Biological therapy, biology, genetic modification, medicine, News, Science, science news

A successful first for gene therapy

Who would like to hear some really good news? Thought so. One of the promises of the molecular biology and genomics revolutions was that gene therapy – replacing defective, disease-causing genes with functioning ones, or otherwise treating these diseases by genetic means – would become a reality. Even, optimistically, something commonplace. Like so many things, however, it has proved more complicated than hoped, and those longed-for treatments elusive. There has never been a therapy of any kind that alters the disease progress of a neurodegenerative disease – until now.

Recent results of a (phase 2) clinical trial were published in The Lancet last month of a new drug to treat Spinal Muscular Atrophy (SMA), a devastating disease that is the leading genetic cause of death in early childhood. About 1 in 11,000 children inherit a defective, deleted copy of the SMN1 gene (“survival motor neuron 1”), and about 60% of those have the severest form. The disease destroys the nerves (motor neurons) responsible for movement: those babies with the severe form never achieve independent sitting; most will die from respiratory paralysis by the time they are two. Horrible.

The trial reports on a drug called nusinersen. I say drug, but it’s not a drug in the conventional sense of pharmacology: it is in fact what is called an anti-sense oligonucleotide (ASO). Sounds complicated – yes and no. Essentially, in the process of getting functional protein from your DNA code, it is first “transcribed” into an RNA intermediate (mRNA), before being “translated” into protein. The RNA intermediate is a sequencce of bases that is complementary to the DNA coding sequence. An antisense RNA is an RNA molecule that is complementary to the RNA intermediate and will bind to it. This affects how it is translated into protein. An “oligonucleotide” is just a short string of around 25 bases. What an ASO does is affect the splicing machinery. Uh-oh, more terminology. Bear with me.

Survival of infants with SMA is dependent upon a small amount of normal SMN protein translated by the backup SMN2 gene. Now, genes have regions that code for protein (exons) and regions that don’t (introns): getting the correct protein depends upon “splicing” out the non-coding bits correctly. The protein made from the SMN2 gene, due to a variant in this splicing process, usually skips out exon 7. So it’s not as effective as the SMN1 protein because it can’t completely compensate for it. The ASO used here binds repressive sites within SMN2 exon 7 or the introns on either side, promoting inclusion of this exon 7, increasing production of functional SMN protein. This helps rescue the motor neurons and restore function.

Here’s a nice diagram from a related news feature in Science magazine

Science, Vol 354, Issue 6318, pp.139-1360


The drug is injected intrathecally, i.e. into the spine, and so travelling through the brain and spinal cord. Infants treated with this showed dramatic improvements, so much so that the placebo control was later abandoned because it would have been unethical to continue to deny these patients access to the treatment. Most of the patients improved, and some did so dramatically, achieving milestones never seen in children with that severity of condition. It’s not a miracle cure (few things are): it can’t restore motor neurons that are already dead, and the children did not achieve a mobility comparable to those without the disease, but the improvements were substantial. Of the 20 babies that started treatment, 13 are still alive and breathing on their own today, at 2 and 3 years old, even though half of untreated babies with this form of SMA ordinarily die or end up on ventilators before their first birthdays. What’s more, the improvements are continuous: they keep getting better motor function the longer they continue with the treatment. The drug was sent for fast-track approval with the European Medicines Regulatory Agency and the FDA – the FDA approved it on 23rd December.

The figure below is the last slide I had in a lecture on control of gene expression (i.e. how and when genes are turned on and off, and how much protein is made). It was for first year pharmacy students. It depicts the different potential control points from DNA to final protein product (and then the degradation of that protein). I gave them examples of drugs that targeted various processes (in pink). The green arrows with question marks are points of control that are potential targets, but are largely unexplored. This ASO would act at stage 2, RNA processing control. Almost all drugs in current use target protein activity: they affect the activity of enzymes (biological catalysts) or recognise and stimulate/inhibit the proteins that cells used to signal to each other during control of bodily processes. In a sense this is logical, but in another sense it’s clear there’s a lot of unexplored potential out there, particularly for diseases caused by (or contributed to) faulty genes. This treatment is a great first step into a new era of gene therapy.




Finkel RS. et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase II, open-label dose escalation study. Volume 388, No. 10063, p3017–3026, 17 December 2016,

Wadman, M. Antisense rescues babies from killer disease.  Science 16 Dec 2016: Vol. 354, Issue 6318, pp. 1359-1360 DOI: 10.1126/science.354.6318.1359


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