Creating Gene Therapies for Cystic Fibrosis

The curative power of gene therapies

Long before the human genome had been sequenced, many diseases were known to have a genetic origin. In the 1960s, shortly after the discovery of DNA, scientists began to suspect that we could tinker with pieces of DNA to alter monogenic diseases – those with a single genetic culprit. In the 1980s, our understanding of how DNA worked, and how we could manipulate it, started to be substantial enough to consider using genes as therapies.The first person to receive a gene therapy – a 4-year-old girl with a certain type of severe combined immunodeficiency (SCID) – was treated in 1990. Scientists inserted a copy of the gene she was missing into her blood cells using a viral vector. Gene therapy was born.

Around this same time – 1989, to be precise – scientists also identified the gene that causes cystic fibrosis (CF). CFTR encodes an ion channel, and patients with mutations that prevent this channel from being produced or from working properly develop CF. Malfunctioning CFTR means that cells in the lungs and other tissues of people with CF accumulate chloride ions inside. WIthout the free flow of chloride ions, the surfaces of those cells are improperly hydrated, and thick mucus builds up. This leads to the symptoms of CF, which include persistent lung infections and tissue destruction in organs like the pancreas.

So if we know which gene causes CF, and we’ve known about gene therapies for decades, why isn’t there a curative gene therapy for CF?

Delivering the gene to the right place

It turns out that getting genes to the right tissues is really hard. To date, almost all gene therapies that are approved or in late-stage trials can be grouped into two categories: those that deliver genes to blood cells outside the body (as was done for the SCID gene therapies); and those that deliver the therapy to the liver, which then acts as a mini-factory, releasing therapeutic proteins into the blood. Neither of these strategies will work for CF. Getting CFTR into lung epithelial cells and other cells that are affected in CF is an enormous challenge.

Recent developments in lipid nanoparticles (LNPs), however, could turn these fat globules into gene therapy favourites. Advances in the construction of these delivery vehicles, which are the biological equivalent of bubble wrap, are encouraging. Choosing the lipid components carefully has recently made it possible to direct LNPs towards particular tissues. We’re designing strategies to help even further, by adding tissue-specific ‘address labels’ to the bubble wrap, with the aim of using them to deliver a curative therapy to all tissues affected in people with cystic fibrosis.

Our other big challenge is in the cargo itself. At the moment, LNPs are predominantly used to deliver mRNA, rather than DNA. Although this is an important development, most famously used to deliver COVID vaccines, we see this as a stepping stone to something bigger. Whereas mRNA therapies are transient, because the mRNA degrades within days or  weeks, we think we can use LNPs to deliver DNA. If we can get that DNA to stick around, this could be a long-term, curative therapy.

The opportunity here is enormous, and is one that we are actively working on at Deep Science Ventures. Jey Jeyakumar joined us earlier this year, with the broad remit of identifying innovative solutions to develop curative therapies for CF. By evaluating the constraints within the field, he has identified that LNPs could be ripe for DNA-based curative therapies. If we can develop a novel system to target DNA-containing LNPs to different parts of the body, these could form the basis of curative therapies in multiple monogenic diseases, or diseases in which a single gene could have therapeutic value.

Jey is now hiring a co-founder to found his company. If you are an entrepreneurial LNP specialist, who is interested in founding a company within this area, we want to hear from you! Please see more details on the role and the application process on this job description.