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Gene Therapy
Introduction
- It is introduction of new genetic material into cells of organism for therapeutic purposes.
- It is a treatment modality where normal genes are inserted into autologous hematopoietic stem cells.
- These stem cells are subsequently transplanted back into the patient.
- Expression of inserted gene results in cure of disease.
- Genetic material which is not integrated into host genome, is sometimes expressed from episomal DNA. In such situation, expression of gene is lost after few cell divisions. This is unsuitable for any application that needs long term expression of a gene. But, in this case, there is no risk of insertional mutagenesis.
Prerequisites for gene therapy
- Knowledge of the abnormal gene sequence responsible for disease phenotype
- Corresponding normal gene sequence available
- Cells responsible for disease phenotype must be identified and accessible for genetic manipulation
- Availability of means of introducing and expressing the correct gene sequence in the cells such that the disease phenotype can be reversed.
Vector used in gene transfer
- They are modified viruses which are unable to produce progeny virus except in specific cell lines.
- These cell lines are genetically modified to complement the replication defect in virus vector
- Ex: EB1 deleted adenovirus is capable of replicating in p53 deficient cells.
Vector | General information | Advantages | Disadvantages |
MoloneyMurine Leukemia virus (Retrovirus) | The packaging system and long terminal repeats are retained, while structural and replicative genes (gag, pol and env) are replaced by gene ofinterest | Stable integration into dividing cells. Minimalimmunogenicity Stable packaging system | Low titres Limited insert size Risk of silencing Risk of insertional mutagenesis
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Adeno associated virus | DNA contains 2 inverted terminal repeats, which have site specific integration in chromosome 19. | Integrates diving cells Infects wide range of cell types | No stable packaging cell line Very limited insert size. Induction of antibodies on repeated use. |
Lentivirus |
| Integrates into both dividing and non-dividing cells | Highly immunogenic |
Adenovirus | Being tried in CFTR gene transfer to respiratory epithelial cells in cystic fibrosis Factor VII and VIII gene transfer to hepatic cells. | Infects wide range of cell types Infects non-dividing cells High titres Accepts 12 to 15kb DNA inserts | Highly immunogenic Non integrating |
Herpes virus |
| High titres Accepts large DNA inserts | No packaging cell lines Non-integrating Difficult to scale up for human use May be cytotoxic to target cell |
Liposomes |
| Easy to prepare in large quantity Virtually unlimited insert size Non-toxic and can be given repeatedly | Inefficient in entering the cell Non integrating |
Gene gun technique | DNA is coated onto colloid gold particles and is driven at high speed by gas pressure into the cell. |
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Applications
- Hemoglobinopathies- Sickle cell anemia, thalassemia- Insertion causes switching of beta chain to gamma chain synthesis.
- Hemophilia
- Primary immunodeficiency diseases- X linked SCID, Wiskott Aldrich syndrome
- Malignancies-
- Adenovirus in which E1 region is replaced by human wild type p53 expression cassette. Ex: Gendicine for treatment of head and neck squamous cell carcinoma.
- Others- Goucher disease, Fanconi anemia
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