With the publicized announcement on June 1st 2021 that the UK National Health Service had treated a 5 month old baby suffering from a severe form of Spinal Muscular Atrophy (SMA) with Zolgensma, a gene therapy with a list price £1.795million, gene therapies have been widely discussed in the popular media.
The root cause of SMA is an absence of SMN (survival motor neuron) protein, essential to motor neuron cells which control muscle function. Without this protein, the cells die leading to muscle weakness, difficulty in breathing, eating and moving, eventually leading to life threatening conditions in severe forms. Zolgensma is an SMN1 gene enhancing therapy which works by replacing the function of the missing or faulty SMN1 gene which encodes SMN protein with a new, working copy. A virus, adeno-associated virus 9 (AAV9) is the vector which carries the replacement gene into the body and this “infects” the cells with the new DNA, but does not change or become part of the child’s DNA.
Although the concept of gene therapy (i.e. DNA-based medicines that insert a healthy gene into cells to replace those missing or mutated) was first discussed in the early 1970s, it is still not widely known or understood. During the intervening decades there have been ups and downs in interest and it was not until 2003 that the first treatment was approved. This was in China, with a product called Gendicine for head and neck cancer. In the Western World, the first approval was not until Glybera by the EMA in 2012 (subsequently removed by the manufacturers). It took even longer for the first US approval of Kymriah for acute lymphoblastic leukemia in 2017 and to date there are only a handful more approvals. Potential applications are in treatment of diseases caused by recessive gene disorders (cystic fibrosis, MD etc), certain viral infections such as AIDS, and cancer. More recently retinal gene therapy has generated positive international news too. Could it be that after half a century the vision of genetic medicine is becoming more of a reality?
Over the past decade there have only been 15 ATMPs (Advanced Therapy Medicinal Products) approved in Europe, however four of these were subsequently withdrawn leaving only 11 with marketing authorization. Although it is reported that there are over 500 clinical trials ongoing in the EU since 2009, this doesn’t mean to say that there will be a tidal wave of these products emerging soon.
From a characterization standpoint, these rapidly developing technologies are complex and very different to traditional biopharmaceutical products. Currently in the field of Gene Therapy, recombinant adeno-associated viruses (rAAVs), initially discovered as a contaminant of adenovirus preparations, are the most widely used delivery vehicle for therapeutic administration of transgenes due to their high transduction efficiency, high levels of gene expression and favorable safety profile. As AAV capsid proteins are critical for viral infectivity and the AAV vector potency, complete characterization of the constituent Virus Particles (VPs) of AAV vectors, including their sequences and post-translational modifications (PTMs), is highly recommended. For example, it has been shown that deamidation of a number of Asparagine residues can have a significant impact on transduction activity and can also be an early factor in terms of loss of vector activity. In depth structural characterization of viral proteins is therefore essential to ensure AAV product quality and consistency.
The development pathways for these novel products appears to be both costly and lengthy. Regulatory pathways are also having to evolve. To add to the scientific challenges, these products often target conditions that affect very few patients, making commercial viability an issue even if marketing approval is granted. For example, only around 40 babies are born every year with the most severe form of SMA, however if left untreated then they would rarely live beyond two years old. The driving force for effective treatment for conditions where all else fails is very strong and gene therapies may slowly become the “game-changers” if not the “blockbusters”.