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#apaperaday: HDAC inhibitors as pharmacological treatment for Duchenne muscular dystrophy: a discovery journey from bench to patients

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled:  HDAC inhibitors as pharmacological treatment for Duchenne muscular dystrophy: a discovery journey from bench to patients

Today’s pick is from @TrendsMolecMed by Mozzetta et al on HDAC inhibition as a treatment for Duchenne muscular dystrophy. Selected for the @TREAT_NMD @jwmdrc week as it outlines therapy development from preclinical to clinical doi 10.1016/j.molmed.2024.01.007

Disclaimers: Givinostat is an HDAC inhibitor in clinical development for Duchenne. It is developed by Italfarmaco. I am an ad hoc consultant for this company and we have also done contract research for them.

First some background to explain what HDAC is and does. Our genes consist of DNA, which is a very long thin thread. To prevent this from tangling and breaking the DNA is wrapped around histones

When DNA is tightly wrapped transcribing genes is difficult. How to loosen it up? Adding an acetyl group on a lysine in histone proteins. This reduces the positive charge of the histone. DNA is negative, so it will extend. Like 2 magnets with the same poles cannot be close

Histone acetylases (HATs) add the acetyls, while histone deacetylases (HDACs) remove them. So HDAC inhibitors prevent the removal and allow DNA to be more open. There are different classes of HDAC based on where in the cell they are located and what they target.

Note that acetyl groups are not only added to lysines in histones but also in other proteins. This can have an effect on eg stability or location of the proteins. A chemical to inhibit HDACs was discovered in a bacteria culture. However that compound was very unstable.

Medicinal chemistry helped to make other HDAC inhibitors with more druglike properties. These inhibitors can sometimes inhibit all HDACs but sometimes are specific for a class or a type. 5 HDAC inhibitors are approved so far for various types of cancer

So how can HDAC inhibitors be used to treat a muscle disease like Duchenne? Due to lack of dystrophin, Duchenne muscles are continuously damaged. Damage repair in muscle requires a time sensitive interplay of processes and cells. Due to chronic damage this is lost

Givinostat, a panHDAC inhibitor can synchronize this. At least in mdx mice it increases follistatin, so muscle regeneration and growth is promoted. It inhibits proinflammatory macrophages so repair is not stuck in early regeneration but also differentiation can happen

It prevents fibroadipogenic (FAP) cells from transdifferentiating into fibrotic and fat tissue but rather do what they are supposed to do during muscle repair: support the muscle stem cells.

In mdx mice this led to less fibrosis & inflammation, better regeneration, less membrane permeability & improved muscle strength & performance. In early stage Duchenne patients biopsies there was less fibrosis in muscles after a year of givinostat treatment compared to baseline

In a placebo controlled trial Givinostat treated patients performed better on the 4 stair climb test (primary endpoint) and most other secondary tests including less fat in the muscle measured by MRI. A dossier has been submitted to FDA and EMA

Authors stress that when there is too much pathology in the muscle FAPs appear to become resistant to givinostat’s effect. This is why givinostat was tested in young patients. However i do not think this means it will only work in young patients

Muscles are damaged and lost at different rates per muscle for Duchenne patients. In a non ambulant patient the muscles in the leg are likely beyond the point of no return. However there may be muscles left in the arms and respiratory muscles and sometimes only in the hand

Another point authors make is that givinostat treatment does not address the cause of the disease: lack of dystrophin. However we should not forget that dystrophin restoring approaches restore only partial functional dystrophin for most patients.

Thus damage and repair will still happen and support to improve repair is likely of added therapeutic value. Finally authors discuss side effects such as GI problems and thrombocytopenia. The latter means that sometimes the dose has to be lowered. This is something to monitor.

Authors point out lacking an HDAC is often lethal during embryonic development. However inhibiting is not the same as deleting. especially when we inhibit post natally. I do not want to trivialize the side effects. The thrombocytopenia is something that will have to be monitored.

Furthermore we do not know what the long term treatment effects will be. This is of course the case for all new therapies and a risk families and patients have to weigh against the risk of what happens when they are not treated