Sonic hedgehog gene promotes hair growth in resting hair follicles
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  • Sonic hedgehog gene promotes hair growth in resting hair follicles

  • Sonic hedgehog gene promotes hair growth in resting hair follicles

    The October 1999 issue of The Journal of Clinical Investigation reports an interesting breakthrough by gene therapists, led by Ronald G. Crystal at the Weill Medical College of Cornell University in New York. The group reported that they have forced resting hair follicles of mice into their growth phase by exposing the cells to the activity of the Sonic hedgehog gene. Sonic hedgehog, SHH for short, helps guide hair follicles from a resting stage into growth activity. SHH is particularly important in the embryonic formation of hair follicles.

    Crystal along with collegues Noboru Sato and Philip Leopold used an adenovirus, one of the viruses that cause the common cold as a carrier of the SHH gene, to insert the Sonic hedgehog gene into the mouse's follicle cells. Because viruses can penetrate a cell and force it to make the products of the genes they carry, these infectious agents are very useful vehicles for genes of interest to gene therapists. Crystal's team stripped out the genes that allow the virus to replicate and replaced them with a copy of SHH. It is possible to use many other viral vectors to carry genes into cells.

    The virus plus SHH gene was injected into the skin of young mice whose hair follicles had just entered their resting phase. To distinguish any unusual hair growth, the team of scientists dyed the mice's fur bleach-blonde. A few days later, vigorous tufts of black hair, the mice's natural color, started to sprout immediately around the sites where the virus had been injected. Analysis of the follicle cells showed the Sonic hedgehog gene was active in the injected areas where hair was growing but not elsewhere.

    Crystal's experiment seems to show that the cells infected with Sonic hedgehog were forced into their growth phase ahead of the surrounding follicle cells, which remained in a resting, telogen state.

    So what they have done is brought forward the natural hair follicle cycle and induced anagen in hair follicles that were previously in telogen. Presumably repeated application of sonic hedgehog might keep hair follicles, originally forced into telogen through disease, in an indefinite anagen phase. In theory this may have application to hair loss conditions where there is an increased number of follicles in a telogen state such as telogen effluvium and early stages of androgenetic alopecia. It does not have an apparent application to other hair loss diseases such as alopecia areata, although it does show the potential for using gene therapy to treat hair loss.

    In some news reports they have stated that; "to apply this therapy to humans, a person would presumably need to have multiple injections over the scalp”. ..... and ....... "The injections probably would not need to be repeated until the follicles next cycle. Human hair follicles take roughly four years to pass through one turn of the growth, regression, rest phases”.

    However, this statement assumes healthy hair follicles with a normal anagen duration. In hair loss the hair follicles may be pushed into a telogen state by unknown factors. Sonic hedgehog application may not remove those factors, so to maintain hair growth and resist the factors telling the hair follicles to rest, the gene would have to be applied regularly - just how regularly is the question. I skimmed the paper and as far as I could see the hair follicles stimulated into anagen did not stay in that state. They entered telogen along with adjacent hair follicles.

    Also for humans, hair grows in mosaic pattern - not as a wave pattern as occurs in mice. This means not all hair follicles are at the same stage - not all are in telogen at the same time. So to keep different hair follicles at different stages in the hair cycle all in anagen, there would have to be regular maintenance injections. Given that humans have a mosaic pattern of hair growth I expect that the response to SHH injection for humans would be much less apparent than shown in the mouse study. In the mouse study all hair follicles were in telogen at the time of injection. In non-bald humans only 10% of hair follicles are in telogen at any one time and so only 10% can respond to SHH injections.

    At some point soon there will probably be development of a vector to use in a topical application that will introduce whole genes to hair follicles. This will be better than using injections to apply a gene therapy. Recently at the European Hair Research Society conference Dr Robert Smart reported introducing parts of a gene to hair follicle melanocytes using a topical liposome application. Right now, whole genes are too big to penetrate the skin using the liposome preparation - but I expect they are working to solve that problem.

    Over activity of SHH can cause basal cell carcinoma – a common skin cancer. So, I won't be volunteering to try this as a treatment. What would be better is to find a gene regulator that switches on the endogenous Sonic Hedgehog rather than adding extra sonic hedgehog as the investigators have done here. Even then there could be a risk of switching on Sonic hedgehog in the wrong place and inducing carcinomas. Many problems remain to be solved before any clinical trial could be contemplated.

    This is a study that someone had to do sooner or later. Watch over the next couple of years as copy cat papers using different genes, known to be involved in hair follicle development, will be issued.

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