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.

   Surgical therapies:


  • In refractory cases, surgical treatment of PD should be considered.
  • Deep-brain stimulation (DBS) of the subthalamic nucleus (STN) or globus pallidus interna (GPi)  has largely  replaced  ablation  surgery  (e.g.,  pallidotomy  or thalamotomy).
  • DBS is primarily  indicated  for  pts  who  suffer  disability  resulting  from  severe tremor or levodopa-induced motor complications; the procedure is profoundly beneficial to many pts.
  • Contraindications to surgery include atypical PD, advanced cognitive impairment, major psychiatric illness,  substantial  medical  comorbidities,  and  advanced age (a relative factor).


   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.[5] 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.


   Symptomatic approaches:

   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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   3.[Frontiers in Bioscience S6, 65-74, January  1, 2014] Parkinson’s  disease: a review Janice M. Beitz1 1School of Nursing-Camden, Rutgers University, 311 N. 5th  Street, Camden, NJ 08102.

   4.Coune, Philippe G; Schneider, Bernard L.; Aebischer, Patrick (April 2012). "Parkinson's Disease: Gene Therapies". Cold Spring Harbor Perspectives in Medicine. 2: a009431. doi:10.1101/cshperspect.a009431. PMC 3312404 .

   5.Horellou, Philippe; Mallet, Jacques (October 1997). "Ex Vivo Gene Therapy for Parkinson's Disease:lntracerebral Transplantation of Genetically Modified Cells". Molecular Neurobiology. SpringerLink. 15 (2): 241–256. doi:10.1007/BF02740636. Retrieved 12 April 2013.


   7.Forsayeth, J.; Bankiewicz, K. S.; Aminoff, M. J. (2010). "Gene therapy for Parkinson's disease: Where are we now and where are we going?". Expert Review of Neurotherapeutics. 10 (12): 1839–1845. doi:10.1586/ern.10.161.

   8.Campos-Romo, Aurelio; Ojeda-Flores, Rafael; Moreno-Briseño, Pablo; et al. (2012). "Behavioral improvement in MPtP-treated nonhuman primates in the HALLWAY task after transfer of tH cdnA to host astrocytes" (PDF). Acta Neurobiol. Exp. Polish Neuroscience Society- PTBUN, Nencki Institute of Experimental Biology. 72: 166–176. Retrieved 15 April 2013.





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