Gene therapy

Gene therapy is the insertion of nucleic acids such as DNA or RNA into the cells of an individual body, for example, to treat a disease. Classically, an intact gene to be inserted into the genome of the target cell to replace a defective gene that is causative for the development of the disease. In humans, gene therapies have been and are partially successful example carried out in the context of clinical trials. As the world's first finished product in China in 2003 gendicine ( rAD - p53 ) was introduced in November 2012 as the first registration of a gene therapy in the Western world the approval of Glybera ( Alipogentiparvovec ) by the European Commission, for the U.S. is seeking approval. Within Europe include gene therapy medicinal products to the group of advanced therapy medicinal products.

Principle

Usually, the body will be taken from some cells to insert the corresponding nucleic acids these in the laboratory ( in vitro). Then the cells can be propagated, for example, to be then re-introduced into the body. Gene therapy can also directly take place in the body (in vivo). Depending on the nature of the technique used in gene therapy and nucleic acid may integrate into the cell genome, or only temporarily left in the cell. According to the therapeutic effect can be permanent or limited.

Methods

For the transfer, there are various methods to carry a therapeutic nucleic acid into a cell:

  • Transduction: This most commonly used method involves a viral vector (a modified virus), the therapeutic sequence into the cell.
  • Transfection ( chemically ): The nucleic acid and an electrically charged compound (e.g., calcium phosphate ) are added to the cells. The electrically charged compound binds to the cell membrane and is endocytosed, whereby the vector after perforation of the endosomal membrane can enter the cytosol.
  • Transfection ( physically ): In electroporation, a surge makes the cell membrane temporarily permeable, so that the vector can penetrate into the cell.
  • Transfection ( physically ): Microinjection offers high chances for a successful installation of the gene (approx. 1:5), however, each cell must be treated individually.
  • Sperm -mediated gene transfer into oocytes

Limitations and risks

The replacement and permanent insertion of an intact gene in the form of DNA has a chance of success only in so-called monogenic diseases. Diseases that are caused by complex genetic disorders, such as cancer, can not be treated causally with gene therapy. A possible gene therapy may (not the germ line in question ) cells are carried out only in somatic, so that the new genetic information can not be passed on to the children of the treated individual. This is a legal restriction, based on ethical and safety-related aspects. The greatest risk of gene therapy is a non-directional integration of the nucleic acid to improper location within the genome of the host cell. As a site of integration is not yet predictable, other previously intact genes can be disturbed in their function. In the worst case, could the therapeutic benefit of the new gene with a new possibly more severe disease, are conditionally replaced by the disturbance of a previously intact gene.

Currently, gene therapy approaches are limited in practice on two different cell types: accessible stem cells and long-lived, differentiated, post-mitotic cells. Depending on the cell type are different methods of gene therapy are used.

Body cells that are suitable for gene therapy with retroviruses as vector must meet certain requirements:

  • You must be durable enough to survive the " infection," but especially the withdrawal from and re-implantation into the body
  • They shall be easily removable and re- usable
  • They should be durable so that they can produce the new protein for a long time

The following cell types have been found suitable:

  • Skin cells: fibroblasts from the dermis ( not active )
  • Liver cells
  • T cells: T cells ( circulating white blood cells) are responsible for the cellular immune response. The absence of the gene for adenosine deaminase (ADA ), which leads to a " severe combined immunodeficiency " (SCID ), is treated by appropriate treatment of these cells. Another treatment option is a defect in the common chain of several interleukin receptors, X -SCID.
  • Bone marrow stem cells because they produce red and white blood cells. Through gene therapy of rare stem cells genetically related diseases of the blood and the immune system can be treated. Thus, for example, the beta -thalassemia could be ( a lack of β -globin leads to anemia ) by installing a " enhancer sequence " in stem cells treat.

Patient applications

In the services provided by The Journal of Gene Medicine database Gene Therapy Clinical Trials Worldwide more than 1500 clinical trials are listed, which were previously approved (as of 2010 ).

Therapy of SCID

On 14 September 1990 the world's first gene therapy treatment was performed by doctors of the U.S. federal health institution to a four-year girl. The patient Ashanti DeSilva was suffering from a severe combined immunodeficiency ( SCID), a very rare disease (incidence 1:100,000), caused by a severe deficiency of both T-and B- lymphocyte system. For affected by this defect patient's immune system is impaired significantly to complete in its function, that is, there is little or no immune response - even a common cold can mean to the children 's death. Gene therapy that needs to be repeated several times to the limited lifetime of the leukocytes in the patient makes a life without strict quarantine. The gene therapy on Ashanti DeSilva was preceded by a three-year approval process.

The forth identical to the symptoms of disease X -SCID, which occurs due to mutations in the common chain of several interleukin receptors ( y c, CD132 ) was also treated with a gene therapy approach of Alain Fischer in Paris. After the treatment at first largely successful, occurred in some patients after some time on leukemias (See X - SCID).

Jesse Gelsinger case

1999 underwent gene therapy research a setback. In a study conducted by the University of Pennsylvania, led by James M. Wilson series of experiments led to serious complications.

The 18 -year-old Jesse Gelsinger suffered from congenital ornithine transcarbamylase deficiency. He participated in the last of six test stages in part as Family. The September 13, injected him with the dose of adenovirus used as carrier was $ 38 trillion particles. This is far more, are transmitted as in a natural infection. The state Gelsingers deteriorated after injection very fast, so he consequently died on September 17 at a multi -organ failure. Jesse Gelsinger was at that time the world's sixth officially reported dead, who died due to an infection in gene therapy trials applied, artificial with adenoviruses. In each of these six cases to have been the cause of the death has occurred in the opinion of the appropriate test line, the underlying disease.

The senior doctor James M. Wilson was prohibited from any further research on people following this trial by the health authority of the United States. Among other things, because conditions that were set for a trial on humans, were deliberately not complied with. Thus, the health of Jesse Gelsinger was at the beginning of the experiment, although stable, but exceeded his liver values ​​given by the health authority limit.

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