The general approach of gene therapy is nothing more than an extension of the technique for clone selection by functional complementation (Chapter 12). The functions absent in the recipient as a result of a defective gene are introduced on a vector that inserts into one of the recipients chromosomes and thereby generates a transgenic animal that has been genetically cured. The technique is of great potential in humans because it offers the hope of correcting hereditary diseases. However, gene therapy is also being applied to mammals other than humans.
The first example of gene therapy in a mammal was the correction of a growth-hormone deficiency in mice. The recessive mutation little (lit) results in dwarf mice. Even though a mouses growth-hormone gene is present and apparently normal, no mRNA for this gene is produced. The initial step in correcting this deficiency was to inject homozygous lit/lit eggs with about 5000 copies of a 5-kb linear DNA fragment that contained the rat growth-hormone structural gene (RGH) fused to a regulatorpromoter sequence from a mouse metallothionein gene (MP). The normal job of metallothionein is to detoxify heavy metals, so the regulatory sequence is responsive to the presence of heavy metals in the animal. The eggs were then implanted into pseudopregnant mice, and the baby mice were raised. About 1 percent of these babies turned out to be transgenic, showing increased size when heavy metals were administered in the course of development. A representative transgenic mouse was then crossed with a homozygous lit/lit female. The ensuing pedigree is shown in . We can see in that mice two to three times the weight of their lit/lit relatives are produced in subsequent generations, with the rat growth-hormone transgene acting as a dominant allele, always heterozygous in this pedigree. The rat growth-hormone transgene also makes lit+ mice bigger ().
The rat growth-hormone gene (RGH), under the control of a mouse promoter region that is responsive to heavy metals, is inserted into a plasmid and used to produce a transgenic mouse. RGH compensates for the inherent dwarfism (lit/lit) in the mouse. RGH (more...)
Transgenic mouse. The mice are siblings, but the mouse on the left was derived from an egg transformed by injection with a new gene composed of the mouse metallothionein promoter fused to the rat growth-hormone structural gene. (This mouse weighs 44g, (more...)
The site of insertion of the introduced DNA in mammals is highly variable, and the DNA is generally not found at the homologous locus. Hence, gene therapy most often provides not a genuine correction of the original problem but a masking of it.
Similar technology has been used to develop transgenic fast-growing strains of Pacific salmon, with spectacular results. A plasmid containing a growth-hormone gene placed next to a metallothionein promoter (all derived from salmon) was microinjected into salmon eggs. A small proportion of the resulting fish proved to be transgenic, testing positive when their DNA was probed with the plasmid construct. These fish were on average 11-fold heavier than the nontransgenic controls (). Progeny inherited the transgene in the same manner as the mice in the earlier example.
Effect of introducing a hormone transgene complex with a strong promoter into Pacific salmon. All salmon shown are the same age. (R. H. Devlin, T. Y. Yesaki, C. A. Biagi, E. M. Donaldson, P. Swanson, and W.-K. Chan, Extraordinary Growth, (more...)
Perhaps the most exciting and controversial application of transgenic technology is in human gene therapy, the treatment and alleviation of human genetic disease by adding exogenous wild-type genes to correct the defective function of mutations. We have seen that the first case of gene therapy in mammals was to cure a genotypically dwarf fertilized mouse egg by injecting the appropriate wild-type allele for normal growth. This technique () has little application in humans, because it is currently impossible to diagnose whether a fertilized egg cell carries a defective genotype without destroying the cell. (However, in an early embryo containing only a few cells, one cell can be removed and analyzed with no ill effects on the remainder.)
Two basic types of gene therapy can be applied to humans, germ line and somatic. The goal of germ-line gene therapy () is the more ambitious: to introduce transgenic cells into the germ line as well as into the somatic cell population. Not only should this therapy achieve a cure of the person treated, but some gametes could also carry the corrected genotype. We have seen that such germinal therapy has been achieved by injecting mice eggs. However, the protocol that is relevant for application to humans is the removal of an early embryo (blastocyst) with a defective genotype from a pregnant mouse and injection with transgenic cells containing the wild-type allele. These cells become part of many tissues of the body, often including the germ line, which will give rise to the gonads. Then the gene can be passed on to some or all progeny, depending on the size of the clone of transgenic cells that lodges in the germinal area. However, no human germ-line gene therapy has been performed to date.
We have seen that most transforming fragments will insert ectopically throughout the genome. This is a disadvantage in human gene therapy not only because of the possibility of the ectopic insert causing gene disruption, but also because, even if the disease phenotype is reversed, the defective allele is still present and can segregate away from the transgene in future generations. Therefore, for effective germinal gene therapy, an efficient targeted gene replacement will be necessary, in which case the wild-type transgene replaces the resident defective copy by a double crossover.
Original post:
Gene therapy - An Introduction to Genetic Analysis - NCBI ...
- Gene Therapy: Ethical Issues: Information from Answers.com [Last Updated On: February 6th, 2014] [Originally Added On: February 6th, 2014]
- Gene, immune therapy help cancer war [Last Updated On: April 10th, 2014] [Originally Added On: April 10th, 2014]
- Gene Therapy - Genetics Home Reference - Your guide to ... [Last Updated On: April 10th, 2014] [Originally Added On: April 10th, 2014]
- What is gene therapy? - Genetics Home Reference [Last Updated On: April 10th, 2014] [Originally Added On: April 10th, 2014]
- Gene therapy - Wikipedia, the free encyclopedia [Last Updated On: April 10th, 2014] [Originally Added On: April 10th, 2014]
- Gene Therapy PSA Dan Lesser Period 2 - Video [Last Updated On: April 15th, 2014] [Originally Added On: April 15th, 2014]
- Gene therapy basics - Video [Last Updated On: April 15th, 2014] [Originally Added On: April 15th, 2014]
- In vivo gene therapy - Video [Last Updated On: April 15th, 2014] [Originally Added On: April 15th, 2014]
- Ex vivo gene therapy - Video [Last Updated On: April 15th, 2014] [Originally Added On: April 15th, 2014]
- Broad Institute Gets Patent on Revolutionary Gene-Editing Method [Last Updated On: April 17th, 2014] [Originally Added On: April 17th, 2014]
- Gene Therapy - Video [Last Updated On: April 17th, 2014] [Originally Added On: April 17th, 2014]
- Mark Hamalainen: Gene Therapy - Video [Last Updated On: April 17th, 2014] [Originally Added On: April 17th, 2014]
- JFK - Gene Therapy for Brain Tumors - Video [Last Updated On: April 18th, 2014] [Originally Added On: April 18th, 2014]
- Fixing the Liver with New Gene Therapy (Brainstorm Ep178) - Video [Last Updated On: April 18th, 2014] [Originally Added On: April 18th, 2014]
- Gene Therapy | Buzzle.com [Last Updated On: April 22nd, 2014] [Originally Added On: April 22nd, 2014]
- Gene Therapy I - RCN Corporation [Last Updated On: April 22nd, 2014] [Originally Added On: April 22nd, 2014]
- Ricky Ashby Microbiology Podcast - Video [Last Updated On: April 22nd, 2014] [Originally Added On: April 22nd, 2014]
- Regrown nerves boost bionic ears [Last Updated On: April 24th, 2014] [Originally Added On: April 24th, 2014]
- Cochlear Implant Plus Gene Therapy Could Restore Hearing to the Deaf [Last Updated On: April 24th, 2014] [Originally Added On: April 24th, 2014]
- Scientists reverse memory loss in mice with Alzheimer's [Last Updated On: April 24th, 2014] [Originally Added On: April 24th, 2014]
- Bionic Ears Boosted by Gene Therapy and Regrown Nerves [Last Updated On: April 24th, 2014] [Originally Added On: April 24th, 2014]
- Study: Gene Therapy May Boost Cochlear Implants [Last Updated On: April 24th, 2014] [Originally Added On: April 24th, 2014]
- Gene therapy may boost hearing, study finds [Last Updated On: April 24th, 2014] [Originally Added On: April 24th, 2014]
- Pronounce Medical Words Gene Therapy - Video [Last Updated On: April 24th, 2014] [Originally Added On: April 24th, 2014]
- Gene therapy may boost power of cochlear implants, study says [Last Updated On: April 25th, 2014] [Originally Added On: April 25th, 2014]
- Gene therapy shows promise to help people regrow auditory nerve cells [Last Updated On: April 25th, 2014] [Originally Added On: April 25th, 2014]
- Cochlear Implant Also Uses Gene Therapy to Improve Hearing [Last Updated On: April 25th, 2014] [Originally Added On: April 25th, 2014]
- Gene Therapy May Enhance Cochlear Implants, Animal Study Finds [Last Updated On: April 25th, 2014] [Originally Added On: April 25th, 2014]
- Uniqure Gene Therapy Info. - Video [Last Updated On: April 25th, 2014] [Originally Added On: April 25th, 2014]
- Jean Bennett on gene therapy as a treatment for blindness - Video [Last Updated On: April 25th, 2014] [Originally Added On: April 25th, 2014]
- mice-science-AFPrelax-250414.jpg [Last Updated On: April 26th, 2014] [Originally Added On: April 26th, 2014]
- Cochlear implant enhances patient experience through gene therapy [Last Updated On: April 28th, 2014] [Originally Added On: April 28th, 2014]
- Gene therapy may help hearing [Last Updated On: April 28th, 2014] [Originally Added On: April 28th, 2014]
- Ethics of Gene therapy - Video [Last Updated On: April 30th, 2014] [Originally Added On: April 30th, 2014]
- Novel Financing For Gene Therapy Company [Last Updated On: May 1st, 2014] [Originally Added On: May 1st, 2014]
- Gene Therapy To Enhance Hearing - ABC Austrlia News - 2014 - - Video [Last Updated On: May 1st, 2014] [Originally Added On: May 1st, 2014]
- Biotechnology - GMO's & Gene Therapy - Video [Last Updated On: May 1st, 2014] [Originally Added On: May 1st, 2014]
- Cochlear Implant Gets an Upgrade with Gene Therapy - Video [Last Updated On: May 4th, 2014] [Originally Added On: May 4th, 2014]
- Gene therapy for haemophilia - Professor Amit Nathwani - Video [Last Updated On: May 4th, 2014] [Originally Added On: May 4th, 2014]
- Retrovirus in Gene Therapy - Video [Last Updated On: May 4th, 2014] [Originally Added On: May 4th, 2014]
- Regeneron, Avalanche To Develop Novel Gene Therapy Products In Ophthalmology [Last Updated On: May 5th, 2014] [Originally Added On: May 5th, 2014]
- Gene Therapy Used to Preserve Sight in Patients [Last Updated On: May 5th, 2014] [Originally Added On: May 5th, 2014]
- SCID gene therapy class - Video [Last Updated On: May 6th, 2014] [Originally Added On: May 6th, 2014]
- Gene Therapy using SMaRT - Video [Last Updated On: May 6th, 2014] [Originally Added On: May 6th, 2014]
- gene therapy video - Video [Last Updated On: May 9th, 2014] [Originally Added On: May 9th, 2014]
- Chronic Granulomatous Disease (CGD) - Video [Last Updated On: May 12th, 2014] [Originally Added On: May 12th, 2014]
- Gene Therapy (Breast Cancer) - Video [Last Updated On: May 12th, 2014] [Originally Added On: May 12th, 2014]
- Suicide gene therapy - Video [Last Updated On: May 12th, 2014] [Originally Added On: May 12th, 2014]
- Employment of gene therapy in depression (psychiatric disorder) - Video [Last Updated On: May 12th, 2014] [Originally Added On: May 12th, 2014]
- Gene therapy for blindness (2012) - Video [Last Updated On: May 12th, 2014] [Originally Added On: May 12th, 2014]
- AGRC1020 Video Presentation Gene Therapy restores colour vision in monkeys - Video [Last Updated On: May 12th, 2014] [Originally Added On: May 12th, 2014]
- gene therapy~3 - Video [Last Updated On: May 12th, 2014] [Originally Added On: May 12th, 2014]
- Gene Delivery System (In-vivo and Ex-vivo) HD - Video [Last Updated On: May 12th, 2014] [Originally Added On: May 12th, 2014]
- Spark Therapeutics to open headquarters in West Philadelphia [Last Updated On: May 14th, 2014] [Originally Added On: May 14th, 2014]
- Gene Therapy - Nature [Last Updated On: May 14th, 2014] [Originally Added On: May 14th, 2014]
- Gene therapy for RTT syndrome benefits and drawbacks - Video [Last Updated On: May 16th, 2014] [Originally Added On: May 16th, 2014]
- Gene Therapy (Using Biolistic gene gun for gene delivery) - Video [Last Updated On: May 16th, 2014] [Originally Added On: May 16th, 2014]
- Germline Gene Therapy - Video [Last Updated On: May 16th, 2014] [Originally Added On: May 16th, 2014]
- Gene Therapy Biology Project for Swavely - Video [Last Updated On: May 16th, 2014] [Originally Added On: May 16th, 2014]
- Gene therapy extends survival in an animal model of spinal muscular atrophy [Last Updated On: May 22nd, 2014] [Originally Added On: May 22nd, 2014]
- Novel RNAi therapy silences mutated Huntington's disease gene and reduces symptoms [Last Updated On: May 22nd, 2014] [Originally Added On: May 22nd, 2014]
- Global Gene Therapy Market: Analysis, Size, Share, Growth, Trends and Forecast 2013 - 2019 [Last Updated On: May 22nd, 2014] [Originally Added On: May 22nd, 2014]
- Gene therapy hits blood cancers hard [Last Updated On: May 22nd, 2014] [Originally Added On: May 22nd, 2014]
- Spark Therapeutics late-stage gene therapy for inherited blindness takes a $73M step forward [Last Updated On: May 31st, 2014] [Originally Added On: May 31st, 2014]
- Genome Editing to Reverse Bubble Boy Syndrome [Last Updated On: May 31st, 2014] [Originally Added On: May 31st, 2014]
- Genetic Researching: Gene Therapy - Video [Last Updated On: May 31st, 2014] [Originally Added On: May 31st, 2014]
- BEYOND THE BUBBLE: 10 Years of Gene Therapy - Video [Last Updated On: May 31st, 2014] [Originally Added On: May 31st, 2014]
- Gene Therapy Combined with IMRT Found to Reduce the Rate of Positive Prostate Biopsy After Treatment for Intermediate ... [Last Updated On: June 4th, 2014] [Originally Added On: June 4th, 2014]
- Gene therapy combined with IMRT found to reduce recurrence for select prostate cancer patients [Last Updated On: June 4th, 2014] [Originally Added On: June 4th, 2014]
- Gene therapy combined with IMRT reduces rate of positive prostate biopsy after treatment for intermediate-risk ... [Last Updated On: June 4th, 2014] [Originally Added On: June 4th, 2014]
- Bluebird, Agios: Preview of Next Week's Important Pipeline Updates [Last Updated On: June 12th, 2014] [Originally Added On: June 12th, 2014]
- Attack of the B - Team EP8 - Drowning for Science! - Video [Last Updated On: June 12th, 2014] [Originally Added On: June 12th, 2014]
- 3rd International Conference and Exhibition on Cell & Gene Therapy - Video [Last Updated On: June 14th, 2014] [Originally Added On: June 14th, 2014]
- Blood Disorder Patients Respond Strongly to Bluebird Bio Gene Therapy [Last Updated On: June 15th, 2014] [Originally Added On: June 15th, 2014]
- Gene Therapy Partnering Terms and Agreements - Video [Last Updated On: June 15th, 2014] [Originally Added On: June 15th, 2014]
- Gene Therapy - GMAT Free - GFSC120 - Video [Last Updated On: June 18th, 2014] [Originally Added On: June 18th, 2014]
- New Gene Therapy Rapidly Helps Patients With Rare Blood Disorder - Video [Last Updated On: June 18th, 2014] [Originally Added On: June 18th, 2014]
- Isis Could Get a $2 Billion Gain From Heart Attack Trials [Last Updated On: June 22nd, 2014] [Originally Added On: June 22nd, 2014]
- Gene Therapy for Beta Thalassemia - Video [Last Updated On: June 22nd, 2014] [Originally Added On: June 22nd, 2014]
- A level. R.7. Cystic fibrosis and gene therapy (Ms Cooper) - Video [Last Updated On: June 24th, 2014] [Originally Added On: June 24th, 2014]