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Gene
Therapy
Potentially androgenetic alopecia is an ideal candidate disease
to attempt gene therapy. The simple fact that the organ affected
is in the skin makes application of any gene therapy very easy
- simply apply it to the skin! One method of supplying modified
genes to hair follicles using liposomes has already been identified
and announced (Hoffman 1998). Liposomes can be used to target
dyes, melanins, and/or proteins specifically to hair follicles
as well as genes. Of course the question is what to supply to
the hair follicles to stimulate them and ensure hair growth. This
of course is the sticking point. Research into genes that may
be involved in hair follicle growth and androgenetic alopecia
is ongoing with both academic and commercial scientists involved.
Sooner or later genes may be identified that could be used to
switch off the factors that promote androgenetic alopecia and/or
stimulate hair growth. Should such genes be identified I am sure
several pharmaceutical companies will attempt to develop gene
therapy for androgenetic alopecia.
CD2425/retinoid-X-receptor-alpha
L’Oreal research laboratories published an interesting reference
where they examined the effects of retinoid receptors on hair follicles
and hair growth. They first identified that hair follicles express
receptors for retinoic acid. Using hair follicles in culture they
supplied different retinoic acid agonists. The retinoid-X-receptor-alpha
agonist CD2425 stimulated hair growth in vitro. The authors of the
research paper suggested this retinoid-X-receptor-alpha might be
used to stimulate hair growth in humans with alopecia (Billoni 1997).
Isoquinolines
Norreticuline and Reticuline are made by Sunstar Inc. of Japan.
These drugs are Isoquinolines. A short article on Norreticuline
and Reticuline indicated they have stimulatory effects on hair follicle
cells in culture. Investigators then applied the drugs to mice and
observed that Norreticuline stimulated hair growth. The authors
believe the drugs could be employed to promote hair growth in humans
by topical application (Nakaoji 1997).
Cyclosporine
Cyclosporine is the generic name for the brand name products Sandimmune
and Neoral from Sandoz pharmaceuticals. You will often see another
slightly different generic name, cyclosporin-A. They are all the
same thing. Cyclosporine is a polypeptide made from eleven amino
acids. It is naturally made by the fungus Beauveria nivea.
Cyclosporine is a powerful immunosuppressant. It is commonly used
to treat people who have life threatening autoimmune diseases or
for those who have had an organ transplant. Cyclosporine has been
known to induce a side effect of excessive hair growth on the head,
arms and legs in people who use this drug to prevent transplant
rejection. The drug has to be taken orally to have this effect.
Topical application had little or no hair growth promoting effect
when such trials were conducted to see if it could be used to treat
alopecia areata. It is believed that it does not work topically
because the drug molecule is simply too big to get through the skin.
It has been suggested that this problem could be overcome by using
a vehicle to penetrate the skin and take the drug with it.
Some dermatologists are interested in finding out how Cyclosproin
acts on the hair follicles to stimulate hair growth. By identifying
the mode of action they hope to develop a slightly different drug
with the same hair growth promoting effects but with out the immunosuppressive
properties. Research is being carried out to define the drug’s
activity using hair follicle cultures (Maurer 1997).
Tacrolimus/FK506
Tacrolimus is the new generic name for a drug that was initially
called FK506. Both of these names refer to the brand name drug Prograf
from Fujisawa in Japan. Tacrolimus is a potent specific immunosuppressive
agent. It is an antimicrobic macrolide naturally produced by Streptomyces
tsukubaensis. It was actually found by testing soil samples
collected from around Japan. Tacrolimus works to block the genetic
transcription inside cells called CD4 cells. These cells are important
in the regulation of the immune system. Stopping gene transcription
in these cells stops them from responding when there is an antigenic
challenge from an invading pathogen. While this may not sound like
a good idea, the drug action is very important in treating people
who have had organ transplants. The organs have foreign antigens
that identify the donor organ as different from the body. Normally
our immune system would attempt to destroy the transplanted foreign
organ. Tacrolimus is given in low doses to stop an immune system
from rejecting a transplanted organ.
Unlike Cyclosporine, Tacrolimus users do not have the side effect
of hypertrichosis. There is no excess hair growth when the drug
is given orally. However, there are some research reports that suggest
topical application of Tacrolimus promotes hair follicle growth.
When the drug was applied to mice and rats it was found that it
stimulated anagen induction and prolonged hair growth. It was also
found that it could stimulate hair follicles grown in vitro (isolated
follicles put in plastic dishes with a nutrient solution) when added
to culture medium.
How Tacrolimus might work to stimulate hair growth has not been
investigated in detail. It probably works along similar lines to
Cyclosporine that has similar hair growth properties. Some dermatologists
are interested in finding out about how Tacrolimus might work and
then finding an alternative drug to stimulate hair growth but without
suppressing the immune system.
Cytochrome
P-450-aromatase enzyme
As discussed in the web page on androgenetic alopecia Pathogenesis,
women have been found to have up to six time more Cytochrome P-450-aromatase
in their skin around hair follicles compared to men. The presence
of this enzyme is believed to have a significant contribution to
limiting the onset and progression of androgenetic alopecia.
The aromatase enzyme metabolizes androgens to estrogens as part
of the complex steroidal interconversion system going on in our
bodies. The aromatase enzyme thus helps to reduce the amount of
free testosterone and ultimately dihydrotestosterone in our systems.
This reduction in androgen concentration may help reduce and reverse
the effects of androgenetic alopecia. As an added bonus, estrogen
is an indirect antagonist to testosterone and may indirectly help
with promoting hair growth. Aromatase is under investigation for
its potential action as an antiandrogen in treating androgenetic
alopecia. Its actions need to be limited to the areas of hair loss.
Using it systemically may have unwanted side effects, particularly
for men.
Hyaluronic
acid
Hyaluronic acid is under sporadic investigation as a potential
topical treatment for androgenetic hair loss Hyaluronic acid binds
to a cell receptor called CD44. CD44 is well known by immunologists
for being expressed on skin dermis dendritic cells that are part
of the immune surveillance system. CD44 is also expressed on keratinocyte
cell surfaces of the epidermis and this includes cells that comprise
the hair follicle (Yasaka 1995). However, the expression of CD44
in hair follicles changes over time. CD44 is only found in immature
hair follicles and not mature ones. The interaction of Hyaluronic
acid and CD44 expression may have an important role in hair follicle
cell proliferation and differentiation. When organ cultures of embryonic
mouse skin were treated with an enzyme called Streptomyces hyaluronidase
that breaks down hyaluronic acid, the cells that make up the dermal
papilla of hair follicles became compacted (Underhill 1993). So,
removal of hyaluronic acid stops these cells from being active.
This suggests that adding hyaluronic acid should promote hair follicle
cells into activity. Dermal papilla cells are the overseers of hair
follicle growth. When the dermal papilla cells are inactive then
the rest of the hair follicle stops producing hair fiber. So, hyaluronic
acid does not have any antiandrogenic effect but it may have a direct
growth promoting action on the hair follicles.
Advanced
5 alpha reductase inhibitors
5 alpha reductase is a key enzyme that converts testosterone into
the much more potent dihydrotestosterone (see Pathogenesis for more).
Finasteride (Propecia), as a 5 alpha reductase inhibitor, has been
proven effective in stopping and even reversing androgenetic alopecia.
Now that Merck have received FDA approval for their use of Finasteride
as a treatment for androgenetic alopecia all sorts of papers are
being published on new drugs with 5 alpha reductase inhibition properties.
These research papers are primarily aimed at identifying the nature
of a drugs action and/or indicated as potential treatments for prostate
cancer. However, rest assured the idea of using some of these advanced
5 alpha reductase inhibitors as treatments for androgenetic alopecia
is being considered. Below is a table of novel 5 alpha reductase
inhibitor drugs reported in medical literature in the last few years.
| Drug name |
Manufacturer |
Published reference |
| |
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| FR146687 |
Fujisawa |
Nakayama 1997 |
| FK143 |
Fujisawa |
Katashima 1998, Inami 1997 |
| 4-[3-[3-[Bis(4-isobutylphenyl)methylamino]benzoyl]-1H-indol-1-yl]-butyric
acid |
Fujisawa |
Katashima 1998, Katashima 1997 |
| Pyrrole butyric acid derivatives |
Sumitomo |
Kato 1997 |
| MK-0386 |
Merck |
Schwartz 1997, Constanzer 1997 |
| MK-0434 |
Merck |
Grisham 1997, Laroque 1995, Van-Hecken 1994 |
| MK-0963 |
Merck |
Schwartz 1994 |
| Turosteride |
Pharmacia & Upjohn |
Zaccheo 1998, Zaccheo 1997 |
| FCE28260 |
Pharmacia & Upjohn |
Giudici 1996 |
| FCE26073 |
Pharmacia & Upjohn |
Di-Salle 1994 |
| 17 beta-acylurea derivatives of 4-azasteroids |
Pharmacia & Upjohn |
Di-Salle 1992 |
| 19-nor-10-azasteroids |
|
Guarna 1997 |
| 17-azolyl steroids |
|
Njar 1998 |
| PNU 157706 |
|
Zaccheo 1998 |
| RU58841 |
|
De-Brouwer 1997 |
| Chlormadinone acetate |
|
Nukui 1997 |
| Epristeride |
|
Robinson 1997 |
| Somatostatin |
|
Pucci 1997 |
| Inocoterone |
|
Shupack 1992 |
| Cyoctol |
|
de-Zeeuw 1990, Ford 1987 |
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