Gene therapy in Parkinson's disease- a review:
Abstract: Parkinson’s Disease is the second most common progressive neurodegenerative disorder affecting older American adults and is predicted to increase in prevalence as the United States population ages. Resulting from a pathophysiologic loss or degeneration of dopaminergic neurons in the substantia nigra of the midbrain and the development of neuronal Lewy Bodies, idiopathic Parkinson’s Disease is associated with risk factors including aging, family history, pesticide exposure and environmental chemicals (e.g., synthetic heroin use). Its ultimate cause(s) is (are) unknown. Characterized by both motor and non-motor symptoms, PD patients classically display rest tremor, rigidity, bradykinesia, and stooping posture. PD can also be associated with neurobehavioral disorders (depression, anxiety), cognitive impairment (dementia), and autonomic dysfunction (e.g., orthostasis and hyperhidrosis). Recent decades have witnessed a proliferation of medical pharmacologic therapies and innovative surgical interventions like deep brain stimulation (DBS). However, definitive disease-modifying therapy is still lacking.
Gene therapy aims at treating disease by genetically modifying populations of cells that are either directly functionally impaired or capable of relieving the disease symptoms. These genetic modifications can either increase or reduce the expression of specific genes or gene sets, or even restore the normal function of the product of these genes.Various methods have been developed for gene delivery to the target cells, which include viral vectors, and nonviral systems. Nonviral methods, which are marginally used for gene transfer to the central nervous system (CNS), comprise chemical and physical methods, such as gene gun or electroporation.
Introduction and epidemiology: Parkinson’s disease (PD) is the second commonest neurodegenerative disease, exceeded only by Alzheimer’s disease (AD). Parkinson’s disease is a chronic progressive neuro degenerative disorder of insidious onset, characterized by the presence of predominantly motor symptomatology (bradykinesia, rest tremor, rigidity, and postural disturbances). It is also associated with a diversity of non-motor symptoms(such as hyposmia, rapid eye movements, sleep behaviour disorder, personality changes, pain, paresthesias and depression), which, together with late-onset motor symptoms (such as postural instability and falls, freezing of gait, speech and swallowing difficulties), are presently one of the most difficult challenges the treating physician is faced with when dealing with patients with a long duration of the disease.
Parkinson’s disease is a universal disorder, with a crude incidence rate of 4.5–19 per 100000 population per year. As this is a chronic disorder with a prolonged course, prevalence is much higher than incidence. Crude prevalence estimates vary from 18 per 100000 persons in a population survey in Shanghai, China, to 328 per 100000 in a door-to-door survey of the Parsi community in Bombay, India. Age-adjusted rates give a more restricted range of 72–258.8 per 100 000 persons.
Although the disease usually begins in the fifth or sixth decade of life, recent evidence shows increased incidence with advancing age. It has long been recognized that a small proportion of patients develop the disease at an early age. Patients presenting with the disease before 40 years of age are generally designated as having “early-onset” PD. Among them, those beginning between 21 and 40 years are called “young-onset” PD while those beginning before the age of 20 years are called “juvenile Parkinsonism”. Contributions from the fi eld of genetics have demonstrated that a large proportion of “young-onset”, and “juvenile” cases are of genetic origin, while the majority of the remaining cases are presently considered to be sporadic. Some of the late-onset PD cases are also found to have a genetic component. Although PD has been traditionally considered to affect individuals from both sexes equally, data recently published show a higher proportion of males to be affected by this disorder, with a male to female ratio of 1.9.
Pathophysiology: Most PD cases occur sporadically and are of unknown cause. Degeneration of pig-mented pars compacta neurons of the substantia nigra in the midbrain resulting in lack of dopaminergic input to striatum; accumulation of cytoplasmic intraneural inclusion granules (Lewy bodies).
Cause of cell death is unknown, but it may result from generation of free radicals and oxidative stress, inflammation, or mitochondrial dysfunction; no environmental factor has yet been conclusively determined to cause typical PD. Rare genetic forms of parkinsonism exist (~5% of cases); most common are mutations in glucocerebrosidase, LRRK2, α-synuclein or parkin genes. Early age of onset suggests a possible genetic cause of PD, although LLRK2 mutations cause PD in the same age range as sporadic.
Risk factors and diagnosis: Age is the most potent risk for PD with an average age of onset of approximately 50 to 60 years. Two other risk factors have shown to be important: family history (a genetic link) and pesticide exposure.
PD diagnosis is a clinical diagnostic decision that is based upon the presence or manifestations of rest tremor, rigidity, postural instability (gait disturbance) and bradykinesia. If a patient history reveals gradual symptom progression and then he/she responds well to drug therapy with levodopa, PD is likely the correct diagnosis. Differential diagnosis is challenging given the fact that the classic PD symptoms (e.g., rest tremor, rigidity etc.) can be present in other neurodegenerative disorders. Careful history taking and astute physical assessment coupled with initial medical therapy (e.g., the individual’s response to pharmacotherapy) are necessary to distinguish idiopathic PD from Essential Tremor, DLB, CBD, MSA, PSP, or secondary Parkinsonism due to drugs, toxins and head trauma.
Neurologic imaging plays a small role in PD diagnosis and is not used routinely. Studies like magnetic resonance imaging (MRI), ultrasonography, positron emission tomography (PET) scan, etc., lack evidence in diagnosing PD. At best they may help distinguish PD from MSA or Essential Tremor but not idiopathic PD itself .
Imaging of the brain dopamine system in PD with positron emission tomography (PET) or single-photon emission computed tomography (SPECT) shows reduced uptake of striatal dopaminergic markers, particularly in the posterior putamen with relative sparing of the caudate nucleus , reflecting the degeneration of nigrostriatal dopamine neurons. Imaging can be useful in patients where there is diagnostic uncertainty (e.g., dystonic tremor, essential tremor) or in research studies, but is rarely necessary in routine practice because the diagnosis can usually be established on clinical criteria alone.
Clinical Presentation: Presentation with tremor confined to one limb or one side of body is common. Other findings: rigidity (“cogwheeling”—increased ratchet-like resistance to passive limb movements), bradykinesia, fixed expressionless face (facial masking) with reduced frequency of blinking, hypophonic voice, drooling, impaired rapid alternating move-ments, micrographia (small handwriting), reduced arm swing, and flexed “stooped” posture with walking, shuffling gait, difficulty initiating or stopping walking, en-bloc turning (multiple small steps required to turn), retropulsion (tendency to fall back-wards).
Nonmotor aspects of PD include depression and anxiety, cognitive impair-ment, sleep disturbances, sensation of inner restlessness, loss of smell (anosmia), and disturbances of autonomic function. Normal muscular strength, deep tendon reflexes, and sensory examination. Diagnosis based on history and examination; neuroimaging, EEG, and CSF studies usually normal for age.
Medical therapies: Medical therapies are the mainstay of treatment for PD. They include pharmacotherapy and nonpharmacological alternative approaches such as exercise, education, support groups speech therapy and nutrition.
Pharmacological approaches to PD revolve around dopamine deficit or in inappropriate dopamine/other neurotransmitter imbalances. The American Academy of Neurology recommends initiating drug therapy once patients develop functional disability. Seven types of drugs are used to treat motor symptoms in PD patients. They include: Carbidopa/levodopa (Sinemet), dopamine agonists (both ergot and non-ergot types), monoamine oxidase-B (MAO-B) inhibitors, injectable dopamine agonist (apomorphine, or Apokyn), N-methyl-DAspartate receptor inhibitors, and anti-cholinergics. For initial therapy, levodopa, non-ergot dopamine agonists (pramipexole, or Mirapex; ropinirole, or Requip) and MAO-B inhibitors (selegine, or Eldepryl; rasagiline or Azilect) are commonly used.
GENE THERAPY: Gene therapy-The main idea of the gene therapy is to create new generations of cells that produce particular neurotransmitter (dopamine) and then transplant these cells to the patients with PD. This is because the neurons cannot proliferate nor be renewed; and replacing lost neurons it is a process that is currently going under investigation.
Also, the use of embryonic dopaminergic cells cannot be used because these cells are difficult to obtain and modifications of cell can only be made on somatic cells, not germline. With the modifications of the transplanted cell, there can be a change in the expression of the genes or normalize them.
Types of gene therapy:
There are several types of gene therapy. There are therapies for symptomatic approaches like the production of ectopic L-dopa, the full ectopic dopamine synthesis, the ectopic L-dopa conversion or the use of glutamic acid descarboxylase (GAD). Also there are disease modifying therapies like NTN or GNDF (glia cell line-derived neurothrophic factor), the regulation of the α- synuclein and Parkin gene expression. Currently the main studies are using AAV2 as a vector platform, making it the standard vector for this disease although a lentevirus has also been used. In the different types of the gene therapy, the investigations are encoding enzymes that are necessary for dopamine synthesis, such as tyrosine hydroxylase, GTP cyclohydrolase 1 and AADC.
A symptomatic approach is a treatment focused on the symptoms of the patients. The first one, consists in the ectopic dopamine synthesis. Here, the production of ectopic L-dopa in the striatum is another alternative gene therapy. This therapy consists on transferring the TH and GTP cyclohydrolase 1 genes into the MSNs because the endogenous AADC activity is able to convert the L-dopa into dopamine.
Dopamine synthesis can be fully ectopic. In this case, the enzyme AADC it is in charge of converting the levodopa to dopamine. In Parkinson disease, the loss of neurons from the nigrostriatum leads to the inability to convert levodopa to dopamine. The goal of AAV2-hAADC is to restore normal levels of AADC in the striatum so there could be more conversion of levodopa, and therefore reducing levodopa- induced dyskinesia. Using the gene therapy, in 2012, an experiment was accomplish with primates testing tyrosine hydroxylase (TH) transgene in primate astrocytes. Gene therapy was made with the transfer of a TH full-length cDNA using rat TH. The results showed behavioural improvement in the monkeys that received the plasmid, unlike the control monkey.
Another type is the ectopic L-dopa conversion in which they use a gene enzyme replacement therapy that can be used to increase the efficacy of the pharmacological L-dopa therapy by using AAV vectors. This AAV vectors have been designed to send the AADC coding sequence to the MSN (medium spiny neurons) in the striatum to be able to convert administered L-dopa into dopamine.
Other kind of gene therapy as a symptomatic approach is the use of glutamic acid decarboxylase (GAD) expression in the subthalamic nucleus. This is a gene enzyme replacement therapy that can be used to increase the efficacy of the pharmacological L-dopa therapy by using AAV vectors. This AAV vectors have been designed to send the AADC coding sequence to the MSN in the striatum to be able to convert administered L-dopa into dopamine. A phase 2 study, published in the journal Lancet Neurology Parkinson, says that a gene therapy called NLX-P101 dramatically reduces movement damage. In this study, they used glutamic acid decarboxylase (GAD).
ProSavin uses LentiVector technology to deliver the genes for three enzymes that are required for the synthesis of dopamine. The product is administered locally to the region of the brain called the striatum, where dopamine is needed.
ProSavin converts cells into a replacement dopamine “factory” within the brain, thus replacing the patient's own lost source of the neurotransmitter in a tonic level analogous to natural dopamine supply in the absence of Parkinson’s disease. In early- stage Parkinson’s disease, levadopa (L-DOPA) tablets are effective in managing the symptoms. L-DOPA is a chemical building-block which the body converts into dopamine. However, the body progressively loses its ability to convert L-DOPA to dopamine and its effectiveness is reduced with long-term use. ProSavin is designed to restore local continuous dopamine release to control symptoms without side effects.
Conclusion: Parkinson’s Disease represents a major clinical challenge since it is one of the most common neurodegenerative diseases, affects primarily a population of aging individuals, a group that is growing rapidly in the world, and lacks a therapeutic means to influence the inexorable loss of dopaminergic innervation. Parkinson’s Disease itself does not cause death but is associated with increased morbidity and mortality. Knowledge of the disease manifestations, treatments, and progressive long-term course is essential for optimal care and enhanced quality of life for people with Parkinson’s disease.
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