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Weekly treatment with SAMiRNA targeting the androgen receptor ameliorates androgenetic alopecia.

ABSTRACT: Androgenetic alopecia (AGA) is the most common type of hair loss in men and women. Dihydrotestosterone (DHT) and androgen receptor (AR) levels are increased in patients with AGA, and DHT-AR signaling correlates strongly with AGA pathogenesis. In this study, treatment with self-assembled micelle inhibitory RNA (SAMiRNA) nanoparticle-type siRNA selectively suppressed AR expression in vitro. Clinical studies with application of SAMiRNA to the scalp and massaging to deliver it to the hair follicle confirmed its efficacy in AGA. For identification of a potent SAMiRNA for AR silencing, 547 SAMiRNA candidates were synthesized and screened. SAMiRNA-AR68 (AR68) was the most potent and could be efficiently delivered to human follicle dermal papilla cells (HFDPCs) and hair follicles, and this treatment decreased the AR mRNA and protein levels. We confirmed that 10 µM AR68 elicits no innate immune response in human PBMCs and no cytotoxicity up to 20 µM with HFDP and HaCaT cells. Clinical studies were performed in a randomized and double-blind manner with two different doses and frequencies. In the low-dose (0.5 mg/ml) clinical study, AR68 was applied three times per week for 24 weeks, and through quantitative analysis using a phototrichogram, we confirmed increases in total hair counts. In the high-dose (5 mg/ml) clinical study, AR68 was given once per week for 24 weeks and showed 83% efficacy in increasing hair counts compared with finasteride. No side effects were observed. Therefore, SAMiRNA targeting AR mRNA is a potential novel topical treatment for AGA.

SUBMITTER: Yun SI

PROVIDER: S-EPMC8803970 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Weekly treatment with SAMiRNA targeting the androgen receptor ameliorates androgenetic alopecia.

Yun Sung-Il SI Lee Sang-Kyu SK Goh Eun-Ah EA Kwon Oh Seung OS Choi Woorim W Kim Jangseon J Lee Mi Sun MS Choi Soon Ja SJ Lim Seung Sik SS Moon Tae Kee TK Kim Sin Hae SH Kyong Keeyeol K Nam Gaewon G Park Han-Oh HO

Scientific reports 20220131 1

Androgenetic alopecia (AGA) is the most common type of hair loss in men and women. Dihydrotestosterone (DHT) and androgen receptor (AR) levels are increased in patients with AGA, and DHT-AR signaling correlates strongly with AGA pathogenesis. In this study, treatment with self-assembled micelle inhibitory RNA (SAMiRNA) nanoparticle-type siRNA selectively suppressed AR expression in vitro. Clinical studies with application of SAMiRNA to the scalp and massaging to deliver it to the hair follicle c ...[more]

PMID: 35102171

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Project description:Asymmetric small interfering RNAs (asiRNAs) that mediate RNA interference have been investigated for therapeutic use in various tissues, including skin tissue. Androgenetic alopecia (AGA) is caused by a combination of genetic factors, resulting in sensitivity to dihydrotestosterone (DHT), which binds to the androgen receptor (AR) to mediate a series of biomolecular changes leading to hair loss. This study aimed to evaluate the therapeutic potential of a cell-penetrating, AR-targeting asiRNA (cp-asiAR) for AGA treatment, which was designed to silence the AR gene. AGA mouse models were developed by stimulation with DHT, and ex vivo human scalp tissues were also used for analysis. Cp-asiAR-mediated changes in mRNA expression and protein levels of AR were assessed along with the examination of phenotypic improvements in mouse model of AGA. We also assessed downstream signaling associated with AR in primary human dermal papilla (DP) cells. Several cp-asiARs were screened for selecting the optimal sequence of AR using cell lines in vitro. A cholesterol-conjugated, chemically modified cp-asiAR candidate was optimized under passive uptake conditions in vitro. Intradermal cp-asiAR injection efficiently reduced mRNA and protein levels corresponding to AR in mouse models. Moreover, cp-asiAR injection promoted hair growth in mouse models with DHT-induced AGA. In ex vivo human hair follicle culture, the proportion of telogen hair decreased, and the mean hair bulb diameter increased in the cp-asiAR-treated group. In isolated primary human DP cells, AR expression was effectively downregulated by cp-asiAR. Furthermore, cp-asiAR attenuated DHT-mediated increases in interleukin-6, transforming growth factor-β1, and dickkopf-1 levels. No significant toxicity was observed in DP cells after cp-asiAR treatment. Cp-asiAR treatment showed effective downregulation of AR expression and prevention of DHT-mediated alterations in the hair cycle and hair diameter, indicating its potential as a novel therapeutic option for AGA.

Project description:BackgroundAndrogenetic alopecia (AGA) is the most common form of hair loss. Studies have suggested a potential link to metabolic disorders, but with conflicting results. To elucidate the lipidomics profile and sex-specific variations in AGA, while exploring correlation between AGA and metabolic syndrome (MetS).MethodsThe AGA patients (n = 83) and healthy controls (n = 84) were collected in the study. The lipid profiles were analyzed using ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). Serum levels of important factors associated with AGA, namely dihydrotestosterone (DHT), prostaglandin D2 (PGD2) and transforming growth factor-β1 (TGF-β1) were quantified using ELISA.ResultsCompared with controls, AGA patients had a higher probability of MetS (26.51% vs 11.9%, P < 0.05). Fifty-one differentially expressed lipids were identified in AGA. The kind of triglyceride (TG) were significantly increased, while phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylglycerol (PG), phosphatidylinositol (PI), and phosphatidylserine (PS) exhibited remarkable decrease. PC (16:2/21:6), PC (34:4p), PE (41:7), PE (44:12), PG (40:9), PI (32:2) and TG (15:0/18:1/18:1) were identified as potential biomarkers of AGA with the highest specificity. The levels of DHT, PGD2 and TGF-β1 were significantly elevated in AGA. All seven lipids showed significant correlations with DHT, PC (34:4p) and TG (15:0/18:1/18:1) were significantly associated with PGD2, TGF-β1 displayed exclusively correlation with TG (15:0/18:1/18:1) (all P < 0.05). Furthermore, these lipids were also significantly linked to systolic blood pressure and BMI, while some of them also showed significant associations with total cholesterol and HDL-C. In subgroups, forty-two differentially expressed lipids were identified in male AGA vs male control and eighty-one in female AGA vs female control. PC (16:2/21:6) was the only specific lipids common to both sexes.ConclusionsAberrant lipid metabolism was observed in AGA, with distinct lipidomic profiles between male and female AGA. The potential biomarkers were closely related to DHT, PGD2, TGF-β1 and MetS-related indicators. It provides the foundation for revealing the mechanisms of AGA.

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Weekly treatment with SAMiRNA targeting the androgen receptor ameliorates androgenetic alopecia.

Publications

Weekly treatment with SAMiRNA targeting the androgen receptor ameliorates androgenetic alopecia.

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