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Gene Therapy for Treatment of Parkinson's disease
#1
Parkinson's disease is a common disease among the elderly and hence, much research is going on related to it to devise new methods to reduce the suffering of the aged.


As average age of the population has risen considerably owing to the discoveries of new medicines and treatments for many life-threatening diseases. The number of patients suffering from Parkinson's disease (PD) has risen and this has lead to a rise in the cost of treatments and therapeutics. Among the different types of treatments like brain surgeries, etc. gene therapy has evolved to be a better form of treatment for Parkinson's disease in the last few years.

PD is a degenerative disorder, belonging to the movement disorder group. It is a chronic disease of the central nervous system (CNS) and mainly associated with the impairment of the patient’s motor skills and even speech. The uncontrolled movements, tremors, rigidity of muscle, bradykinesia i.e. slowing of the physical movement, etc, characterize the PD, though the symptoms and their severity varies with the individuals. There may be many causes for a patient to suffer from PD. Some reasons like head injury, trauma, drugs, etc may cause PD, while some other idiopathic or unknown causes may result in Parkinson's disease like the presence of some genetic mutations. The main reason for the development of Parkinson's disease is the insufficient secretion of dopamine by the dopaminergic neurons, which leads to the decreased stimulation of motor cortex by the basal ganglia. The conversion of L-dopa by the L-amino acid decarboxylase (AADC) to dopamine takes place in the nerve terminals, which thereby controls the skeletal muscle motor activity.

Many types of therapeutics have been developed for PD. The administration of levodopa is one such method, which was found to produce much relief in the symptoms of Parkinson's disease in the sufferers of Parkinson's disease without any side effects. However, it does not help in the prevention of degeneration of the neurons. Hence, research for alternative methods of treatment was carried out. The surgical therapy for Parkinson's disease was also developed. In this the cells and tissue implantation was done for replacing the degenerated nerve cells and tissues. However, it was seen that the replacement of neuronal cells could not be considered a possible therapy in all cases, which led to research in the neurotrophic factors (NTF) and gene therapy.

Gene therapy in Parkinson's disease uses two approaches: One is to relieve the motor symptoms by introducing the genes of dopamine synthesizing enzymes into the striatum and thus restoring the production of dopamine and the other is to control the degenerative process of the neurons by the transduction of the cells with the genes encoding neurotrophins. From the elaborate study of the molecular mechanisms involved in the formation of dopamine from L-dopa, it was seen that three enzymes were involved in the process: Tyrosine Hydroxylase, Aromatic L- Amino Acid Decarboxylase (AADC) and GTP Cyclohydrolase I. Hence the transduction of the genes of the three enzymes together were found to have a better effect on the symptoms as well as the production of dopamine, as was studied in rat models. The glial cell derived neurotrophic factor (GDNF) is one of the most important neurotrophic factors that helps in the survival of the dopaminergic nigrostriatal neurons and thus prevents their degeneration. It remains to be seen if GDNF can regenerate the axons of the nigrostriatal neurons.

The preclinical gene therapy studies in Parkinson's disease are mainly concerned with the selection of a proper vector for gene delivery; the optimum delivery vector for crossing the BBB; and the optimum delivery of gene within the target. The choice of adeno-associated virus, serotype 2 (AAV2) as the most abundantly used vector for gene therapy of Parkinson's disease has been due to the advantages it provides over other vectors like: Its neuron specificity and the prevention of evoking of immunological response against the encoded transgene, its clinical safety, and its large scale production by commercial entities. The other virus vectors used safely for the gene therapy are Lentiviruses (LVs) vectors, Herpes Simplex Virus-1 (HSV-1) vectors, etc for their specific advantages. Other non-viral vectors have also been used such as liposomes as they are devoid of any immunological effect within the body compared to the viral vectors. The introduction of the neurotrophic factors by gene therapy has been studied only in rat models and not in human parkinsonian models. Hence, it needs to be translated effectively for the use of NTF gene therapy in Parkinson's disease patients. Thus, Gene therapy can provide to be a better course of treatment in patients who are in advanced stage of Parkinson's disease and have become non-responsive to medicines, etc. The future of gene therapy for Parkinson's disease is bright once the complete mechanism of the development of Parkinson's disease in majority of the patients is studied extensively.
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#2
Parkinson’s disease (PD) is a common neurodegenerative disorder that will assume increasing clinical importance in an ageing society, with an average age of onset between 60 and 65 years, but a peak incidence is found between the ages of 70 and 79 years. The specific incidence is dependent on the age structure of the population studied and is difficult to assess precisely but is around 17 per 100,000 according to a systematic review in this area.

The use of gene therapy to treat PD necessitates the use of a suitable method of delivery for the synthesised nucleic acid—viral or nonviral. The choice of vector greatly influences the technique used for delivery, as a peripherally administered vector must be able to cross the blood-brain barrier with an acceptable degree of tissue specificity. Alternatively, the surgical techniques used for deep brain stimulation can be harnessed to deliver the vector directly to a specific brain region.Nonviral techniques are technically and conceptually more straightforward but are less well suited to treating a chronic neurodegenerative disorder such as PD, due to the short duration of gene expression that is typically achieved. Low transfection rates mean that experiments using nonviral vectors have often used multiple dose regimens. This poses particular problems for translation to human studies if repeated intracerebral injections, with their associated risks, are needed to achieve a meaningful clinical response. This approach may still prove effective, as seen in a recent study using the human glial cell-derived neurotrophic factor (GDNF) gene and a neurotensin polyplex nanoparticle vector in an animal model of PD, finding that a single intracerebral injection of the agent may prove sufficient to induce a biochemical and functional response. Other nonviral vector studies in animal models of PD have incorporated region-specific ligands in order to maximise tissue specificity using intravenous vector administration. For example, one group has used Trojan horse liposomes and a monoclonal antibody to the transferrin receptor to facilitate transport across the blood brain barrier of a peripherally administered therapeutic plasmid containing DNA for GDNF. They also incorporated the gene promoter for tyrosine hydroxylase (TH), a key enzyme in the synthesis of dopamine, to restrict expression of the transgene to catecholaminergic neurons.Viral vectors, derived from either DNA or RNA viral vectors, are generally considered to be a more practical approach, with the potential to cause long lasting gene expression via episome formation or DNA integration into the host genome. A range of different types of viruses, each with different properties and advantages, have been exploited in the search for a suitable vector for gene therapy in PD. These are detailed below, with particular attention to adeno-associated viruses which comprise by far the largest category of vectors used in clinical trials to date.
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#3
The good news in the treatment of Parkinson’s disease is that the vaccines for Parkinson’s disease had entered successfully into first phase of clinical trials & hopefully will be in market soon upon passing remaining two clinical trials. These are therapeutic vaccines for treatment of Parkinson’s disease, chronic human disorders including neurological condition and even cancers.
The underlying molecular cause of the disease is a protein called alpha-synuclein. Normally this protein is found throughout the neocortex, hippocampus, substantia nigra, thalamus and cerebellum, although its precise function remains unknown. Importantly, this protein is very unusual and it does not fold up like the majority of proteins. Its unfolded appearance means that it is particularly susceptible to getting tangled up and forms protein aggregates within brain cells, thus affecting cell death occur. The formation of protein aggregates results in brain disorders, including Alzheimer’s disease and Creutzfeld-Jacob disease.
Discovering the protein aggregates role in brain diseases, therapeutic vaccination might therefore represent a promising future treatment for several neurological conditions. Therefore these vaccines target alpha-synuclein protein and currently in trials, namely PD01A.
The results are expected in July 2014 and the funding Michael J. Fox Foundation and other regulatory authorities will assess the safety of the vaccine in both men and women with Parkinson’s disease.
Another research in this field carried out the first genome wide evaluation of variants of gene linked to Parkinson’s disease. And the initial results had shown that people with genetic variants in gene HLA, SNCA, RIT2 had higher than average risk of Parkinson’s disease. This invention is further helping in treatment of Parkinson’s disease.
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