Various approaches are currently used to treat and manage psoriasis, and biological treatments are
often the latest approaches. All biological treatments have major side effects as they are given
systemically via injections. One of the latest biological treatments for psoriasis, one which has
shown great efficacy with fewer side effects, is Secukinumab. Secukinumab is an anti-IL17
antibody that works by stopping the action of IL17, a cytokine that is known to have a major role
in the pathogenesis of psoriasis. This work is based on the development of a new way to commence
drug therapy to reduce the side effects of the treatment.
Our work is based on the studies of the genotoxicity of the drug Secukinumab in its bulk and
liposome form using comet and micronucleus assays on lymphocytes. The results from both assays
have illustrated the safety of the drug and demonstrated the reduction of the DNA damage induced
in both healthy individuals and patients with psoriasis. Secukinumab significantly decreases-H2O2 induced damage and efficiently attenuates its adverse effects both in the comet (p<0.0001) and
micronucleus assays (p<0.01). The two concentrations of Secukinumab used (2.1 and 2.8μg/ml)
efficiently decreased H2O2-induced DNA damage in both groups to nearly the level of the negative
control. Overall, Secukinumab reveals protective and anti-genotoxic effects by demonstrating its potential in reducing DNA damage caused by oxidative stress and by not inducing any further
damage in the lymphocytes of either healthy individuals or patients. Liposomes are highly versatile
which have been proven efficient for therapy and research applications. The discovery of new
therapies in the treatment of psoriasis is a considerable challenge and is now a necessity. Our study
was the first one to determine the genotoxicity of various concentrations of the drug in the
lymphocytes of psoriasis patients compared to healthy individuals. In the MTT assay, the data
showed a decrease in % cell survival rates after exposure to different concentrations of
Secukinumab. Also, the results demonstrated no statistically significant differences on
confounding factors such as ethnicity, smoking, drinking habits, gender and age among psoriasis
patient and healthy controls. The regulation of gene expression levels of IL-17, IL-22 and RORC
were assessed after treatment with Secukinumab in the bulk and liposome form via RT-PCR analysis. Secukinumab bulk (2.1μg/ml) treatment significantly down-regulated gene expression of
IL-17, IL22 and RORC to 0.46-fold, 0.47-fold and 0.5-fold, respectively. However, Secukinumab
liposome (2.1μg/ml) only decreased the expression of IL-17 and IL-22 significantly, by 0.46-fold
and 0.53-fold, respectively. On the other hand, studying the expression of P53 and P21 using
qPCR revealed that Secukinumab bulk and liposome has no effect on the expression of these genes
in lymphocytes from healthy individuals and psoriasis patients.
Western blotting was used to investigate the effect of Secukinumab in both forms on protein
expression levels IL-17, IL-22 and RORC. Analysis of the results showed that Secukinumab bulk
and liposome had no significant effect on expression levels of any of these proteins in lymphocytes
derived from healthy individuals. However, there was a statistically significant down-regulation
observed in the protein expression levels of IL-17, IL-22 and RORC in lymphocytes obtained from the psoriasis patients, confirming the sensitivity of the compromised lymphocytes from patient group to Secukinumab treatment. With Secukinumab (bulk form) administration, a 0.5-fold
decrease was observed in IL-17, 0.59-fold decrease in IL-22, and a 0.6-fold decrease in RORC
expression. However, liposome form reduced their levels to 0.47–fold, 0.5-fold and 0.47–fold,
respectively, when compared to the control group. While it had no significant effect on expression
of P53 and P21 proteins in lymphocytes from healthy individuals and psoriasis patients and there
was no difference observed in their regulation. In conclusion, the use of Secukinumab liposome as
topical drug delivery system may be suitable replacement for improving the drug bioavailability
and its side effects. / Libyan Cultural Attaché and Libyan embassy
| Identifer | oai:union.ndltd.org:BRADFORD/oai:bradscholars.brad.ac.uk:10454/19972 |
| Date | January 2022 |
| Creators | Layas, Gazala I. |
| Contributors | Najafzadeh, Mojgan, Anderson, Diana |
| Publisher | University of Bradford, School of Chemistry and Biosciences. Faculty of Life Sciences |
| Source Sets | Bradford Scholars |
| Language | English |
| Detected Language | English |
| Type | Thesis, doctoral, PhD |
| Rights | <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/"><img alt="Creative Commons License" style="border-width:0" src="http://i.creativecommons.org/l/by-nc-nd/3.0/88x31.png" /></a><br />The University of Bradford theses are licenced under a <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/">Creative Commons Licence</a>. |
Page generated in 0.0023 seconds