Epigenetic therapy for lupus on the horizon

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Epigenetic therapy for lupus on the horizon



Dec 28, 2005



Janis

Winston-Salem, NC and Charlottesville, VA - Much of the variability

in severity, organ involvement, and response to therapy among

patients with systemic lupus erythematosus (SLE) is blamed on

differences in gene expression. That, in turn, is due to epigenetic

mechanisms such as changes in chromatin structure caused by

acetylation, methylation, or phosphorylation of histone, one of the

" master regulators " of gene expression.

A research team led by Dr Nilamadhab Mishra (Wake Forrest University

School of Medicine, Winston-Salem, NC) reports in the November-

December 2005 issue of the Journal of Proteome Research that a mouse

model of lupus has aberrant histone codes caused by posttranslational

changes in acetylation and that these bad codes can be " reset " by

treatment with a histone deacetylase (HDAC) inhibitor [1]. The

investigators think that this is why HDAC inhibitors reduced kidney

disease, skin disease, and lymphoproliferation in previous studies

with these mice [2,3,4].

Since one of those compounds was the widely used antiseizure drug

valproic acid (divalproex sodium, [Depakote, Abbott Laboratories]),

clinical trials in lupus patients could begin relatively soon, and

Mishra told rheumawire that such a study is on the drawing board.











By resetting the defect, these drugs may produce better outcomes than

other treatments.













" Do not give up hope! " Mishra advises rheumatologists. " Besides

genetics, epigenetics plays a major role in complex diseases like

lupus. Now there is great enthusiasm for developing drugs by

targeting single pathways, but trichostatin A [TSA], suberoylanilide

hydroxamic acid [sAHA], or valproic acid can target multiple defects

at the same time. By resetting the defect, these drugs may produce

better outcomes than other treatments. "

Depakote, other HDAC inhibitors " reboot " the chromosome

Mishra suspects that epigenetic changes explain why lupus is more

common in females, why it affects age groups differently, and why

clinical manifestations differ among lupus patients. One of the

changes found in this study, histone 3 (H3) trimethylation,

suppresses one copy in each pair of X chromosomes during development

of female animals. This change was five times more common in the

lupus mice than in normal mice, and the investigators think that it

might shut down a part of the active X chromosome that would

otherwise protect against lupus.

Since epigenetic changes accumulate over time and in response to

environmental factors, they might also explain why one genetically

identical twin can develop lupus while the other does not.

Treatment with the HDAC inhibitors essentially reboots the gene by

stripping away the accumulated epigenetic changes.











These observations may eventually provide the foundation for the use

of combination epigenetic therapy using methylase inhibitors plus

HDAC inhibitors for the treatment of SLE.













The current study showed that lupus-prone mice have both

overmethylation and undermethylation of various histone codes. Two

specific methylation changes and one acetylation change

differentiated lupus mice from normal controls. Treatment with TSA

corrected the site-specific hypoacetylation states on H3 and H4 and

improved the clinical status of the mice.

" Thus, this study is the first to establish the association between

aberrant histone codes and pathogenesis of autoimmune disease SLE.

These aberrant posttranslational histone modifications can therefore

be reset with histone deacetylation inhibition in vivo, " the

investigators write.

They continue, " These observations may eventually provide the

foundation for the use of combination epigenetic therapy using

methylase inhibitors plus HDAC inhibitors for the treatment of SLE. "







Sources



BA, Busby SA, Shabanowitz J, et al. Resetting the epigenetic

histone code in the MRL-lpr/lpr mouse model of lupus by histone

deacetylase inhibition. J Proteome Res 2005; 4:2032-2042. 

Reilly CM, Mishra N, JM, et al. Modulation of renal disease in

MRL/lpr mice by suberoylanilide hydroxamic acid. J Immunol 2004;

173:4171-4178. 

Ziolkowska A, Nghiem A, Snowwhite I, et al. Valproic acid prevents

skin disease and attenuates severity of kidney disease in MRL-lpr/lpr

lupus-like mouse model. 2005 ACR/ARHP Annual Scientific Meeting;

November 12-17, 2005; San Diego. Abstract 1686.

Reilly CM, Mishra N, JM, et al. Modulation of renal disease in

MRL/lpr mice by suberoylanilide hyodroxamic acid. J Immunol 2004;

173:4171-4178. 



http://www.jointandbone.org/viewArticle.do?primaryKey=623273