HDAC2 blockade by nitric oxide and histone dacetylase inhibitors reveals a common target in Duchenne muscular dystrophy treatment.
What are histone deacetylase (HDAC) inhibitors ? HDAC inhibitors work by adding an acetyl group to histones. Histones are proteins that are associated with DNA and regulate gene activity. TSA (trichostatin A) is an example of a HDAC inhibitor which is being studied both as a breast cancer therapy drug and has been studied in both the mdx mouse model (Duchenne) and sarcoglycan deficient mouse model (LGMD).
How do histone deacetylase (HDAC) inhibitors work to treat muscular dystrophy? HDAC inhibitors work by increasing follistatin which antagonizes myostatin. This is yet another example of how inhibiting myostatin improves muscular dystrophy (see prior posts on myostatin inhibition through propetide, ACE-031). It is still unclear if myostatin inhibition will have a therapeutic effect in the CMDs.
What is HDAC2? HDAC2 is a histone deacetylase enzyme. Dr. Puri showed that a mutation in dystrophin leads to an increas in the amount of HDAC2. When he inhibited HDAC2 with an HDAC inhibitor, the dystrophic muscle cells returned to a normal histology (appearance) and function.
What did the clinical trials show?
In the first clinical trial published in 2007, Dr. Puri at Burnham Institute demonstrated that HDAC inhibitors in the mdx mouse and sarcoglycan deficient mouse increased muscle fiber size and decreased inflammation and fibrosis. The HDAC inhibitor, trichostatin A was used.
In the second clinical trial published in 2008, Dr. Puri demonstrated a closer link between HDAC inhibition, NO (nitric oxide) signaling and dystrophin deficiency. He demonstrated:
- increased levels of HDAC2 and HDAC2 activity in mdx mouse muscle.
- downregulation of HDAC2 levels in the mdx mouse has a comparable effect to treatment with NO donors and HDAC inhibition
- restoring NO either by adenoviral expression or exposing mdx satellite cells to NO, led to HDAC2 inhibition
The HDAC inhibitors, follistatin upregulation and inhibition of HDAC2 (NO signal upregulation) represent possible convergent therapies for improving muscle size, decreasing inflammation and fibrosis.
For more information, visit the following sites:
1.Medical News today news release Dec 2008