Reports have appeared in the UK media of the NHS administering the most expensive drug in the world to a 5-month-old boy. Onasemnogene abeparvovec (sold as Zolgensma), costing around two and a half million US-dollars (£1.79 million),* is a gene therapy agent to treat spinal muscular atrophy. The headlines quoted the price but gave scant details on what Zolgensma is and how it works. And when you look a little deeper, it turns out there are some parallels with Covid-19 vaccines.
Spinal muscular atrophy is a serious genetic disorder that affects around 1 in 10,000 people worldwide. Being relatively rare, it’s classified in the pharmaceutical jargon as an orphan disease and until recently received comparatively minor attention. Zolgensma was originally developed by a biotechnology company called AveXis, funded largely from charities and the National Institute of Health in the USA and before this, basic research was carried out by the French Muscular Dystrophy Association. In 2018, Novartis bought AveXis for $8.7 billion, and now manufactures and markets Zolgensma.
Different species possess different numbers of chromosomes. The male Australian ant (Myrmecia pilosul) has just one chromosome, the Adder’s tongue fern (Ophioglossum reticulatum) has 1260 and humans have 46. Our 46 chromosomes are arranged as 23 pairs, one in the pair inherited from the father and the other from the mother. (Pears incidentally, have 34 chromosomes arranged in 17 pairs). Within the chromosomes is DNA, and DNA is arranged into genes. The genes comprise a sequence of DNA bases that code for proteins, and proteins make up the stuff of life for every living organism from bacteria to you and me. The human DNA code is around 3-billion bases long and given this complexity, now and again something goes wrong with one of the genes. This is not usually a problem because if there’s one faulty gene then there’s a duplicate in the other paired chromosome that can still do the job. Occasionally however, the genes on both chromosomes go wrong, in what’s called “autosomal recessive inheritance” and then there can be a problem.
On human chromosome number-5 there are a series of genes collectively known as survival motor neuron genes (SMN). There are two types – SMN1 and SMN2 which make SMN protein, one protein in a group called the SMN complex, which is important in maintaining motor neuron cells. These are the nerve cells which transmit signals from the brain and spinal cord to control muscle contractions. The role of the SMN complex is… well,… complex. It’s involved in processing messenger RNA (mRNA), which is the intermediary molecule between the DNA code and its associated protein. mRNA starts out as a “rough draft” known as pre-mRNA and has to go through a number of processing steps before it’s transformed into the working copy. With a faulty SMN complex that final working copy never emerges and so motor neuron-associated proteins are not made. Over time motor neurons therefore degenerate which leads to progressive muscle wasting and within a year or two, it’s usually fatal.
The body has a back-up to the SMN1 gene – SMN2, but SMN2 typically only makes 10% of the SMN1 protein. Some people with spinal muscular atrophy might have multiple copies of the SMN2 gene, in which case the disease is not as severe. On the whole however, most patients have one inoperative SMN1 gene and two SMN2 genes which only make a fraction of the SMN protein required.
Not that long ago there was not only no treatment for spinal muscular atrophy, but most physicians would say there could never be an effective treatment because the root cause goes back to genetics. They were wrong. Zolgensma is not a drug in the normal sense. It comprises two parts, a length of laboratory-made DNA to replace the faulty SMN1 gene and the husk of a virus called vector adeno-associated virus 9 (AAV9). The viral vector is manufactured in isolated Human Embryonic Kidney cells (HEK293) originally grown by Dutch biologist Alex Van der Eb in the early 1970s. The viral genetic material is removed and the SMN1 replacement gene is placed into the empty shell which acts as a vector, delivering DNA to motor neurones. (Without the vector the body would rapidly break the DNA down). This is similar to the Covid-19 vaccine from the Jenner Institute at Oxford, where they developed technology using adenoviruses and modified Vaccinia Ankara (MVA) virus as vectors for genetic material to code for spike proteins on SARS-Cov-2. As the body translates the code into spike protein, so it primes the immune system against future SARS-Cov-2 infection. If you’ve had the Astra-Zeneca vaccine (developed at the Jenner) then you would have received this type of vector vaccine.
The SMN1 gene delivered by Zolgensma is not incorporated into human DNA, but sits within the cell’s nucleus where the normal molecular machinery translates it to SMN protein. The intention is to administer Zolgensma just once to replace the faulty gene but as experience grows over time, the necessity for further administrations cannot be ruled out.
Currently Zolgensma is approved for children under 2-years of age but timing appears important and it should be given as soon after diagnosis as possible. It is administered by intravenous infusion but research continues to develop delivery systems directly into the cerebrospinal fluid, which could make Zolgensma available to a wider patient base.
Zolgensma is not the first gene therapy agent to be approved, there are around a dozen others in use. To give just one as an example, about one in a million people have a deficiency in their lipoprotein lipase gene leading to elevated levels of triglycerides and ultimately liver and pancreatic disease. A gene therapy agent called alipogene tiparvovec uses the adeno-associated virus serotype 1 as a vector to deliver a copy of the human lipoprotein lipase gene to muscles, thereby bypassing the faulty one.
All gene therapy agents are expensive but they are also state-of-the-art pharmacotherapy based on science which goes back to at least 1953, when the structure of DNA was first elucidated. Science is like that. It’s a series of dots that join together from many sources over many years and at the start it’s impossible to predict what the dot-to-dot picture will look like. Let’s hope we are entering a new age of genetic therapy giving hope where before there was none. And then from there, who knows?
* a confidential deal was struck between the NHS and Novartis Gene Therapies which reportedly reduced the price tag.