Event Review: Darwin Lecture: from gene identification to clinical benefit - the example of cystic fibrosis
27 November 2017
ByAppeared in BioNews 928
This year's event 'From gene identification to clinical benefit - the example of cystic fibrosis' was delivered by Professor Eric Alton at Imperial College London and the Royal Brompton Hospital, a 'leading authority in this country on cystic fibrosis', according to RSM president Sir Simon Wessely.
Cystic fibrosis (CF) causes more deaths than any other inherited disease in UK, with a median survival of 38 years. Professor Alton explained it as a 'genetic disease of lung water movement'. The disease is caused by a mutation in the CFTR (Cystic fibrosis transmembrane conductance regulator) gene, coding for a protein that spans the cell membrane and transports chloride ions and water from the inside to the outside of cells. With a mutated or missing CF protein, not enough water is transported resulting in a build up of dense mucus, especially in the lungs. In the small airways this leads to the build-up of bacteria, virus and dirt and causes chronic lung infections, which can be fatal.
Professor Alton gave the audience an overview of his work during the past 15 years, aiming to bring gene therapy for cystic fibrosis to the clinic.
The goal is to deliver a normal copy of the CFTR gene into the affected lung cells, which would then be able to produce a functioning protein and could regulate mucus consistency.
In practice, the delivery of therapeutic DNA to the lungs proved extremely difficult. 'We are working against evolution,' Professor Alton told the audience. Natural barriers exist to prevent the transfection of cells with foreign genetic material: the foreign genes have to get into the lung first, then across the thick mucus layer, past the cell membrane and finally into the cell nucleus.
The UK Cystic Fibrosis Gene Therapy Consortium, a team of scientists and clinicians working with Professor Alton, found that an ideal vehicle to pass these barriers would be to co- opt the elaborate intrusion machinery of a virus. Viruses can enter human cells to smuggle their genetic material into the cell nucleus.
However, the body's adaptive immune system nixed the researchers' plan: because it memorises viruses, they are recognised and discarded on a second infection, which means that therapeutic gene-carrying viruses only work once in a given patient. Instead, the researchers decided to use small lipid drops or liposomes, to pack the CFTR DNA for delivery. While the method is less efficient (lacking the advanced intrusion machinery that viruses have), liposomes can be administered repeatedly, which is necessary to sustain long-term improvement of the CF condition.
Clinical trials have shown that treatment with the liposomes provided a significant effect of 3.7 per cent protection against a decline in lung clearance compared with a placebo (Alton et al, 2015). The consortium have a final product approved and are entering a period of negotiations with pharmaceutical companies.
Professor Alton concluded his lecture by sketching the team's most recent research efforts: it returned to viruses to deliver the CFTR gene more efficiently. However, this time, the researchers managed to circumvent the body's adaptive immune system by combining two types of viruses: a Sendai virus, which provides a specialised ability to transfect lung cells and a lentivirus, which can insert DNA into the lung cell's genome in the long-term. Professor Alton proudly told the audience that the combined virus proved two orders of magnitude more efficiency at transfecting cultures of human cells than the liposomes. Crucially, the scientists demonstrated that - at least in a petri dish - the combined virus can be administered repeatedly, without the cells developing a resistance and that after two years, the transfected cells still produced the CFTR protein. Nevertheless patients would still need repeated treatments, as lung cells are renewed at least every 16 months.
Finally, Professor Alton reflected on what he had learned from the CF gene therapy effort: that gene therapy was about 'delivery, delivery, delivery'. While 'fantastic basic science' had been crucial to the project, the ultimate measure of success was the improvement for the patients. This had only been possible through partnerships between scientists and clinicians.
Following his talk, Professor Alton replied to audience questions, ranging from technical queries about the virus strategy, to political concerns that the Brexit would affect the funding situation for the project. He also explained the stages that gene therapy would have to go through before becoming standard therapy in the NHS: since gene therapy is expensive, treatment through the NHS becomes a question of balancing the benefit to one patient with benefits to other patients.
The final question linked back to Charles Darwin. Given the prevalence of CF, might there be a selective pressure of carrying the CF mutation - such as in the case of sickle cell anaemia, where heterozygous individuals which carry both a mutated and a healthy copy of the gene, are more resistant to malaria infections? Professor Alton explained three current theories: that carrying the CF mutation might confer cholera resistance (because individuals with a defective CFTR and thicker mucus would lose less water during a cholera infection); typhoid resistance (since Salmonella typhi, the bacterium causing typhoid fever, cannot enter cells with a mutated CFTR protein); and finally tuberculosis. Despite these intriguing possibilities, none of the theories fit with current understanding of the mutation's origins and spread within the human population.
Overall, the lecture was very informative and never lengthy, as Professor Alton didn't miss an opportunity to spice his lecture with jokes and anecdotes, such as declaring a conflict of interest - beard envy to be precise - with lecture's namesake, Charles Darwin. However, the setting was quite formal and the level of the lecture suited an audience with prior medical knowledge not intimidated by the medical habitus and technical terms. The audience was mainly composed of current, future and retired physicians, but I would recommend the lecture to anyone with a serious interest in science and medicine.