Gene Therapy in Parkinson’s Disease

Significant research and several clinical trials have been done regarding the efficacy of gene therapy in Parkinson’s disease (PD). While many claims have been made involving numerous wonder cures for PD, gene therapy may hold the exciting possibility of not only delaying disease progression but also halting it completely. Limitations in the efficacy and success of various medical and surgical procedures, have stimulated the scientists all over the world to explore the possibility of Parkinson’s cure through gene therapy.

Parkinson’s disease is a progressive neurodegenerative disorder where there is steady loss of brain cells of the substantia nigra involved in the production of the chemical neurotransmitter dopamine. The gene therapy approach has a distinct advantage as it might offer new hopes to preserve or restore the damaged dopaminergic neurons through the use of brain growth factors. It might also alternatively increase the production or release of the important enzymes in the synthesis of dopamine neurotransmitter. Refer to Parkinson’s Disease Brain Chemistry for more information.

Medication with levodopa and other related drugs are the mainstay of treatment which can only offer temporary relief but no lasting cure. Research focused on developing other methods, such as gene therapy, which can help to treat or modify the disease process more effectively is continuously being done.

What is gene therapy?

Simply, gene therapy involves the introduction of healthy genes into a person with defective genes which may be the cause of a certain medical problem, such as Parkinson’s disease. The healthy genes are expected to work on the target cells and cause changes in them that will trigger them to resume producing dopamine and thus reduce symptoms or altogether halt the progress of PD. In other words, gene therapy aims to treat the disease by genetic modification of of the group of cells that are functionally impaired or are capable of rectifying the disease symptoms.

Gene  therapy is applicable at two levels. In vivo gene therapy involves the direct genetic modification of the cells inside the body. On the other hand, ex vivo gene therapy focus on the genetic modification of the cells in a culture medium at laboratory level, i.e outside the body, followed by implantation of the final product into the targeted organ in human body.

Gene therapy is used to insert genes, which provide specific genetic instructions to the cells to produce the desired protein. It is usually targeted to a particular area in the brain, which requires the treatment, thereby reducing the chance of unwanted side effects. For this new therapy to be acceptable, the benefits should be long-term and without other complications or side effects. The genes, which are to be inserted are carried on by special transporters known as “vectors”.


Virus Carriers for Gene Therapy

During gene therapy, genetic material is transferred to the recipient using a vector virus which is considered not to be harmful to humans. The vector virus must have lost its ability to reproduce. Either recombinant adeno-associated virus type 2 (rAAV2) or lentivirus vectors have been used in clinical trials in an attempt to trigger :

  • Increased dopamine levels via increased neurotransmitter production.
  • To modulate the excitatory and inhibitory pathways of the brain.
  • To use brain proteins, termed as growth factors
  • Modulation of the neuronal phenotype.
  • Neuroprotection.

Increased dopamine production may be achieved by means of the first two methods, by direct delivery of genes involved in neurotransmitter production (amino acid decarboxylase, tyroxine hydroxylate and GTP (guanosine triphosphate) cyclohydrolase

To bypass the degenerating nigrostriatal pathway, rAAV2 is used to transfer glutamic acid decarboxylase (GAD) to the subthalamic nucleus (STN). GAD acts as a catalyst in the production of a neurotransmitter called GABA, which acts as a direct inhibitor on the overactive cells in the STN.

Protection of the degenerating nigrostriatum (neuroprotection) is hoped to be achieved by striatal delivery of rAAV2 containing the neuroprotective gene neurturin.

The adeno associated virus type 2 (rAAV-2) has a couple of advantages as its is being able to carry genetic material only and directly to the neurons and not to the other supporting structures of the brain. Also, once this vector enters the brain, it is able to carry genetic material to the dopaminergic neurons affected in Parkinson’s disease. It is the most commonly used virus vector in majority of the gene studies carried out for Parkinson’s disease. Also, the role of lentivirus as the vector in gene therapy is crucial too. Because of its larger size and capacity, it is used when more than one gene is to be carried and inserted at the desired cellular level.


The procedure of Gene Therapy.

After the selection of desired genes and suitable vectors, the treatment is to be administered to the relevant and involved area of the brain. So far, the studies for Parkinson’s gene therapy have been directed to a particular region of brain called as Basal Ganglia. This region is predominantly involved with the muscle control action.

Uptil now, the procedure for administration of gene therapy to Parkinson’s patients employs a drilling of hole on each side of the skull. This is followed by injecting the combination of vector virus containing the desired gene in a calculated dosage, to the desired brain region that is the nigro-striatal tract, where the dopamine neurons are genetically damaged, under observation of surgical image guiding technology. The patients are usually discharged after 1-2 days of the procedure.


Stem Cells and Gene Therapy for Parkinson’s Disease

Research continues so as to find newer and more effective means of delivering genes and sustaining their effects. Using stem cells as a means of introducing genes is being studied. It is claimed that hematopoietic stem cells from blood and bone marrow can be genetically transformed outside the body and then re-introduced into the patient so as to eliminate the necessity of repeated introduction of gene into the patient but results have not been too promising. Embryonic stem cells (because of their versatility) may be a better alternative to hematopoietic stem cells but ethical issues may have to be looked into.

Although studies done so far seem promising regarding gene therapy as a means of treating PD, longer follow-up still needs to be done to determine if improvements can be sustained over a prolonged period. It is to be hoped that gene therapy will be more effective and less invasive than the current medical or surgical treatments available, with less side effects.


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