The Future of Hair Regrowth: Part 4 – Stem Cells
Some of the most anxiously awaited treatments on the hair growth horizon are those that seek to harness the power of stem cells to regrow hair. This post will give you a brief introduction to stem cells and describe some of the research and development programs focused on developing treatments for hair loss.
Stem Cells 101
Each tissue and organ in the body is made up of cells with specialized structures and unique functions. These specialized cells are generated by a process called “differentiation”, in which immature, undifferentiated cells give rise to mature, differentiated cells that are equipped to carry out specific roles.
The most versatile type of stem cells, called embryonic stem cells (ESCs), arise in the earliest stages of development and give rise to every cell type in the body. The use of human ESCs has been a source of controversy because their isolation usually requires the destruction of an embryo.
Adult stem cells (ASCs), present in low numbers in the body throughout our lives, are capable of producing multiple cell types but are already committed to a particular developmental pathway. Examples of ASCs include hair follicle stem cells, which are responsible for the growth and maintenance of hair follicles, and hematopoietic stem cells, which give rise to the various red and white blood cells that carry oxygen throughout our bodies and protect us from infections.
Promising Research into Stem Cell-Based Treatments for Alopecia
Earlier this year, the research group of Dr. Roland Lauster at Berlin Technical University published an exciting report1 in the Journal of Biotechnology detailing a method that could lead to a stem cell-based treatment for hair loss.
Dr. Lauster's group isolated dermal papilla cells from human scalp hair follicles and cultured them using the same methods as have been used for culturing embryonic stem cells and mesenchymal stem cells. The cells first formed small clusters and approximately 13.5% of these “microfollicles” eventually began to grow hair-like fibers, as shown by light microscopy and electron microscopy in this figure from the paper.
The authors suggest that their “robust, reproducible method” is a “good jumping-off point for further work” on treating male pattern baldness or chemotherapy-induced alopecia. While the hairs produced in the study were similar to vellus (fine, peach fuzz) hairs, they suggest that “with further experimentation, it may be possible to cultivate hair of different thickness, color or texture.”
Eventually these microfollicles might be produced in large quantities from a patient's own cells and injected back into the scalp, where they could form new hair follicles and grow new hairs.
Histogen and Follica: Company Profiles
Two of the most notable commercial efforts in stem cell-directed therapies for alopecia are being spearheaded by the companies Histogen and Follica. Rather than implanting stem cells into the scalp to create new hair follicles, these companies are developing methods and formulations that would stimulate the development or activity of cells already present in the scalp.
Histogen, Inc.
Location: San Diego, CA
Background: Founded by Dr. Gail Naughton, former co-founder, President and Vice Chairman of the now liquidated human tissue engineering company Advanced Tissue Sciences, Inc.
(click here to listen to an interview with Dr. Naughton on TheBaldTruth.com)
Technology: Histogen's Hair Stimulating Complex (HSC) is a mixture of soluble protein factors such as Wnt7a, VEGF, KGF, and follistatin. These proteins are secreted by cells, called embryonic fibroblasts, which are grown in a controlled laboratory environment.
Development status: Histogen has completed a double-blind, placebo-controlled Phase 1/2 clinical trial of HSC to evaluate its safety and efficacy as an injectable for hair growth. According to the Histogen website, no adverse events were observed and HSC was found to increase hair count, hair thickness, and hair density at the 12 week endpoint with continued growth observed 12 months later.2 No Phase 3 details have been released yet.
Follica, Inc.
Location: Philadelphia, PA
Background: Founded around the pioneering research of Dr. George Cotsarelis, a professor at the University of Pennsylvania, who has been studying hair follicle stem cells for over 20 years and published an early pioneering article in the journal Cell in 1990.3
Technology: Cells in the scalp are coaxed into generating hair follicles by first wounding the target area and exposing the healing tissue to stem cell modulating factors such as Wnt pathway activators.4 The company is developing a device that would perform the wounding in a controlled fashion.
Development status: Follica's development program is still in its early stages. A recent article by Dr. Cotsarelis showed that stem cells are still present in normal numbers in the scalp of men affected by androgenic alopecia,5 suggesting that their focus may shift toward increasing the production of progenitor cells, the next cell type in the differentiation cascade. An article on Xconomy.com this year quoted the CEO as saying that clinical trials are underway outside of the U.S.
Conclusion
While stem cell therapies are exciting and may hold great potential for treating diseases and regrowing damaged tissues, they have proven difficult to commercialize: after 20 years, Geron, one of the leading developers of embryonic stem cell-based therapies for neurological diseases, has given up and shifted towards developing drugs for cancer.
Still, thousands of people who suffer from alopecia hope this promising field of research and development will eventually lead to a solution for hair loss.
Check back soon for the final installment of the Avacor® Hair Regrowth Blog’s series on The Future of Hair Regrowth to learn about some of the many novel, early-stage research programs that may lead to new treatments for hair loss in the future!
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1. Lindner G, Horland R, Wagner I, Ataç B, Lauster R. De novo formation and ultra-structural characterization of a fiber-producing human hair follicle equivalent in vitro. J Biotechnol. 2011 Mar 20;152(3):108-12. Link to PubMed
2. Histogen website. (accessed 11/16/2011) http://histogen.com/applications/hsc.htm.
3. Cotsarelis G, Sun TT, Lavker RM. Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell. 1990 Jun 29;61(7):1329-37. Link to PubMed
4. Ito M, Yang Z, Andl T, Cui C, Kim N, Millar SE, Cotsarelis G. Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding. Nature. 2007 May 17;447(7142):316-20. Link to PubMed
5. Garza LA, Yang CC, Zhao T, Blatt HB, Lee M, He H, Stanton DC, Carrasco L, Spiegel JH, Tobias JW, Cotsarelis G. Bald scalp in men with androgenetic alopecia retains hair follicle stem cells but lacks CD200-rich and CD34-positive hair follicle progenitor cells. J Clin Invest. 2011 Feb 1;121(2):613-22. Link to PubMed
The Future of Hair Regrowth: 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.
Molecular Biology 101: What is RNA?
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.
(For background information on DHT, AR, and 5-alpha reductases in hair loss, see our previous posts on anti-androgens here and here.)
This strategy is supported by several scientific papers, including one published in 2009 that focuses on blocking expression of AR:2
“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.”
Here is an example of how such a treatment might be delivered:
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.
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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
The Future of Hair Regrowth: Part 2 – Next Generation AR Antagonists
The search for new drugs that target prostate diseases may once again lead to new treatments for androgenetic alopecia in the future.
Just as finasteride (Propecia®) was first developed as a treatment for benign prostatic hyperplasia, a new group of androgen receptor antagonists undergoing trials for prostate cancer may prove useful for treating hair loss in coming years.
Dihydrotestosterone (DHT), an androgenic hormone, is widely recognized as a key factor in the development of androgenetic alopecia. DHT's effects on hair follicles are mediated by the androgen receptor (AR). (For more information about DHT, androgen receptors, and AR antagonists, check out our previous post on the science behind anti-androgens.)
“Triple-acting” Androgen Receptor Antagonists
A collaboration between the laboratories of Charles Sawyers (Memorial Sloan-Kettering Cancer Center) and Michael Jung (UCLA) led to the discovery of two diarylthiohydantoin compounds, MDV3100 and RD162, which represent a new class of “triple-acting” AR antagonists.1
These two compounds are derivatives of RU59063, an AR antagonist originally synthesized by scientists at Roussel-UCLAF in the early 1990s.2
Out of 200 derivative compounds the Sawyers and Jung groups screened, MDV3100 and RD162 were two of the most effective inhibitors of AR activity.
Mechanism(s) of Action
MDV3100 and RD162 are unique compared to currently prescribed AR antagonists because they disrupt activity in three complementary ways:
First, they block binding of DHT to AR by occupying the ligand binding site where DHT usually binds. This first line of defense keeps the receptor from being activated by DHT that is normally produced in the body.
Second, the compounds impede movement of AR into the cell nucleus, where the receptor normally binds to DNA and regulates the expression of genes. By keeping AR in the cytoplasm, MDV3100 and RD162 physically isolate the receptor from its site of action.
Finally, they change the shape of AR and reduce its ability to interact with DNA. When the receptor binds to DNA sequences in the genome, it acts as a molecular "on/off switch" for genes that alter cellular behavior.
This third activity is critical for preventing any receptors that are already present in the nucleus from binding to DNA and regulating the expression of genes that are presumably responsible for hair loss.
MDV3100 has a higher affinity for AR and inhibits the receptor more effectively than other currently prescribed anti-androgens like bicalutamide. Initial observations in a Phase I/II clinical trial for advanced prostate cancer have shown promising results and Phase II/III trials are in progress. (Click on the image above to see a full-size version)
Proposed Use of MDV3100 for Hair Loss
The triple-acting AR antagonists MDV3100 and RD162 were first disclosed in US Patent Application No. 20070004753 as part of a series of RU59063 derivatives. While the primary focus appears to be treating prostate cancer, the patent application hints that the drug could also be used to treat androgenetic alopecia:
“Because these compounds are strong AR inhibitors, they can be used not only in treating prostate cancer, but also in treating other AR related diseases or conditions such as benign prostate hyperplasia, hair loss, and acne.”
The patent application goes on to describe how the compounds could be formulated for topical administration:
“The diarylhydantoin compounds of the invention can be formulated as pharmaceutical compositions and administered to a subject in need of treatment, for example a mammal, such as a human patient, in a variety of forms adapted to the chosen route of administration, for example, orally, nasally, intraperitoneally, or parenterally, by intravenous, intramuscular, topical or subcutaneous routes, or by injection into tissue.”
“For topical administration, the diarylhydantoin compounds may be applied in pure form. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.”
Other Next-Generation Androgen Receptor Antagonists
Another androgen receptor antagonist to watch in the future is VN/124-1, discovered at the University of Maryland School of Medicine.3
VN/124-1 appears to work on AR by a different mechanism than MDV3100: reducing the expression of AR, i.e. the number of receptor molecules available to bind DHT.
“VN/124-1 was significantly more potent than the other compounds, with nearly complete reduction of AR expression at 15 µM in LNCaP cells, and 89% in LAPC4 cells.”
“The active ingredient, such as one or more CYP17 inhibitor(s) or compositions including any active ingredients may be administered by methods known to those skilled in the art including, but not limited to, intraperitoneally, intravenously, orally, subcutaneously, intradermally, intramuscularly, intravascularly, endotracheally, intraosseously, intra-arterially, intravesicularly, intrapleurally, topically, intraventricularly, or through a lumbar puncture (intrathecally).”
Conclusions
The next generation of AR antagonists are potent inhibitors of the androgen receptor that may hold promise for treating androgenetic alopecia in the future.
However, in order to realize this potential, several hurdles must be overcome, including tests on topical absorption and systemic toxicity, side effects, and efficacy in treating androgenetic alopecia. These studies will require a significant investment of time and money, so we will likely have to wait at least a few years before we know if any of these compounds will become available as a treatment for hair loss in the future.
Stay tuned in the coming weeks for another look into The Future of Hair Regrowth when the Avacor® Hair Regrowth Blog explores the promise of RNA interference technology for treating hair loss!
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1. Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, Wongvipat J, Smith-Jones PM, Yoo D, Kwon A, Wasielewska T, Welsbie D, Chen CD, Higano CS, Beer TM, Hung DT, Scher HI, Jung ME, Sawyers CL. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009 May 8;324(5928):787-90. Link to Pubmed
2. Teutsch G, Goubet F, Battmann T, Bonfils A, Bouchoux F, Cerede E, Gofflo D, Gaillard-Kelly M, Philibert D. Non-steroidal antiandrogens: synthesis and biological profile of high-affinity ligands for the androgen receptor. J Steroid Biochem Mol Biol. 1994 Jan;48(1):111-9. Link to Pubmed
3. Handratta VD, Vasaitis TS, Njar VC, Gediya LK, Kataria R, Chopra P, Newman D Jr, Farquhar R, Guo Z, Qiu Y, Brodie AM. Novel C-17-heteroaryl steroidal CYP17 inhibitors/antiandrogens: synthesis, in vitro biological activity, pharmacokinetics, and antitumor activity in the LAPC4 human prostate cancer xenograft model. J Med Chem. 2005 Apr 21;48(8):2972-84. Link to Pubmed
The Future of Hair Regrowth: Introduction
So far, many of our posts here on the Avacor® Hair Regrowth Blog have focused on current and past options for treating hair loss. One of our last posts cataloged some outdated patent-medicine treatments for baldness that would raise eyebrows and FDA warning flags today.
Now in our new series, “The Future of Hair Regrowth,” the Avacor team will highlight some exciting possibilities for hair regeneration that are either currently in development or undergoing preliminary research.
New treatments can take twenty or thirty years (and hundreds of millions of dollars) to develop, so it is unlikely that any of these options will be on the market by next year. But if you are experiencing hair loss and are looking for the best way to grow and keep your hair, you will probably want to know about any promising technologies on the hair growth horizon.
One of the most exciting and anticipated potential treatments for hair loss comes from our own bodies: stem cells. We will give a basic review of what stem cells are, how they are important for hair regeneration, and how they might be employed in hair regrowth treatments.
RNA interference (RNAi) is a relatively new technology that can block the expression of a particular gene with great specificity. RNAi has yet to be used widely in the clinic, but many companies are developing targeted therapies to treat such wide ranging diseases as cancer, macular degeneration, and viral hepatitis.
Several research institutes and pharmaceutical companies are working on a new generation of androgen receptor antagonists. One of these drugs, currently known as MDV3100, is being developed for prostate cancer but is also considered a potential candidate for treating androgenetic alopecia.
In the final post of the series we will give a few glimpses of very early stage research programs and patent applications that may lead to promising hair loss treatments in coming years.
So bookmark the Avacor Blog and check back soon for a look into the Future of Hair Regrowth!
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