A Potential Role for miRNAs in Topical Drug Development

February 2013 | Volume 12 | Issue 2 | Editorials | 152 | Copyright © February 2013


Joshua W. Hagen MD PhDa and William R. Levis MDb

aDepartment of Medicine, New York Downtown Hospital, New York, NY bDepartment of Dermatology, New York University, New York, NY

Abstract
MicroRNAs (miRNAs) have recently emerged as a family of important regulatory molecules with far-reaching implications for the practice of medicine, especially with regard to our understanding of disease pathogenesis, improved diagnostics, and potential for new therapeutics. Numerous publications have revealed roles for miRNAs in many aspects of dermatology,1 raising the issue of the potential for modulating miRNA activity in dermatologic diseases as an effective means of treatment, especially using topically delivered preparations. The field of topical delivery of small RNA therapeutics remains in its infancy, but significant advances have been made that promise future benefits for the field of dermatology. The most advanced of these are efforts to bring topical small interfering RNA–based treatments into clinical use for the autosomal dominant, keratinopathic pachyonychia congenita (PC)2-4 as well as for reducing pigmentation in melasma.5 Employing technology ranging from creams to cell-penetrating peptides to microneedle arrays, there is great potential for targeted delivery of small RNA therapeutics, including miRNAs.
Diphenylcyclopropenone (DPCP) is a compound that has been used to treat skin cancers such as metastatic melanoma (MM)6,7 as well as the autoimmune disease alopecia areata (AA).8-10 In both cases, the treatment works in approximately half of patients and fails to work in the second half. Immunologically, it is likely that different mechanisms or pathways are involved in how DPCP works against cancer, where upregulation of CD8 killing is desirable, whereas for AA downregulation of CD8 activity is likely required. A DPCP gel formulation is currently in clinical trials as a measure of immunocompetence in human immunodeficiency virus–positive subjects11 as well as for a treatment for warts, melanoma, and pending for AA (ongoing trials, W.L.R., 2012). Study of the molecular mechanisms, including changes in miRNA regulation, by which DPCP achieves therapeutic effect is important,12,13 as it is theoretically possible to improve the efficacy for cancer and autoimmune disease by manipulating topically the specific pathways that work in parallel to, and/or synergize with, the mechanisms of DPCP. Taking advantage of the growing collective data set on the roles of miRNAs in skin diseases and the rapidly advancing drug delivery technology available today, treatments such as DPCP and many others like it represent candidates for studies investigating how concurrent modulation of miRNA activity influences therapeutic efficacy.

Disclosures

Dr. Levis is an advisor for Hapten Pharmaceuticals in the development of a DPCP gel formulation. Dr. Hagen has no relevant conflicts of interest to disclose.

References

  1. Schneider MR. MicroRNAs as novel players in skin development, homeostasis and disease. Br J Dermatol. 2012;166(1):22-28.
  2. Hickerson RP, Smith FJ, Reeves RE, et al. Single-nucleotide-specific siRNA targeting in a dominant-negative skin model. J Invest Dermatol. 2008;128(3):594-605.
  3. Leachman SA, Hickerson RP, Schwartz ME, et al. First-in-human mutation-targeted siRNA phase Ib trial of an inherited skin disorder. Mol Ther. 2010;18(2):442-446.
  4. Smith FJ, Hickerson RP, Sayers JM, et al. Development of therapeutic siRNAs for pachyonychia congenita. J Invest Dermatol. 2008;128(1):50-58.
  5. Yi X, Zhao G, Zhang H, et al. MITF-siRNA formulation is a safe and effective therapy for human melasma. Mol Ther. 2011;19(2):362-371.
  6. Damian DL, Shannon KF, Saw RP, Thompson JF. Topical diphencyprone immunotherapy for cutaneous metastatic melanoma. Australas J Dermatol. 2009;50(4):266-271.
  7. Damian DL, Thompson JF. Treatment of extensive cutaneous metastatic melanoma with topical diphencyprone. J Am Acad Dermatol. 2007;56(5):869-71.
  8. Alkhalifah A, Alsantali A, Wang E, McElwee KJ, Shapiro J. Alopecia areata update: part II. Treatment. J Am Acad Dermatol. 2010;62(2):191-202.
  9. Ohlmeier MC, Traupe H, Luger TA, Böhm M. Topical immunotherapy with diphenylcyclopropenone of patients with alopecia areata-a large retrospective study on 142 patients with a self-controlled design. J Eur Acad Dermatol Venereol. 2012;26(4):503-507.
  10. El-Zawahry BM, Bassiouny DA, Khella A, Zaki NS. Five-year experience in the treatment of alopecia areata with DPC. J Eur Acad Dermatol Venereol. 2010;24(3):264-269.
  11. Levis WR, Holzer AM, Leonard LK. Topical diphenylcyclopropenone as a measure of immune competence in HIV-seropositive subjects. J Drugs Dermatol. 2006;5(9):853-858.
  12. Wolf J, Levis WR. The study of simple chemicals in animals and man: mechanisms of contact sensitivity. J Drugs Dermatol. 2012;11(10):1166-1173.
  13. Vennegaard MT, Bonefeld CM, Hagedorn PH, et al. Allergic contact dermatitis induces upregulation of identical microRNAs in humans and mice. Contact Dermatitis.2012;67(5):298-305

AUTHOR CORRESPONDENCE

William R. Levis MDwilliam_levis@yahoo.com
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