A gene silencing treatment for a rare, but debilitating genetic disorder has been recommended for NHS use by the National Institute for Health and Care Excellence (NICE).
Acute hepatic porphyria (AHP) refers to a family of four genetic conditions causing recurrent attacks of severe abdominal pain and vomiting as well as neurological problems such as anxiety, depression and seizures. The disease is caused by genetic variants that introduce defects in haemoglobin synthesis, which leads to the build-up of toxic molecules called porphyrins in the liver.
'Some patients experience regular, intense pain, have to spend long periods of time in hospital and be unable to continue working or have a normal social life,' explained Professor David Rees, director of the National Acute Porphyria Service (NAPS). 'By using this pioneering 'gene silencing' approach... we now have a better chance to help many of those affected live a more normal life.'
Currently available treatments mitigate symptoms of AHP but are not effective in preventing attacks in the long term and have strong side-effects. An ongoing clinical trial has shown that the new drug givosiran can prevent up to 74 percent of attacks by suppressing the activity of ALA synthase-1 – an enzyme that is overactive in AHP and contributes to the toxic accumulation of porphyrins.
Unlike some other forms of gene therapy, gene-silencing does not change patients' DNA. Rather, it uses an RNA interference (RNAi) approach to control the activity level of the ALAS1 gene by intercepting the messenger RNA copied from the gene. This prevents cells from using the RNA as a template to make the enzyme. To maintain a target gene 'silent', treatments need to be ongoing. Givosiran, for example, is administered as a monthly injection to suppress ALAS1.
Givosiran, which was approved last year by the European Medicines Agency, is recommended by NICE for the most severe AHP cases, where attacks occur four or more times a year. The approval has been welcomed by NAPS and the British Porphyria Association.
'I suffered a progressive deterioration in health with each attack: increased weakness, more pain, more fatigue' said Sue Burrell, who took part in the clinical trial. 'Givosiran has been completely life-changing. I am able to contribute to family life, to my life, to think of the future.'
In the UK, gene silencing has already been used to treat amyloidosis, another rare genetic disorder (see BioNews 1006), as well as to reduce cholesterol levels (see BioNews 1111). Because it tackles diseases at their root cause with high specificity, this therapeutic approach opens a door to the personalised treatment of many other genetic conditions.