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Acne Pathogenesis

  • Follicular hyperkeratinization, inflammation, follicular colonization by Propionibacterium acnes, and dys-seborrhea are the pathogenetic factors that interact to produce acne lesions at the level of the pilosebaceous unit (Nast et al, 2012; Picardo et al, 2017).
  • Although the exact sequence of events is not entirely clear, it has been demonstrated that sebum alterations (both quantitative and qualitative) account for the major factors involved in acne pathogenesis along with inflammation.
  • The clarification that sebum alterations and inflammation represent the primary events in acne pathogenesis, indicates that these phenomena could be the optimal primary therapeutic targets for the treatment of acne.

NAC-GED-0507 anti-inflammatory and sebogenesis-modulating effects in insulin stimulated SZ95 sebocytes

Insulin/Insulin growth factor-1 (IGF-1) signaling, has been identified as a major acne pathogenetic factor in adolescents in western countries, where high-glycemic load diets (leading to increased serum levels of insulin and IGF-1), combine with physiological pubertal rises in insulin.

NAC-GED-0507 anti-inflammatory activity on insulin-stimulated SZ95 sebocytes

NAC-GED-0507 reduces the mRNA and protein expression of pro-inflammatory cytochines induced by insulin.

NAC-GED-0507 anti-inflammatory and sebogenesis-modulating effects in insulin stimulated SZ95 sebocytes

NAC-GED-0507 effects on insulin induced sebogenesis (Oil Red staining)

NAC-GED-0507 effects on insulin induced sebogenesis (Nile Red cytofluorimetry)

NAC-GED-0507 effects on insulin-induced fatty acid synthesis
(gas-chromatography mass-spectrometry analysis)

NAC-GED-0507 down-regulates insulin-induced lipogenesis as evidenced by a significant reduction in lipid accumulation (microscopy) and number of lipid-positive cells (cytofluorimetry). NAC-GED-0507 down-regulates fatty acid synthesis; the effect is more pronounced on monounsaturated fatty acids (MUFA), especially on C16:1 (the most representative MUFA found to correlate with acne clinical manifestations). This effect is due to NAC-GED-0507 inhibition of insulin-induced increased expression of lipogenesis key enzymes (data not shown).

Acne Nonclinical Pharmacology Summary & Conclusion

Summary

In the SZ95 sebocyte cell line NAC-GED-0507:
  • Down-modulated insulin or LPS-induced inflammatory cytokines
  • Reduced insulin-induced lipogenesis as evidenced by a significant reduction in insulin induced lipid accumulation and reduced number of lipid-positive cells
  • Down-modulated the insulin-induced expression of enzymes involved in sebogenesis (SREBP-1, FADS-2, FAS, SCD-1)
  • Inhibited the synthesis of bound Fatty Acids (FA) induced by insulin. The down regulation was more pronounced on MUFA and, among these, on C16:1 (the most representative MUFA that is thought to play a role in acne development)
  • Inhibited insulin-induced Akt/mTOR signaling (known to mediate insulin-induced cellular growth, proliferation, lipid synthesis)
  • NAC-GED-0507 effects on SZ95 cells are counteracted by the co-administration of the PPARγ antagonist GW9662 or abolished in SZ95 PPARγ silenced cells

Conclusion

NAC-GED-0507 is an innovative molecule, with a novel mechanism of action, for the treatment of acne for its ability to counteract several pathogenetic processes:
  • increased sebogenesis
  • alteration of sebum composition
  • development of inflammation

NAC-GED-0507 shows to inhibit the effects induced on sebocytes by insulin.

Insulin/Insulin growth factor-1 (IGF-1) signaling, has been identified as a major acne pathogenetic factor in adolescents in western countries, where high-glycemic load diets (leading to increased serum levels of insulin and IGF-1), combine with physiological pubertal rises in insulin.

NAC-GED-0507 Clinical Pharmacology

Preliminary clinical pharmacology data were obtained on samples of sebum collected during the Phase 1 clinical study GED-0507-ACN-01-14 from acne patients treated with NAC-GED-0507 Gel for 12 consecutive weeks.

Ottaviani et al., J Eur Acad
Dermatol Venereol 2020

Results

Treatment with NAC-GED-0507 Gel led to:
  • decrease in cytokine IL-1α secretion
  • decrease in lipid peroxidation
  • change in the composition of sebum with a significant decrease of sapienic acid (the MUFA considered to play a prominent role in acne pathogenesis)
  • decrease in the activity of the sebaceous desaturase enzyme, FADS2
  • decrease in Akt/mTOR pathway activation
  • increased levels of PPARγ

Therefore the pharmacological anti-inflammatory and lipid-modulating activity demonstrated in vitro has been confirmed in the clinics.

NAC-GED-0507 a potential acne disease modifying agent

Studies on SZ95 sebocytes at different differentiation grade

Ottaviani et al., J Eur Acad Dermatol Venereol 2020

Results

The effect of insulin on SZ95 sebocytes is more pronounced in poorly differentiated sebocytes. In less differentiated SZ95 sebocytes, compared to differentiated sebocytes, insulin induces a stronger lipogenic boost and inflammatory response.

Pretreatment of low differentiation grade SZ95 sebocytes with NAC-GED-0507 induces sebocytes differentiation, making the cells less sensitive to insulin, and thus reducing the strong lipogenic and inflammatory effects induced by insulin.

Conclusions

NAC-GED-0507 treatment, could lead to acne prevention and prevention of acne relapse by inducing differentiation of poorly differentiated sebocytes.
NAC-GED-0507 would change the course of acne disease particularly in adolescents, in which a low differentiation grade of sebocytes makes the cells more responsive to insulin (whose physiological pubertal raised levels together with the high levels induced by high glycemic load diets have been identified as a major factor for acne onset in adolescents).

Psoriasis Pathogenesis

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Potential Indications

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References

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