Human Gene Therapy
Everybody carries about half a dozen defective genes. Many don't know this, unless someone they know is affected by a genetic disorder.(1) The genetics of many diseases are passed from one generation to the next by inheriting a single gene, such as Huntington's disease. Many other diseases and traits are influenced by a collection of genes.(4) About one in ten people has, or will develop, an inherited genetic disorder. Approximately 2,800 specific conditions are known to be caused by defects, or mutations, in just one gene. Most of us don't suffer any harmful effects from our defective genes because we carry two copies of nearly all genes. In most cases one normal ...view middle of the document...
It is not likely germline therapy will be tried on humans in the near future due to ethical problems and technical difficulties.(1)
In vivo gene transfer is the introduction of genes to cells at the site at which they are found in the body. Ex vivo gene transfer is the transfer of genes into viable cells that have been temporarily removed from the patient and are then returned following treatment.(6)
Foreign DNA can be injected into the cell, or its entry can be facilitated by various chemical or electronic ways, but these methods aren't very efficient. One requirement for gene therapy is that sufficient amounts of corrective DNA are delivered to enough cells to be therapeutically beneficial. An ideal gene delivery vehicle or vector would be able to enter a large number of cells and integrate its DNA into the host's chromosomes. Coincidentally, some kinds of viruses are perfectly adapted to do just that.(2)
Viral vectors can be split into different groups: retroviral vectors, lentiviral vectors, and adenoviral vectors. A few more are under investigation.(5) The principle of all these vectors is to remove the disease causing components of the virus and insert recombinant genes that will be therapeutic to the patient. The modified viruses cannot replicate in the patient, but do retain the ability to efficiently deliver genetic material.(4)
Retroviruses have a limitation because they are unable to infect non-dividing cells. This problem was overcome by the ex vivo gene transfer.(5) Richard Mulligan and his coworkers created a retrovirus capable of infecting cells and splicing a corrective gene into chromosomes. The problem with retroviruses is that scientists have no control over how many copies of the gene become integrated or where on the chromosome they insert. The vector's genetic load may be inserted into a different gene, disrupting its expression. It could also put a cell onto a path of cancerous growth if the gene integrates within the regulatory region of a gene responsible for controlling cellular proliferation. These must be considered, even though they are remote possibilities.(2)
Lentiviruses are a special type of retrovirus. The most notable is HIV. These viruses are able to infect non-dividing cells and can therefore be used for in vivo gene transfer. This system offers a targeted delivery and stable expression of the genetic material that is delivered.(5)
Adenoviruses can infect both dividing and non-dividing cells.(5) Like retroviruses, adenoviruses deliver their genetic load to the nucleus, but (except under rare circumstances) the genes do not integrate into the resident chromosomes. This relieves concern about random genetic integration, but it also means that the therapeutic gene is only temporarily active. The adenoviral vectors have to be repeatedly administered in order to maintain a steady therapeutic dose.(2) A disadvantage of adenoviral vectors is that the host is producing an immune response. This kills...