Gene therapies are all the rage these days in the world of emerging biotech. It’s not hard to understand why. It has never been cheaper (on a giant scale) to understand human genetics and the human genome. We’re also living at a point in time where technologies to deliver whole genes or “correct” existing genes is no longer science fiction. Let’s start this with a quick vocab lesson because a lot of these terms are thrown around in different ways and may hold different meanings based on whomever is using them. So, for the purposes of this blog post I am sharing how I simply define them (I am removing a lot of complexity).

First, a quick biology refresher: DNA makes RNA, which makes protein.

Gene therapy: a drug or procedure that delivers a gene, which then codes for specific proteins. In the context of CF, that would mean a created gene delivered to target cells containing disease-causing CFTR genes. The newly administered gene then codes for the correct CFTR protein, whereas the disease-cause CFTR gene codes for the dysfunctional CFTR protein. The newly minted, functioning CFTR proteins do their jobs correctly.

Gene editing: a technology that changes an existing gene to whatever is desired. In the context of CF, a gene editing technology (maybe you’ve heard of CRISPR), would be used to edit the mutated disease-causing CFTR gene to allow for the creation of functional CFTR protein.

Bonus… RNA Therapeutic: Cuts the gene part out of the process. A specific RNA code is sent to target cells, which then creates the protein desired (like functional CFTR).

Each of these methods possess their own unique challenges, characteristics and potential benefits.

Today… we’re only talking about gene therapies

Earlier this week it was announced that 4D Molecular Therapeutics has dosed its first CF patient in an early-stage clinical trial. The gene therapy space in cystic fibrosis is already crowded (and even more so if you count the gene editors), but to learn one of the companies is dosing patients just shows how important this step is, especially for the non-modulated part of our population. Non-modulated patients (largely) have nonsense mutations in their CFTR genes that do not code for the creation of CFTR protein. Modulator drugs don’t work for this population because there is nothing for them to modulate.

Gene therapy (or gene editing, or even RNA therapy) is thought to be the best path forward because the drugs should, in theory, turn a patient’s body into a CFTR protein producing machine. The upside here is that patients may not have to frequently dose these drugs and that the effect on health could be significant.

One potential downside here is that inhaled gene therapies, (presumably…) like 4D Molecular Therapeutics’ lead CF drug candidate, will only have effect on the respiratory parts of cystic fibrosis. Of course, most people with CF – me included – will tell you that’s the most important part. Unlike Trikafta, Kalydeco, etc., though, which offer systemic benefits, you would not expect an inhaled drug to have an impact on, say, the pancreatic disease embedded in cystic fibrosis. Of course, improved respiratory health could greatly and positively affect other parts of the body (just look at how well some transplant patients do with other areas of their health), but these benefits likely wouldn’t come from the drug.

This particular gene therapy is inhaled and uses a viral vector to get into the cells, which is the classic method used for gene therapies. Viruses have one goal in their lives: reproduce. They way viruses do that is by infecting cells, replicating, and moving onto new cells. If you’re trying to get a gene therapy into as many target cells as you can, a virus is an excellent way to do it. It’s a super exciting technology and it’s one that is perfect for CF since CF is caused by a single protein. The idea is simple: replace the dysfunctional protein with one that works.

What I am most interested in as an observer is how these newest generation of gene therapies work. One downside to viral vector gene therapies that is their cargo can only be so “big,” which means the size of the CFTR gene on the molecular level matters. Historically, CFTR has been too big for the viral vector of choice in gene therapies (AAV). So, to fit the functioning gene inside the vector, certain parts of the gene have historically been omitted. I don’t know how 4D is handling this challenge. But simply, if the CFTR is too big for a vector, then it’s like trying to build a complete Lego set with fewer bricks than the directions call for. The structure is there, but the resulting building could be missing important pieces. If the wrong important piece is missing, then you may not get the impact you intend to get. Today’s CF gene therapy researchers need to answer one big question: how can the entire CFTR gene get into human cells? I wonder how 4D is going about that challenge. Have they tinkered with the vector to allow for more cargo? Of course, since viral vectors also leave a risk of immune response.

I’m also looking forward to seeing the solution to another challenge: getting through the thick sticky mucus in CF lungs. The thick, sticky mucus that’s long been associated with CF can make our lives a living hell, but it can be difficult to get drugs inside lung cells.

In a perfect world, one or more of these gene therapies proves effective and non-modulated patients can start to benefit from disease modifying medication. I can’t imagine a world where a patient on a modulator would also take a gene therapy simply because of the cost if not for other quality of life reasons (like adding on an additional drug). I could imagine a scenario where a patient who may have some intolerance to a CFTR modulator could opt for a gene therapy instead.

Gene therapies are going to be extremely expensive for society. If you think Trikafta has a high price tag, you’re going to be in a rude awakening when gene therapies come to the table. The cost to manufacture them combined with a smaller target population is going to complicate that price tag.

It’s prudent that society and our payers begin think about novel ways to pay for these drugs. I still hold that gene therapies — given their unique dosing schedules and smoothed annual prices — should be cost effective to society when the things that matter to patients are also considered in the equation (spoiler alter: most cost effectiveness bodies don’t like to consider the things that matter to most people), like lower healthcare utilization, less time out of the work force, future genercization, and less time contributed to care. Combined with modulators, however, and without any documented potentiating power, I can’t imagine they would be considered cost effective together.

Nonetheless, gene therapies are going to be far more difficult to produce at scale than say something like Trikafta, which is just a couple chemicals mixed together in a pill (talk about oversimplifying something!). Production is a challenge these drug companies (and society) need to think about.

This is an exciting time for CF families, and it is an important fundamental step towards disease modifiers for even more people living with the disease. We should all be excited.