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Hair Loss Research > Gene Therapy

Gene Therapy

An even more advanced technique for solving inherited hair loss in the future is gene therapy. Gene therapy is the process of changing genes of existing cells in the body, and thereby altering cell function. It is a medical treatment still in its infancy, and there have only been a few recent examples of gene therapy working. But it is a potential future baldness treatment method worth exploring.

Gene therapy requires learning how an inherited medical condition occurs at the DNA molecule level, and then going in and fixing it. With gene therapy, the hair follicles with DHT-sensitive cells could be changed into follicles with DHT-resistant cells, and the hair follicles would continue to grow new hairs for a lifetime. But gene therapy involves several very difficult to achieve steps. The first step is figuring out which of the tens of thousands of genes on strands of DNA are involved in the characteristic to be altered, and the second step is figuring out how exactly the target genes are to be changed, so that they give instructions for making the slightly different proteins that will achieve the desired effect. The third step is getting the target cells in the living organism to incorporate the new and improved genes as replacements for the old undesirable genes.

Gene Identification:

Figuring out which genes are involved in the genetic condition to be changed is not an easy task. Despite all the advances in mapping genes in recent years, we are still very far away from knowing what most of these genes do. We certainly do not have a good understanding of all of the genes that affect the cycle of hair growth, and especially which genes are responsible for inherited hair loss. It is most likely that several genes are responsible for making proteins that cause certain hair follicles to be DHT-sensitive.

Future studies will likely involve comparing the genes and resulting proteins in different follicles from a single individual. In a given individual with androgenetic alopecia (pattern hair loss), some hair follicle cells will express the characteristic of DHT-resistance (the follicles at the back of the scalp), while other hair follicles on the same person will express the characteristic of DHT-sensitivity (at the hairline, for example). Both follicles contain cells with identical DNA, but they express different characteristics. So identifying the responsible genes will be tricky. And even after we identify these genes, we have to figure out how to change them ever so slightly so they will make proteins that create DHT-resistant hair follicles. But scientists have been making progress in gene identification.

Modifying Genes:

In a paper presented in the January 30, 1998 issue of the journal "Science", researchers led by Angela Christiano, PhD identified a defect in a single gene responsible for a rare type of inherited baldness called generalized atrichia observed in a Pakistani family, in which affected individuals are born with infant hair that falls out and never grows back. Shortly after birth, affected individuals are completely hairless. The gene, called hairless, was mapped in humans to chromosome 8p21, and was the first example of a single gene defect being identified as a hair loss cause. Christiano was careful to point out that this was just a first step towards identifying genes that affect hair loss. (Science, January 30,1998, vol 279, No. 5351)

Later in the same year, in a paper presented in the September 11, 1998 issue of the "American Journal of Human Genetics", Christiano's team reported on members of a family of Irish Travelers who also exhibited congenital atrichia, in which affected individuals are born with infant hair that falls out and never grows back. Genetic analysis of the Irish Travelers revealed that a mutation of the hairless gene was again responsible for the hair loss condition, however the mutation was different from the one that resulted in hair loss in the Pakistani family.

In a paper reported in the November 25 1998 issue of "Cell", researchers led by Elaine Fuchs, PhD induced the formation of new hair follicles in mice that were genetically engineered to constantly produce a stabilized form of a protein called beta-catenin. Beta-catenin is a multi-functional protein, which signals a variety of cellular functions, but is normally quickly degraded within a cell after being produced. Researchers altered the mouse gene that contains instructions for making the beta-catenin protein in such a way that the beta-catenin produced was resistant to being broken down. The resulting accumulation of beta-catenin caused a massive growth of new hair follicles to grow in normal mouse skin, until there were hair follicles branching from existing hair follicles. Eventually the mice also developed hair follicle tumors as a result of over-expressing beta-catenin. (Fuchs, university of Chicago 1998) (Gat, Dermatology Focus Vol. 19, No. 2, Summer 2000).

In the October 1999 issue of "The Journal of Clinical Investigation", researchers led by Ronald Crystal MD forced resting hair follicles of mice into the growth phase by exposing cells to larger than normal quantities of a protein produced by the Sonic Hedgehog Gene (abbreviated Shh).

The papers presented by these three groups of genetic researchers reveal the complexity of the task of understanding the genetic basis for inherited hair loss, and reveal the monumental task of figuring out how to correct the condition at the molecular level. In the first case, Angela Christiano's team identified a gene that can cause total hair loss when mutated in either of two different ways. In the second example, the team led by Elaine Fuchs mutated a gene in such a way that it coded for the creation of a slightly different protein that caused massive new hair follicle creation. And the third example showed that increasing the exposure to a naturally occurring protein could signal hair follicles to shift from the resting phase into the growth phase. And while all of these genes and their respective proteins appear to play some role in hair follicles, they are also known to affect other cells and systems in the body. Genetics is very complicated.

But suppose that at some point in the future we develop an adequately complete understanding of how all the genes, and their respective proteins, affect inherited hair loss. And suppose that we can also determine how exactly we want to alter the genes so that the proteins they make result in hair follicles that are DHT-resistant, rather than DHT sensitive, but without causing unwanted side effects.

Changing Genes in Living Cells and Living Organisms:

The third challenge of gene therapy is delivering the new-and-improved genes to the target cells, and then to have those cells use the new genes to make the corresponding new proteins, and then to have the altered cells express the desired characteristic.

The correct target cells are critical to successful gene therapy. If mature cells are altered, the benefits of the gene therapy go away after those cells wear out and are replaced with new cells having the original DNA. For a long-lasting effect, stem cells are targeted. When successful, the altered stem cells will then create altered transient amplifying cells, which in turn will create altered specialized cells that will express the desired characteristics.

The most common altered gene-delivery method involves using crippled viruses to insert desired genes into the target cells. Outside of the laboratory, viruses are tiny organisms that infect cells by replacing some of the cell's DNA with virus DNA. After infection by a virus, a cell begin to make the proteins the virus DNA tells it to make, causing the expression of various diseases. Scientists use the virus infection mechanism to deliver desirable DNA.

First, they cripple the virus DNA so that it cannot reproduce or cause harmful effects, but is still able to insert new DNA into target cells. The desired genes are spliced onto to the virus DNA, and the viruses insert the new DNA into the target cells. The viruses can be injected directly to the location where the stem cells are, or the stem cells may be cultured in a laboratory, altered by viruses containing the new DNA, and then the altered stem cells can be placed back into the organism.

There are many areas of gene therapy that need refinement. Identifying genes, determining exactly how to change them to code for the desired proteins, avoiding an immune response when the viruses are injected directly into the organism, getting an adequate quantity of target cells to take up the altered DNA regardless of how it is delivered, and getting the cells to express the characteristics coded by the altered genes, once the new DNA is inserted, all need more work. But forward progress is being made.

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