22 May 2023

A new US study will investigate whether a class of cancer growth blockers – HDAC inhibitors – could also reduce the pain and damage caused by sickle cell disease.

Sickle cell disease is caused by mutations in the gene for haemoglobin subunit-beta, also known as β-globin. These mutations change the structure of haemoglobin, which reduces its capacity to carry oxygen. It also leads to the ‘sickle’ shape of red blood cells, which block blood vessels and cause painful episodes called vaso-occlusive crises. 

Foetuses and babies carry a different type of haemoglobin which does not contain the β-globin  subunit and so does not lead to ‘sickling’ of red blood cells. However, within the first few months after birth, most babies have little to no foetal haemoglobin left.

Treatments which reactivate the key gene that produces foetal haemoglobin could therefore have potential as therapies for sickle cell disease.

One class of drugs which can switch genes back on are HDAC inhibitors, which are currently used for the treatment of some cancers. Now a new trial is investigating whether the HDAC-inhibitor panobinostat can switch back on the foetal haemoglobin gene in adults to help ease the issue of inefficient oxygen delivery in sickle cell patients.

The trial is being led by Dr Abdullah Kutlar from the Medical College of Georgia and Augusta University Health, and Professor Betty Pace from Augusta University.

“HDAC inhibitors are drugs known to change the expression of certain genes,” said Dr Kutlar. “When you inhibit the histone deacetylases, what you do is enable some of the genes that have been shut down by certain mechanisms to get expressed again. That is important for sickle cell because we know in adults that the fetal haemoglobin gene is shut down and we know fetal haemoglobin works very well as a disease modifier.”

Panobinostat is a pan-HDAC inhibitor, which means it silences more than one type of histone deacetylase enzyme. Early studies in mice and humans have shown that panobinostat can reactivate the gene that produces foetal haemoglobin.

Hydroxyurea, the first sickle cell drug approved by the U.S. Food and Drug Administration, also increases foetal haemoglobin, though exactly how this happens is not clear. Nevertheless, Dr Kutlar says, if panobinostat continues to show promise, he plans to pair the two drugs to see if they work efficiently together.

The phase 1 trial will explore panobinostat’s safety and efficacy in 18 patients – none of whom take hydroxyurea. They will take either 15 or 20 milligrams several times per week and their levels of the foetal haemoglobin and levels of F-cells will also be monitored.

“It’s not going to be a cure for sickle cell disease but it’s going to be a significant disease modifier, which will let these patients survive longer without so much organ damage and hopefully without so much pain,” said Dr Kutlar.

Source: Medical College of Georgia


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