off- and on-medication state27. At a 12 month follow-up, off-medication motor scores improved by 39% for GPi and 48% STN stimulation, while dyskinesia was reduced by 89% through stimulation at the GPi and 62% through the STN29.
After 24 months, DBS remained effective in both the GPi and STN. Patients receiving STN stimulation required lower doses of dopaminergic agents than those receiving pallidal stimulation but experienced increased levels of depression and a greater decline in visuomotor processing speed11. Four years post-operation, STN and GPi DBS continued to display significant improvements of 50% and 39%, respectively, compared to baseline UPDRS scores. The daily dosage of L-dopa was significantly reduced (35%) in the STN-treated group only32. These studies show a significant and substantial therapeutic benefit for at least 3–4 years in a large cohort of patients with severe Parkinson’s disease.
At three-month follow-up appointments in the aforementioned studies, cognitive and behavioral complications such as depression, confusional state, and lack of impulse control were only observed with STN stimulation. By six months, adverse events included intracranial hemorrhage in 7 of 91 patients along with resulting neurological deficits and persistent dysfunction (hemiparesis, aphasia, and cognitive dysfunction). Stimulation was frequently associated with muscle twitch and paresthesia, but these were typically transient and disappeared with adjustment of the stimulator settings27. In one-year appointments, the most frequent perioperative complications included mild delirium, transient anxiety, and deterioration of cognitive facilities29. During two-year appointments, serious adverse events occurred in 51% of patients undergoing pallidal stimulation and in 56% of those undergoing subthalamic stimulation, with no significant between-group differences at 24 months; these included confusional state, device complications, and depression11. At four-year follow-ups, adverse events included cognitive decline, speech difficulty, instability, gait disorders, and depression. These were more common in patients treated with DBS of the STN32.
Stem Cell Therapy
The primary cause of PD is the loss of nigrostriatal dopamine neurons resulting in severely impaired motor and mental functionality; thus, transplantation of functional tissue would theoretically revitalize the striatum and partially restore the striatal release of dopamine, resulting in significant clinical benefits. As such, stem cell therapy (SCT) centers on the possibility of utilizing stem cells as an interminable source of dopaminergic neurons for transplantation33. Stem cells can self-proliferate and are multipotent; self-proliferation being the ability to divide and reproduce into the same type of cell, and multipotency being the potential to differentiate into a wide range of different cell types34. As a result of multilineage differentiation potential and proliferative capabilities, stem cells allow for the implantation of new cells to replace damaged ones35.
Since the first clinical trials in the late 1980s using fetal midbrain tissue to replace lost DA neurons, hundreds of patients worldwide have undergone neural fetal tissue grafting, with many showing long-term graft survival, good clinical outcomes, and physiological release of dopamine over decades36. Throughout the progress of stem cell therapy, many different types of cells have been used for DA neuron derivation and differentiation, drug screening, and cell therapy for PD37. Of these, mesenchymal stem cells (MSCs) have received the greatest attention38.
Mesenchymal stem cells, also termed bone marrow stromal cells, can be readily harvested from patients or donors for use in therapies39. Bone marrow, umbilical cord blood, and adult adipose-derived stromal tissue have been used as sources of MSCs for autologous grafts. Through animal models and in vitro trials, MSCs have demonstrated immense capability to stimulate endogenous neural growth and induce synaptic formation38. Additionally, they display relatively less immunological reaction in respect to other adult stem cells due to the lack of major histocompatibility complex II. To date, these cell types have demonstrated positive safety profiles and high potential in human clinical trials38.
In research utilizing MSCs, a clinical trial in advanced PD patients using unilateral transplantation of autologous bone marrow-derived MSCs into the sublateral ventricular zone reported modest clinical improvement with no adverse effects. In this trial, there were no PET assessments before and after transplantation in order to determine graft survival or changes of DA striatal function35. Thus, the mechanisms underlying the reported modest improvements are still relatively obscure.
Conclusion
Overall, pharmacotherapy is by far the most frequently studied and administered treatment, given that it is almost universally prescribed upon a PD diagnosis. The combination of L-dopa and Carbidopa resulted in a change in UPDRS score of 9.2-9.8 units and was received with minimal side effects, making it a clear candidate for continued use. Deep brain stimulation in the GPi and STN resulted in drastic UPDRS score changes of 16 and 23, respectively, but both were accompanied by a dangerously high frequency and magnitude of adverse events that dramatically disincentivized frequent administration. AADC and TH-AADC-CH1 gene therapy resulted in UPDRS score differences of 12-14 while offering comparatively few occurrences of detrimental side effects. Stem cell treatments also exhibit promise in ameliorating PD motor symptoms, although results are still inconclusive given the absence of available clinical data utilizing UPDRS to gauge the efficacy of stem cell therapy.
Based on these findings, I recommend a combined administration of the drugs L-dopa and Carbidopa with gene therapy as a platform for future treatment and development. This treatment course offers significant benefits in ameliorating the motor symptoms of PD while retaining a relatively low hazard regarding potential adverse events. For instance, while deep brain stimulation offers a greater reduction in UPDRS motor scores40, it also carries the significant risk (over 50%) of adverse events such as hemorrhage, persistent dysfunction, and cognitive decline caused by device and operation complications11. It is worth noting that research into and advancements of each of these treatment categories is ongoing, but as of right now, gene therapy appears to show the greatest promise for treatment and further development.
At this time, potential targets of genetic treatment for Parkinson’s have been identified and categorized as either disease-modifying or non-disease-modifying based on mechanisms of therapy. While this review focuses primarily on non-disease-modifying treatment options, disease-modifying gene therapies such as GDNF, NRTN, BDNF, and Nurr1 have recently become the subject of a great deal of attention and could potentially present not only symptomatic treatments but monotherapeutic cures for PD, given their capacity for neurorestoration and neuroprotection20. With further development enhancing safety and efficacy, it is possible that symptomatic therapy may be able to functionally cure Parkinson’s motor symptoms, enabling patients to lead fully satisfying lives.
Catherine Duan, Youth Medical Journal 2021
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Youth Medical Journal 