Gene Therapy for Parkinson's Disease

Parkinson's disease (PD) is decribed as loss of dopaminergic neurons that located at the substantia nigra. PD causes changes in balancing both expiratory and inbitory pathways of brain system thus affecting movement control by the brain.

By medication approaches in mainstream therapy is that taking dopamine repalacement is commonly used. Other than that, surgical treatment to improve motor function and increasing brain's cell activities also have been done to cure PD or reduce PD's symptoms (Deep brain stimulation).

For medication ( taking drugs) approach, patients should be respond well for number of years. But, for a long term treatment, " wearing off" could possibly happened as it will develop after years of treatment with levadopa (dopamine replacement)

Gene Therapy (GT)

GT approach have potential advantages that could be useful in treating PD. By concept, GT approach will make the cell to produce protein that they do not normally produce which genes was inserted and provide specific genetic order or instructions for cell to produce desired protein thus enhance the possibility of curing PD. The protein produced are formed in normal cellular division and proliferation and give benefit of less causing side-effects.

More than that, GT could target specifically to it's target location where the treatment are needed. GT also does need or relying on any mechanical or electrical method which make it is the best way to curing PD and produce less side-effects.

The treatment strategy

Treatment strategies combination are needed which protein and target location of the treatment should be identified. For a simple example :

1. A strategy to improve the delivery dopamine to the region of the brain of PD's patients
2. In the other hand, one more strategy was done at the same time to provide growth factor support to brain regions that could help recover damaged nerve cell and eventually will reduce PD's progressions.

GT relies on transporting DNA into targeted brain's cell. A vector was needed as to protect and transport the DNA so that it can be delivered at exact location of target site. For this case, most common vectors are used which are adeno-associated virus type 2 , adenovirus, lentivirus and herpes virus. The selected virus was used as these type of virus does not have any ability to reproduce themselves and did not causing disease.

Adeno-associated virus type 2 (AAV-2) is one imprortant type of virus which it carries DNA only to neurons and once inside the brain, it was proven to efficiently carry DNA to neuron that affected in PD. Most GT studies shows that they will use AAV-2 as vector

Once vector have selected, the treatment should be administered on relevant area of brain (Basal Ganglia).

Basal Ganglia are part of interconnected deep brain area that involves in control for movement. The pathways of Basal Ganglia are connecting the sunstantia nigra to the putamen ( area dopamine is released) and then towards globus pallidus . GT for PD have been administered by drill a hole in each side of patient's skull and injecting the  viral vector in appropiriate doses int the targeted brain region using image-guided surgical techniques.

The treatments usually performed in standard operate room / in radiology suites. The recovery will take time in fast manner where patients usually discharged from ward in 1 / 2 days of GT.

Approach of GT for PD

1.  Increase dopamine production in specific area of brain. 
2. Adjust the pathway of ecitatory and inhibitory of the patient's brain.
3. Using growth factor to protect the progression of PD

                      Gene therapy for PD by Weill Cornell Brain and Spine Center

                        Gene therapy for reversing Parkinson Disease by CBS news

Overview of Gene Therapy 2.0

History of Gene Therapy

• Mendel Experiment in 1865 introducing law of heredity where prediction of inheritance are found.

• Avery and his co-researchers in 1940s found a genetic information that encoded by specific DNA

• Watson & crick suggest that DNA is in double helix formation and it can replicates and will inherit complex genetic information

• Nirenberg in 1961 deciphered triplets of genetic code

• First gene therapy journal was published in 1990, Human Gene Therapy
• Ashanti De-Silva, 4 years old with ADA-Deficient Severed Combined Immunodeficiency was treated with gene therapy

• Alain Fischer was successfully cured by gene therapy for  SCID -XI  (bubble boy)

Gene Therapy

1. Corrected genes are inserted into genome of patient's DNA to replace the "false" gene that can cause disease. 
2. A vector (eg. virus) that have been genetically altered  can help deliver the therapeutic gene to the patient's target cell to disrupt the cancerous cell growth
3. Virus genome have been manipulated to remove gene that causing disease & inserting a " correct" ones
4. Viral vector will infect target cells that happened to be in various parts of patient's body and organs

Limitation of Gene Therapy

1. Patients should be undergo various treatment / therapy in order to fully recoovered
2. The stimulation of immune response could jeopardize the gene therapy effectiveness
3. Vector that have been chosen could posses toxicity, and induce inflammatory response during therapy
4. Multi gene disorder eg. alzheimer and heart disease are difficult to treated

Post-natal Gene Therapy

Correction of deleterious effects of genetic disease which can be treated for a long term integration of gene sequences into patient's genome. Commonly, retrovirus vector could be used to correct inherited monogenetic disorders.

Type of post-natal Gene Therapy

• Replacement GT
• Gene addition

Pre-natal Gene Therapy

Targeting genetic disease that requires life-long correction of genes

Objectives of Pre-natal GT are: 

• To avoid early onset manifestation of disease that could threat life
• To obtain permanent corrections by stable transduction of cell population
• Avoid immune response againts therapeutic vectors .

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Overview of Gene Therapy

Gene Therapy is a method to introduce DNA / RNA of specific gene into target cell of patients that found to be lacked of that partcular gene in order to correct / disrupt it's pathological process to prevent it to become worsen.

Most common approach used are the replacement/ supplementation of that mutated gene with a correct copy of gene to restore their specific functions.

Strategies of Gene Therapy (GT)

• Replacement GT
• Knock-out GT
• Suicide GT
• Immuno-modulatory GT

Replacement GT

Method of GT that replace the mutated gene in order to keep normal cell growth and division under control with corrected (normal) copy of gene.

eg. Gene coding for p53 have to be replaced in order to prevent gene mutation in cancer that could lead to cell apoptosis, cell death and development of tumor.

Limitation : Large no. target genes have been known to maintain malignancy, not enough cancer cell that could be transduced are limiting the curing process of tumor.

Knock-out GT

GT that targets products of oncogenes in order to inactivate and reduce it's cellular proliferations

eg.  Deliver modified / mutant oncogene to negate / counter-attack the effects of the cancer- causing oncogen (bad) thus inhibiting the oncogene proliferation processes.

Bystander effects may happened as the death of more cells are occur than the no. it have been transduced. (for Knock-out and Replacement GT)

Suicide GT

Transduction of a gene that eventually will transforms into a non-toxic form of drugs / pro-drug into a toxic substances.

Immuno-modulatory GT

GT that inducing cellular immune response to tumor cells. Mechanism that been used are injecting a suspension of irradiated tumor cell that already been transduced with a cytokine gene to skin of patients to stimulate response against tumor-specific antigens (vaccinating against cancer).

principles : 

1. Tumor cell removed from patient's body modified with cytokine gene
2. Transplant the cytokine gene back into patients ( right after the cell have been irradiated to prevent further cell division) 
3. The patient's anti-tumor immune response will be activated.

How we insert " good" gene in patient's body?

By the help of VECTORS

The most used vectors in GT are virus vectors as viruses viruses have evolved to have function to infecting cells with specificity & efficiency. It can transfecting their own DNA into the genome of host cells. In this case, it would allows viruses to produce many new viral particle during period of synthesis of the cell itself.

Which virus is the best?

• Virus that transfer well the genes to cells
• Virus that recognizes and infects specific cells
• Virus that alter the cell's DNA permanently 

Example of virus that have been used in GT :

Retrovirus

Adenovirus

Lentivirus

Poxvirus

Herpes virus

Strategies of Trans-gene delivery

Ex-vivo - Cells are removed from body-transgene delivered-cells cultured--cell return to body

In-vivo - Trangene are delivered directly into host ( cell do not remove from patient's body)

                                  Ex vivo and In vivo of GT by Pedro Laurenco

Targeted cells could be both healthy and cancerous cells.

Eg. targets Healthy cells - replacing mutated gene with a corrected gene

Eg. targets Cancer cells - Cancer cells targeted by gene to destroy the cells  (suicide gene)

                                Gene Therapy principles by Shomu's biology

Problems of GT 

• More efficient ways to deliver the genes to the patient's DNA/ RNA should be identified
• Vectors that could focus specifically on target cells should be developed and produced
• Vectors should be always ensured to successfully insert corrected gene to target cells
• Delivering of gene to target cells in DNA/ RNA should be efficient and focused
• The transplanted gene should be always ensured to specifically controlled by patient's own physiological signalling

Future of cancer GT

• Competence of GT will be increased by transduction
• Advances of technique in order to induce expression of transduced gene
• Advances of method of inducing anti-tumor responses at systematic level of responses
• Advances of vectors study for enhance vector's specification and  quality of works
• Andances in induction of cell death (apoptosis)

Introduction of Parkinson's Disease

Parkinson's disease is a chronic and progressive movement disorder. It comes from disorder of nervous system that may affects movement of muscle in the patient's body.

Parkinson's have led to malfunction and death of vital nerve cells (neurons) that located in brain specifically in area called substantia nigra. The dying neuron will produce dopamine ( a chemical that functioned to send message to part of brain that responsible in controlling coordination and movement of body). As progressing development of parkinson's disease, the amount of dopamine that have been produced in the brain seems decreasing and make the person to unable to control his/ her movement normally.  When the reason of loss of nerve cells in unclear, scientist thinks that parkinson's disease may caused by a combination of genetic and environmental factors.


Starting from tremors, parkinson's disease shows gradual symptom that that eventually will leads to slowing of movement and stiffness.

In the early stage of parkinson disease, the disease may not be recognized or detected by patient through little face expression changes. The gradual stages can be identified when arms of patient can not swing well and the patient's speech may affected as well,

In some cases, the doctor may suggest that the patient should undergo surgery to regulate certain regions of brains thus improving the symptoms that occur.

                                    Parkinson Disease & Dopamine by Dr. Prodigious

The symptom for Parkinson's Disease 

1. Shaking of parts of body. The shaking event may happened at parts of body when it is in rest motion. Usually involving fingers and hands where back and forth motion of thumb rubbing with forefinger are commonly known.
2. Muscle stiffness may occur at different part of body.
3. Stooped posture & impaired balance of body
4. Loss of unconscious movement such as swinging arms when walking, blinking and smiling.
5. Hard to writeby using hands.
6. Slowed movement as ability to move are reduced gradually as the stages of parkinson are worsening.
7. Speech of the patients may be changed as they will speaks more soft than usual, quick and hesitating in talking.

                                   Parkinson's disease by khana academy medicine

Parkinson's Disease Diagnosis

The significant symptoms of parkinson can be distinctive enough for a doctor to diagnose the patient in his / her office. There was no brain scan / blood test that can confirm the presence of the disease. However, if one does not having any response towards the drugs that specifically used to cure parkinson's disease, it still possible that the person may have another type of movement disorder that causing the same symptoms as parkinson's disease. 

The Treatment for Parkinson's Disease

Most treatment that have been done are objectively to restore the balance of neurotransmitter acetylcholine & dopamine by increasing the levels of dopamine by help of certain drugs. If the drug treatment makes the patient's disease worsen, a deep brain simulator implantation may subjected to the patient.

Medicine for Parkinson's Disease

1.  L-dopa.The drug will be metabolized by the body to create & produce dopamine. This drug should be taken as by giving dopamine directly to the patient does not affect the disease because of brain's defense system that blocking the direct dopamine from being used by the patient's system. Carbidopa will be taken by patient in order to suppress nausea and other side effects. The combination of L-dopa & carbidopa are called as Sinemet. If L-dopa is been taken alone ( no carbidopa ) , it is advisable to not taking it at same time when consuming foods that contain vitamin B-6 as it will interfere the effectiveness of the L-dopa.
2. COMT inhibitors( eg, tasmar & Comtan) are drugs that usually taken with L-dopa. The symptoms relief can be prolonged as it blocks enzyme activity that breaks down dopamine. Tasmar are rarely used as it is proven to cause liver damage.
3. MAO-B inhibitors also have function to block enzyme activity that can break down dopamine. It have been taken alone (in early parkinson's disease) or along with other drugs ( progression of disease)
4. Dopamine agonist is dopamine like drugs that directly imitates dopamine actual activity on the brain. It tends to replace the activity of original dopamin that significantly been reduced as parkinson's disease progressed.

Future Treatment for Parkinson's Disease

Rather than correcting the neurotransmitter imbalance by help of drugs, neurosurgeons & neurologists have found various steps of grafting cells that producing dopamine in the brain in parkinson's disease patients. This research are still in their early stages where stem cell research are playing important roles in this field.

By having surgical technique, a lesions in the globus pallidus / thalamus are created. These two are parts of brain that ultimately involved in parkinson's disease. This technique seems successful for years & been replaced by deep brain simulation (DBS). 

For DBS, a wire is placed deep inside the patient's brain in specific area depending on the symptoms that been produced by the patient's body. DBS will provide dramatic improvements in parkinson's disease treatment & one of successful therapy for tumor and rigidity effects.

Glial-cell derived nerve growth factor also been investigated to treat parkinson's disease & other neurodegenerative diseases. The nerve growth factor are produced naturally by patient's tissue throughout the body. Scientist have prove that injections of the substance can help preserve & restore nerve cell in brain & spinal cords and eventually will produce dopamine & help restoring muscle movements.

                                Deep Brain Simulation (DBS by Mount Sinai Hospital)

Living a Healthy LIFE

It is very important for us to maintain our daily exercise programme and stay socially active. In many cases of parkinson's disease, a weakening of social relations because of physical difficulties that have to be taken by the patients could lead to depression. Be aware of the symptoms and quickly seek for medical attention for prevent the disease from becoming more severe. Preventing are more better than curing. Take attention in campaign that can create awareness of society towards parkinson's disease so that everyone can live a healthy life. :)