Part 3 – RNA Interference
Another possible strategy for combating androgenetic alopecia in the future could involve harnessing a molecular phenomenon known as RNA interference (RNAi) to block the expression of the genes that cause hair loss in the first place.
Ribonucleic acid (RNA) is a biological polymer that is essential for all known forms of life. One type of RNA, known as messenger RNA (mRNA), carries genetic information derived from DNA (the master genetic "blueprint") out of the cell nucleus to the cytoplasm where it is translated into proteins (e.g., receptors or enzymes).
(For more details on RNA check out the entry on Wikipedia.)
The Science Behind RNAi
Years of research on gene expression in plants, worms, and eventually mammals, have led to the understanding that small fragments of nucleic acids like RNA can specifically block the production of any given protein in a cell.1
Small interfering RNAs (siRNAs) are short fragments of RNA, approximately 19-23 nucleotides in length, which recognize and bind to specific sequences in a target mRNA and recruit RNAi machinery (including an enzyme called "Dicer") that chop up the target mRNA. Once the mRNA is cleaved, it can no longer be translated into the corresponding protein it encodes. With the sequencing of the human genome completed, siRNA sequences can be designed to specifically target almost any gene.
RNAi technology could be utilized in the context of treating androgenetic alopecia to inhibit the production of proteins that are involved in hair loss or that slow the growth of hair.
Given the widely recognized role of dihydrotestosterone in hair follicle miniaturization and pattern hair loss, two particularly attractive targets for RNAi therapy are the androgen receptor (AR) and the 5-alpha reductase enzymes.
“Antiandrogen therapeutic oligonucleotides targeting the downregulation of the AR expression is advantageous because both will be possible to eliminate the only way for androgens to act and simultaneously this strategy allows the medication to be topically administrated. In fact, this could be very useful in a long-term treatment of, for instance, androgenetic alopecia...”
A Possible Manufacturer?
A company called Sirna Therapeutics described just such an approach in a patent application, published in 2005 as US 2005159376 A1. In the application, Sirna suggested using siRNA targeting either AR or 5-alpha reductase to treat alopecia:
“Specifically, the invention relates to small nucleic acid molecules [...] capable of mediating RNA interference (RNAi) against 5-alpha reductase and/or androgen receptor. Such small nucleic acid molecules are useful, for example, in providing compositions for treatment of traits, diseases and conditions that can respond to modulation of 5-alpha reductase and/or androgen receptor expression in a subject, such as alopecia, acne, polycystic ovary disease, prostitic hypertrophy, and prostate cancer.”
Since RNA does not cross the cell membrane or the skin barrier efficiently, one approach for delivering siRNA molecules is to encapsulate them in a sphere of "phospholipids" similar to those that make up the cell membrane. These spheres, known as liposomes, would cross through the skin and facilitate the entry of siRNA into the desired cells in the hair follicle.
“The siNA molecules of the invention are added directly, or can be complexed with cationic lipids, packaged within liposomes, or otherwise delivered to target cells or tissues. The nucleic acid or nucleic acid complexes can be locally administered to relevant tissues ex vivo, or in vivo through direct dermal application, transdermal application, or injection, with or without their incorporation in biopolymers.”
Not Quite There Yet
While the approach outlined above will theoretically be effective as a treatment for androgenetic alopecia, some details still need to be worked out. Delivery with simple liposomes works very well in cell culture models, but may not be as effective in the more complex environment of the skin. According to a review article published this year:
“More efficient drug delivery vehicles are therefore being sought. Among the newly emerging concepts, drug delivery systems based on nano- and microparticles, which efficiently penetrate via the follicular route, are highly promising approaches.”3
“Nevertheless, this is still a very incipient area that promises to bring new and highly targeted strategies for skin and hair diseases.”
As with all the other treatments described in this series of posts, any therapeutic strategy would need to be tested in clinical trials to make sure it is safe and effective before approval by the FDA.
Thanks again for joining us this week as we look into The Future of Hair Regrowth. Don't forget to come back soon for the next installment in the series, which will cover what may be the most promising area in hair growth research today: stem cells.
1. Zamore PD, Tuschl T, Sharp PA, Bartel DP. RNAi: double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals. Cell. 2000 Mar 31;101(1):25-33. Link to PubMed
2. Dugour A, Hagelin K, Smus C, Balañá ME, Kerner N. Silencing the androgen receptor: new skills for antiandrogen oligonucleotide skin and hair therapy. J Dermatol Sci. 2009 May;54(2):123-5. Link to PubMed
3. Araújo R, Fernandes M, Cavaco-Paulo A, Gomes A. Biology of human hair: know your hair to control it. Adv Biochem Eng Biotechnol. 2011;125:121-43. Link to PubMed
Lack of Evidence for Safety and Efficacy?
Several online distributors now offer products that contain minoxidil in higher doses than have been approved by the U.S. Food and Drug Administration (FDA) or that contain minoxidil in combination with additional active pharmaceutical ingredients.
Although the FDA has only approved minoxidil at concentrations of two percent (2%) for women or five percent (5%) for men in the treatment of hair loss, some products available over the internet contain minoxidil at concentrations as high as 15%. Many are formulated with additional ingredients such as azelaic acid, retinoic acid, caffeine, and even finasteride (the active ingredient in Propecia®), in combinations that have not been reviewed by the FDA.
The FDA evaluates two major concerns when considering new drug applications – safety and efficacy. Until these products are tested in clinical trials, there is no way to ensure that they are safe or to know whether high doses of minoxidil even provide any benefit over products that have been approved by the FDA.
Some consumers may find the marketing of these products to be misleading because of references to the FDA or to claims based on FDA-approved products containing 2% or 5% minoxidil.
The website for MinoxidilMax claims to offer “effective hair regrowth products... for male pattern baldness (alopecia androgenetica)” with “unmatched effectiveness.” Their products are manufactured “by an FDA registered cGMP compliant facility,” contain “the only effective ingredient approved by FDA in topical hair regrowth solution,” and have “the maximum strength of FDA approved hair growth stimulator (15% minoxidil).”
Consumers who read further on the company's website may be surprised to find that their products are not FDA-approved and that “the statement on this website has not been evaluated by the FDA. This product is not intended to diagnose, treat, cure or prevent any disease.”
Another manufacturer, Perfect Image Solutions, offers high dose minoxidil products “specifically formulated to treat conditions associated with male pattern baldness (Androgenetic Aloepicia).”
The FAQ section of the website relies on the long history of FDA-approved minoxidil products like Rogaine® to imply that high dose minoxidil products must also be safe:
“How do I know using a high concentration of minoxidil isn’t an overdose?
Minoxidil has been on the market for over 20 years with an extremely low incidence of side effects, especially from topical application.”
Although claiming that the products are “clinically proven to yield unparalleled results in the field of hair loss,” manufactured in an “FDA registered cGMP compliant facility,” and that all ingredients, “including Minoxidil must meet all FDA guidelines,” the website does not provide any evidence of clinical trials demonstrating the safety or efficacy of its products.
FDA Takes Action
Earlier this year, Regrowth LLC, a well known distributor of high dose "specialty" minoxidil formulations (formerly sold under the name Xandrox), released the following statement on its website:
“We're very sorry to inform you that Regrowth LLC has to suspend all operations at this time. In an ongoing audit, the U.S. FDA has deemed our medications to be 'unapproved illegal drugs'.”
Regrowth LLC had been selling minoxidil formulations containing 15% minoxidil (three times the FDA-approved dose contained in products such as Rogaine® and Avacor Physicians Formulation®).
On May 25, 2011, the FDA initiated a recall of 57,999 bottles of Regrowth LLC's products, stating that “[t]hese products are unapproved drugs and may present potential health hazards.”1 Based on this recall, it would not be surprising if the FDA takes action to stop other distributors of high dose minoxidil formulations/combinations from selling unapproved drugs in the future.
At the time of posting this article, we are unaware of any clinical trials proving that products containing higher concentrations of minoxidil than 5% are safe or more effective than FDA-approved products containing 5% minoxidil.
In January, Dr. Glenn Charles, a member of the International Alliance of Hair Restoration Surgeons, commented:
“I have not seen any studies comparing 5% Minoxidil with higher % Minoxidil concentrations. I would imagine that the incidence of side effects might be higher with greater % of Minoxidil. However, many of the reported side effects might actually be caused by the other ingredients in these hair loss products containing Minoxidil.”
If you are still interested in experimenting with formulations containing high dose minoxidil or combinations with other active ingredients, it may be a good idea to consult with a physician before you begin using any such products.
1. Enforcement Report for May 25, 2011: RECALLS AND FIELD CORRECTIONS: DRUGS - CLASS II. FDA.gov (accessed September 8, 2011).
2. Photo above from Occupycorporatism.com