10-05-2012, 04:35 PM
(This post was last modified: 10-05-2012, 06:07 PM by Administrator.)
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.
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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