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Review Article
Year : 2018   |  Volume : 10   |  Issue : 3   |  Page : 107-112  

Gene therapy as a potential tool for neurodegenerative disorders: Possible highlights

Raman Kumar Tripathi, Arti Rana, Shamsher Singh

Correspondence Address:Department of Pharmacy Practice, I.S.F College of Pharmacy, Moga, Punjab, India. Neuroscience Division, Department of Pharmacology, I.S.F College of Pharmacy, Moga, Punjab, India

Source of Support: Nil, Conflict of Interest: None declared

DOI: 10.4103/2231-4040.197331


Gene therapy is the transmission of genes into the patient to treat the illness. Gene can be transferred through somatic and germline techniques. In the somatic type of gene therapy, the genes are transmitted in the germ cells or stem cells whereas in germline gene therapy the genes are transmitted in the DNA or genome so it can pass to the offspring. The carriers used in this purpose are viral and non-viral vectors. Basically, these viral and non-viral carriers help to transfer the genes which further show its expression either by synthesizing proteins or causing mutation of DNA. Gene therapy is used in the cure or management of monogenic disorders and polygenic disorders; moreover, it is also a potential target for neurological disorders like in Alzheimer disease (AD) using gene therapy it is possible to inhibit, the progression of amyloid-beta peptide, a protein which causes amyloid plaques. Similarly, in Parkinson disease, the transfer of Neurturin, an analog of glial cell line-derived neurotrophic factor helps in survival of the dopaminergic neurons. In Huntington’s disease (HD), ASOS is used in the gene silencing which forms the protein known as Huntingtin. The HD may also be cured by the Casper cas 9 therapy. It would edit the DNA so that it will not make Huntingtin protein by transcription, thus treating the disease. By using this technique it’s useful to treat various disorders as genetic predisposition or in which the available drugs are unable to prevent or treat such problems as neurological and some of the non-neurological.

Keywords: Alzheimer disease, Crispr Cas9 Therapy, gene therapy, Parkinson’s disease

How to cite this article:
Tripathi RK, Rana A, Singh S. Gene therapy as a potential tool for neurodegenerative disorders: Possible highlights. Pharmaspire 2018;10(3):107-112.


Gene therapy is the transmission of genes into the patient to treat the illness. First, the gene therapy has got succeeded in 1990 for treating AshiDesiva who was suffering from adenosine deaminase severe combined immunodeficiency. The genes can interpret into proteins which can interfere with expression of the gene on the target or can precise the genetic mutations. Gene therapy can be helpful in the improvement of genetic defects, avoid cardiovascular diseases, remove cancerous cells, block neurological disorders, and even removal of infectious pathogens.[1] In gene therapy, the WBC of the patient is Singh3collected, maintained under suitable environment for mixing with a viral vector carrying gene. After mixing, the cell of the patient becomes genetically modified and has the gene with therapeutic activity. After that, the genetically modified cells are transmitted to the patient so it can produce the hormones or the proteins which are deficient or required by the body.[2]
The gene molecule is wrapped within a vector, which transmits the molecule which is required for the desired action inside cells.[3] There are two methods which can help in significant gene transformation, that is, somatic and germline. In somatic cell gene therapy (SCGT), the genes are transmitted into any type of cell other than a gametocyte, germ cell, or stem cell.[4] SCGT represent normal and clinical research, in which modified DNA is used to cure disease. In the US more than 600 trials have been performed using SCGT. Its main focus is on genetic disorders which can be in severe condition; this includes hemophilia, immunodeficiencies, cystic fibrosis, and thalassemia. [5] Such monogenic disorders are decent to treat with somatic cell therapy. The complete improvement of disorders mainly genetic and the standby of the number of genes are not yet possible. Only a few numbers of trials are in the very high success stages. Another is germline gene therapy (GGT), the germ cells are modified or changed by introducing the beneficial genes into their DNA or genomes.[6] The modification in the germ cells cans results that all the cell of the organism will have the altered gene. The GGT is heritable and passes to offspring. Australia, Germany, Canada, Israel, Switzerland, and the Netherlands have made a ban to GGT to use in humans for the reason that they do not have proper knowledge about risks to the offspring.[7] This therapy is beyond the FDA regulation because they have no federal control over human genetic modification.
These genes are transmitted using a suitable carrier which is called a vector, and the process is mediated by gene transformation. Two types of vectors are ideal for gene therapy that is viral and nonviral. In the viral vector technique, the viruses introduce their DNA into the host cell, they interfere with the host DNA and replicate it and make its copies.[8] Retroviruses are of those types. Scientists substitute the therapeutic genetic material (DNA) with virus’s genetic material. Some viruses have RNA, and gene therapy may also do in that way.[9] There are some viruses which were used for the gene therapy in humans such as retroviruses, herpes simplex, adenoviruses, vaccinia, and adeno-associated virus. Like the DNA and RNA of the viruses, the altered DNA can also be degraded into the host DNA, and it will become aneternal part of the host’s DNA in infected cells [Figure 1].[10]
In non-viral methods have some advancement over the viral methods such as they are having a large scale of production and also having low host immunogenicity.[11] However, they have less therapeutic effectiveness because they initially produce low levels of transfusions and gene expressions. Later technology helps to overcome this deficiency. It includes the injection of naked DNA (genetic material), electroporation, gene gun method, sonoporation, and magnetofection.[12] There is also use of lipoplexes, dendrimers, oligonucleotides, and inorganic nanoparticles in non-viral methods.

Injection of naked DNA

It is the simplest technique of the non-viral methods of gene therapy. The clinical trials are done with intramuscular injections of DNA plasmid. It occurs in success, but the expression is very low as equated to the other non-viral vectors.


It is a process which uses the high voltage’s short pulses to carry DNA through the cell membrane. The shock due to the high voltage causes the formation of the temporary pores in the cell membrane, which allows DNA molecules to pass over the membrane.[13] The efficacy of electroporation method is too high, and it works through a wide range of cell types. There is also having the high death rate of cells, so its use has become limited, including clinical application.

Gene gun

In this physical method, there is the bombardment of particles thus results in DNA transfection. In this technology, DNA coating is there with the help of gold particles, and it’s enveloped in a device which will help in penetration of DNA into the cells with force.


The ultrasonic frequencies are used in sonoporation method to transport DNA into cells.[14] The method of cavitation is due to the ultrasonic waves so that the DNA could transfer into the cells.


DNA is mixed with the magnetic particles so that the DNA can come in contact with the cell layer. It is done by a magnet which is placed under the culture medium dish.


It is used in the gene therapy to deactivate the genes which are involved in the pathological or disease condition,[15] for example, the use of antisense-specific to interrupt the transcription of the infected gene.


It is used in the construction of the synthetic vector in the gene therapy because the DNA should be protected from the damage so that it may give its therapeutic action efficiently [Figure 2].[16]

Gene therapy as therapeutic approach

Gene therapy in Alzheimer’s Disease (AD)

AD commonly referred as Alzheimer is a neurodegenerative pathological condition which is of chronic time starts slowly but become worse at the later stages. It’s the most common cause of dementia also called senile dementia. It affects more than 40 million people worldwide. Short-term memory loss is the most common symptom of the AD.[17] As the disease progresses, it causes mood swings, motivational loss, and language problems. The exact cause of the Alzheimer is not properly understood, and its molecular mechanism is hidden. Genetic factors or mutation in the genes is one of the crucial factors behind its pathophysiology.
The AD is considered as a synapses and neuron’s loss particularly in the cerebral cortex and some of the subcortical areas. The atrophy of the defected regions includes parietal and temporal lobe degeneration and few areas of the cingulate gyrus and frontal cortex. The nuclei of the brain stem such as locus coeruleus have also degenerated. The people having the AD with a mild type of cognitive impairment are suffering from reduced size of the specific regions of the brain, these studies are done using MRI and PET. The microscopy of the people’s brain who is having Alzheimer can show a clear image of neurofibrillary tangles and amyloid plaques. Plaques are condensed, typically insoluble deposits of cellular material outside and beta-amyloid peptide and around neurons. The masses of the microtubule-associated protein tau are neurofibrillary tangles which are hyperphosphorylated and gather inside the cells. Some adults develop plaques as the aging process, and Lewy bodies are common in the patients with the AD. The enzymes exert its action on the amyloid precursor protein and cut it into the fragments; these beta-amyloid fragments combine to form senile plaques in the AD. Scientists have effectively inhibited a gene which can cause Alzheimer’s, and it can be done using a new technique to deliver drugs directly to the brain.[18] They have used exosomes, as a drug carrier to carry the medications into the brains of mice in the trials. They have targeted the exosomes to carry particular into the brains, for example, Beta-secretase 1, a gene which develops a protein linked to Alzheimer’s disease. Exosomes can transfer the specific cargoes to the brain cells, so this technique is very useful. The problem with this is that it is not tested on human beings. Neurotrophic factors are proteins that may promote the cell growth so that it can develop and provide protection or act as a neuroprotective in some neurological disorders, both in the central nervous system and peripheral nervous system that makes it ideal for the gene therapy. In London, researchers from Imperial College in research have established a gene therapy that has gain success to slow down the progression of Alzheimer’s disease in mice.[19] To treat the disease condition, scientists made a modified virus using a lentivirus vector so as to target specific cells. These modified viruses contain a gene called Peroxisome proliferatoractivated receptor gamma coactivator 1 (PGC1)-alpha, which prevent the formation of an amyloid-beta peptide, a protein which causes amyloid plaques. The patient with AD has the amyloid plaques and can cause brain cell death. The aggregation of amyloid plaque in AD reduces cause death or cortical hippocampal neurons. In one of the pre-clinical study, the mice treated with the modified virus carrying gene were successfully recovered.[20] The results have shown that the mice with the PGC1-alpha gene have produced very few or some amyloid plaques as compared to the untreated mice that had multiple plagues after 4 months. In Lund University in Sweden, it has been studied that the gut bacteria are also responsible for the progression of AD.[21] It can also be used to avoid and treat the disease in further studies [Figure 3].[22]

Gene therapy in Parkinson disease (PD)

In PD the degeneration of the dopaminergic neurons in substantia nigra affects the normal coordination. The symptoms might include difficulty in walking, shaking, slowness of movement and thinking, and behavioral problems. In the advanced stage of disease, dementia could also be there.[23] The causes include both the genetic and environmental factor. It is adult onset disease. There is a high risk in those peoples who are in exposure to the pesticides or other environmental toxins. Other than this chronic smokers or having tea and coffee are having less risk for Parkinson disease.[24] In this disease, the motor dysbalance results from the neuronal deaths in the substantia nigra, a part of midbrain that relies on dopamine production. Growth factors or nerve growth factors are the major substances to support the normal functioning of the adult brain. It also protects the death of the neurons and stimulates the cell functioning in the animal models having diseases such as the AD, PD, and ALS. The transfer of growth factors such as Neurturin and glial cell line-derived neurotrophic factor in the brain of human can helps to improve motor coordination in PD. In the previous few years, some of the studies have utilized these factors for enhancing dopaminergic neuronal survival or to prevent their degeneration.[25] The use of in vitro techniques for culturing dopaminergic neurons has also gained success through synthesizing there combinant form of the protein that is a neurotrophic factor. This also helps in prevention of apoptosis of motor neurons which are induced by axotomy (cutting of axons). Direct administration of growth factor into any area of can produce toxicity. Hence, for specific targeting, gene delivery is an effective gun which could help to achieve target based delivery of proteins. The utilization of these techniques safely reduces to inject the drug into brain instead program the neurons to make drug using a genetic code (DNA).[26] Sharon Jukela was a PD patient and she was in very bad condition.[27] Medicines are giving her relief, but a lot of side effects were there.[28] After that, she offered for a Clinical Trial at Stanford Medical Centre by looking at the effectiveness of the treatment of gene therapy [Figures 4 and 5].[29]
Nowadays, VY-AADC therapy is running under clinical trials in which AADC gene is directly targeted to brain cells in putamen region. In this therapy, patients are challenged with standard care treatment that is through converting levodopa into dopamine. In one of the cohort study carrying bilateral injections of VY-AADC01 in the putamen region has improved their motor function. After this study, there was the reduction of daily oral levodopa standard care therapy of about 10% of the patients.

Gene therapy in Huntington’s Disease (HD)

It is an inherited disorder which affects basal ganglia, Produces Jerky body movement the advancement of the disease. Usually, the disease persists in age between 30 and 50 years but 8% of the cases are under 20 years. It’s affecting 30,000 people and 1,50,000 having chances of HD.[30] They also have changes in mood and behavior such as depression which increases the risk of suicide. It is inherited, but 10% of the cases records from mutations. It is initiated by a gene known as huntingtin. The expression of huntingtin gene is present in every mammalian cell. It interferes in the functioning of transcription, intracellular transporting and cell signaling by interacting with their proteins. Huntingtin is also associated with the embryonic development in animals. The mutated gene by doing damage to the ubiquitinprotease system activates the caspase which is a type of enzyme having a role in catalyzation of apoptosis. It is also responsible for the controlling of the production of the brain-derived neurotrophic factor that is having a role in the protection of neurons and regulates neurogenesis, and it prevents the programmed cell death thus acts as an anti-apoptotic agent. It also functions as the facilitator of the synaptic transmission and vesicular transport and controls neuronal gene transcription. The increased expression of huntingtin leads to the decrease of the mutant huntingtin and survival of brain cells are improved, whereas the reduced expression of huntingtin will result into the more presence of mutant huntingtin. The disease condition is not due to the inadequate production of huntingtin, but it is due to the increased toxic functioning of mutant huntingtin in the body.
The damage of the brain cells results from the spreading of cytosineadenine- guanine triplet which repeats in the genetic coding of huntingtin protein. The huntingtin is mainly found in the brain and the testes and also found in lungs, liver, and heart.[31] The people who are having HD have the same type of mutation this gives an aim to target research at ASOs ends and try to all approaches to shutting up the genes. ASOs are the drugs which can modify DNA structure and are useful to down suppress certain genes. Interstimulus intervals- Huntington (ISIS-HTT) Rx is the drug developed by the same people ASOs, so the mice have been successfully treated in the trials which are having HD.[32]
The results of human trials are also good. First of all, the ISIS drug targets the genes which are responsible for the disease and thus silencing them. The problem is that the drug is inserted into the cerebrospinal fluid around the brain. It should cover all parts of the brain, but it is not finding its way to the striatum which is the part of the brain which is most damaged by the disease. The use of viruses in the silencing of the gene is also done. The virus invades and infects cells to send the signals or messages to the brain to stop the formation of the mutated HD gene.[33] The virus should enter into neurons to completely be successful in this process, but the thing is unsuccessful. The editing of the huntingtin gene can also treat the HD.[34] This can be achieved by the Crispr Cas9 Therapy which uses gene therapy to deliver endonucleases which can be manipulated to cut DNA. It has to create a proper viral vector which could carry the genomic Crispr Cas9 instructions and would be able to pass the blood-brain barrier. The new viral vector has to be made by combining the properties of various vectors by pseudotyping this would have specific envelope proteins to correspond to the receptor sites on the blood-brain barrier.[35] After then, vector would enter into the brain through receptor gated endocytosis. When the Crispr Cas9 Therapy will work, then the cassadine endonucleases would be guided to the extra repeats in the DNA sequence and cut out the extra repeats. This therapy can cure the inherited disorders [Figures 6 and 7].[36]



Gene therapy is a useful tool with great efficacy and fewer side effects as compared to the other medication or technique. According to the concept of gene therapy, the various types of genetic neurological disorders can be cured such as AD, PD, and HD. In the AD, the PGC1- alpha gene is used to prevent the development of amyloid plaques whereas in PD the neurturin growth factor is helpful and in case of HD, the ASOS gene silencing and Crispr Cas9 Therapy is used in the inhibition of the formation of huntingtin protein.

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