First gene silencing drug offered on NHS

By Philippa Brice

8 July 2019


A new type of medicine that uses an approach called ‘gene silencing’ has been approved for use in the National Health Service (NHS) in England.

The medicine, patisiran (brand name Onpattro) is used for a condition called hereditary transthyretin amyliodsis (hATTR), a severe and potentially life-threatening condition for which the only other treatments available are typically to manage symptoms, sometimes requiring drastic measures such chemotherapy, stem cell or liver transplants. The new medicine, in contrast, has been hailed as making the ‘previously untreatable, treatable’; it actively targets the underlying disease mechanism, rather the symptoms it causes, and can halt and even reverse the process.

With final guidance for use from NICE in progress, patisiran is also the first gene silencing drug to have been approved by the US regulator the FDA in 2018. A second drug called inotersen (brand name Tegsedi) has also been approved for use by NICE for the treatment of hATTR; this is another type of gene silencing medicine, though it uses a different mechanism from Onpattro to silence the defective transthyretin gene that causes illness by producing defective TTR proteins that cause toxic accumulation in body organs.

Prof Julian Gillmore of the Royal Free Hospital in London, an amyloidosis expert, told the BBC that: "This has very far-reaching potential consequences, it has a huge potential".

Treatments using gene silencing have also been developed and trialled for the rare metabolic disease porphyria, and it is expected that more will follow.

What is gene silencing?

It effectively does what it says, ‘silencing’ specific genes. In nature, gene sequences within DNA are actively expressed by being copied to make matching messenger RNA (mRNA) sequences, which then direct the production of proteins. One process for suppressing or blocking this process of gene expression is a mechanism called gene silencing, whereby another type of RNA called small interfering RNA (siRNA) binds to and blocks specific mRNAs.

The technique, a form of epigenetic modification, is also called RNA interference. It was discovered over twenty years ago and the potential for therapeutic application was considered almost immediately, but it has taken a long time to effectively harness it for new gene silencing medicines. This is largely due to challenges in creating effective delivery systems (much as with gene therapies) that will get the treatment to the target organ or organs intact.

Implications for rare disease treatments

These new gene silencing medicines are an important step forward for highly personalised therapeutics – and clearly, potentially life-changing for recipients; however, they are only likely to be used for very rare and severe conditions in the near future. This is primarily because they are extremely expensive; costs for both Onpattro and Tegsedi have been estimated at around £300,000 per year; Onpattro is delivered by intravenous infusion every three weeks, whilst Tegsedi uses weekly subcutaneous injections.

A number of companies are reportedly developing gene silencing based therapeutics for a range of conditions, including attempts to produce delivery mechanisms that could target different parts of the body, such as inhalable treatments for cystic fibrosis. This is good news for rare disease patients, but is likely to pose problems by way of ever-rising costs for funders. Clearly, any future health system with limited financial resources – and they will be – will have to ensure that innovations in science and technology deliver significant cost savings through efficiencies, better prevention, and earlier and more precise diagnoses and interventions to offset the upfront costs of highly personalised therapeutics. This is an issue that will also shape ongoing development of the pharmaceutical and biotech industry and their relationships and reimbursement mechanisms with healthcare providers.

What about gene therapy?

The important distinction between gene therapy / genome editing and gene silencing treatments are that the former, by acting to correct the underlying genetic defect, are a form of semi-permanent or (ideally) permanent cure, whereas gene silencing is a lifelong treatment for a disease. Gene therapy agents also have to directly target (and change) DNA within a cell, whereas gene silencing targets smaller, more accessible RNA molecules in cells.

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