Can gene therapy fix any genetic defect?

I was recently reminded of a pretty incredible story.

In 2003, Beatrice “Bea” Rienhoff was born with contracted fingers, wide eyes, and a lack of muscle tone. It was clear by 6 months that she was not reaching developmental milestones on time and she was diagnosed with “failure to thrive”. Unfortunately, such a vague diagnosis has poor treatments and her parents were only given flax seed oil as a therapeutic. No prognosis was able to be made.

So far, this story is sad, but not incredible. This sort of experience happens to thousands of parents every year. There are over 20,000 protein-coding genes in the human genome, and mutations in any one of them can cause unpredictable effects on the development of a child. 

However, this story did not happen to an average parent. It happened to Hugh Rienhoff, a pioneering geneticist. He reacted to Bea’s diagnosis the only way he knew how: by acting like a geneticist.

After attempting to DIY scan Bea’s genetic code for damaging mutations, he managed to convince Illumina, a sequencing giant, to sequence his and his entire family’s DNA for free (a $350,000 value at the time). After finding a mutation in muscle-development genes (exactly where he had expected to find the mutation), he linked up with experts on muscle-development to figure out the precise effect of that mutation. Finally, 10 years later, he published a paper on the mutation as a whole, along with a band of researchers who helped him along the way.

I’m a huge fan of this story because it’s like the scientific version of this quote from Snow Crash by Neal Stephenson.

Until a man is twenty-five, he still thinks, every so often, that under the right circumstances he could be the baddest motherfucker in the world. If I moved to a martial-arts monastery in China and studied real hard for ten years. If my family was wiped out by Colombian drug dealers and I swore myself to revenge. If I got a fatal disease, had one year to live, and devoted it to wiping out street crime. If I just dropped out and devoted my life to being bad.

Just like every man secretly thinks that if his family was wiped out by Colombian drug dealers, he’d become a badass assassin, every physician thinks that if a family member of his was diagnosed with a rare disease, he’d become the foremost expert on it. Hugh Reinhoff actually did it, though. 

There’s something missing from the story, however. Dr. Reinhoff did an incredible amount of work figuring out the exact cause of his daughter’s developmental delay. However, he was unable to fix it. Or, more precisely, given that his daughter seemed to eventually overcome her developmental delays, he thought the risks of an experimental treatment were not worth the benefits.

That brings me to the topic of this blog post. If another well-resourced, determined doctor was faced with the same issue today, and if the developmental delays continued, would that doctor be able to fix the problem? That is, would that doctor be able to fix his daughter’s genome?

The short answer is maybe, but it would require a lot of work and a lot of knowledge that we don’t currently have. For the long answer, read on.

The first problem is that “fixing the genome” is one of those things that sounds straightforward, if difficult, in practice, but is actually quite complex to even define. You might think that fixing the genome just means replacing a malfunctioning gene with a functioning one, like replacing a bad part in a car. 

Unfortunately, every cell in our body gets a copy of our DNA. Totally fixing the genome means fixing every single cell in our body, which is impossible to do. So, our first task in fixing the genome is figuring out exactly which cells need to be fixed. For a connective tissue disorder like the one affecting Bea Rienhoff, the biggest worry is usually the risk of aortic dissection, which is literally a tear in your heart (and as bad for your health as that sounds). So, fixing Bea’s genome would probably mean making sure that the genome in the heart cells is fixed, but there might be other places that the therapy needs to get to as well.

Another big issue with “fixing the genome” is that first word, “fixing”. When you work on a car, fixing means literally taking out the bad part and throwing it out and then installing the good part. That’s easy enough to do if you’re a mechanic. However, a gene therapy has to be its own mechanic, meaning that the machinery for taking out the bad and installing the good has to be included in the therapy, along with the gene itself. This can add a lot of complexity, as whatever vector you use can only carry so much machinery [1].

Often, a gene therapy will instead only contain either a functioning copy of a gene to produce a protein (if the problem is not enough of a certain protein) or it’ll contain something to prevent that protein from being made (if the problem is too much of a protein). Bea’s connective tissue disorder seems to be related to reduced TGF-β 3 signaling, which is a regulatory protein (i.e. it controls what other proteins do).

The obvious solution, then, might seem to be to increase the amount of TGF-β 3 produced. And that probably is the solution. The only trouble is that excess TGF-β 3 can also result in connective tissue disorders, most notably Marfan’s. You have to hit the sweet spot in the amount of  TGF-β 3 produced in order to promote healthy development.

These are all basic issues that we’d need to understand before we could even try to develop a gene therapy for a condition like Bea’s. We’d then have to face the normal issues involved in gene therapy, most importantly the issue of the immune system. Gene therapy, by definition, involves injecting foreign DNA into the human body. The human body has evolved over a very long time to react very aggressively to sudden introduction of foreign DNA, as that is generally not a good thing (with the notable exception of the act of reproduction).

You may be wondering how, given these issues, we’ve managed to have any gene therapies at all. Well, it hasn’t been easy! Gene therapy has been an idea since the 70s, but there have only been 13 gene therapies approved since then. The pace is speeding up though, as all of them have been since 2016.

Perhaps in the near future gene therapy will be almost as straightforward as it seems: figure out what gene is behaving poorly then fix it. But we’re not there yet. For now, it’s still a bit more complicated.

[1] Fun fact: when I say “so much machinery”, the amount of machinery is measured in bytes, not grams, as it’s all just genetic instructions. The actual machinery is contained in the cell. So, adeno-associated virus vectors, which are one of the most common ways that gene therapies are delivered, can only carry about 5kb of DNA.

Adenoviruses and their relatives, by the way, are best known as being the usual cause of colds, but they’re actually great for gene therapies and vaccines. They can carry a lot of DNA, are relatively harmless, and can infect a broad range of cells. If you got the Johnson and Johnson or Oxford COVID vaccine, you’ve been injected with an adenovirus.

Retroviruses (which is the type of virus that HIV is) are also popular, as they’re great at evading the immune system, can also carry a lot of DNA, and are skilled at inserting themselves into the human genome to be expressed. However, their tendency to insert themselves at random places in the genome can have unpredictable effects, including leukemia in one early gene therapy trial.