I’m writing this post after reading this article from the Harvard Gazette, which discussed how the first personalized gene therapy was developed for a newborn baby with severe CPS1 deficiency, a rare genetic disorder that causes buildup of ammonia in the blood. CSP1 is an enzyme that helps convert ammonia (which is toxic in the body) to urea (less toxic). A mutation in the CSP1 gene means that CSP1 is not able to function properly, therefore leading to an accumulation of ammonia in the blood which can lead to brain damage and developmental delays. 

Especially in neonates, this condition can be deadly. In KJ’s case, the CSP1 deficiency was caused by two unique mutations in his genome. As a result, CHOP physician-scientist Dr. Rebecca Ahrens-Nicklas, MD, PhD, who was treating KJ alongside Dr. Kiran Musunuru, MD, PhD, proposed a solution: developing a personalized CRISPR gene editing solution designed to correct KJ’s unique genetic mutations. 

CRISPR is actually a bacterial immune system that protects against phages (viruses infecting bacteria) by recognizing and destroying their DNA. It incorporates snippets of encountered viral DNA into the bacterium’s own genome, creating a “memory” of past infections. If the bacteria becomes infected by the same virus again, it uses the stored DNA as a guide to enable a cutting enzyme (like Cas9) to cut and disable the viral DNA. I won’t go too much into that here, since this article does a fantastic job explaining the origins of CRISPR. 

However, I’m writing this article not because I’m an expert on the subject matter (I’m not, lol), but rather because, as a student, I’m curious as to how CRISPR research and therapies can be used in clinical practice. Reading about – and trying to understand the why’s and how’s – of cutting edge bioengineering research has taught me a lot about science, and I seek to document that learning journey here! 🙂(And maybe you’ll be interested in learning about this kind of stuff, too…) 

Why is KJ’s case a breakthrough? 

The CRISPR therapy used to treat KJ is groundbreaking for a few reasons: 1) it was developed on a rapid timeline (around seven months) and received FDA approval, 2) it’s personalized, 3) it’s in-vivo (meaning that the gene editing occurred in KJ’s body). 

KJ’s therapy required a custom guide RNA that directed the Cas9 enzyme to the appropriate spot in the genome. Usually, the Cas9 enzyme would cut the DNA in that particular spot. However, in this case, KJ’s therapy used base editing technology discovered by Prof. David Liu’s lab at Harvard, which converts one DNA base for another to correct the mutation – without cutting the complementary DNA strands. (The hyperlinked article explains the process very nicely with visuals – give it a read)! 

Can this happen more often? 

Currently, there are numerous CRISPR therapies in clinical trials, namely for the treatment of type 1 diabetes and cardiovascular-related diseases. 

The first FDA approved CRISPR therapy is Casgevy, used to treat sickle cell anemia. It’s an ex-vivo therapy, meaning that blood cells are taken from a patient and modified to produce the correct version of hemoglobin. However, it’s only approved for some mutations causing sickle cell anemia and beta-thalassemia. And, it’s very expensive, costing around $2 million. The cost reflects the fact that Casgevy is a therapy that “cures patients while saving health systems and insurers the cost of life-long treatment.” Setting a high cost is a way for pharmaceutical companies to recoup the investment, and accounts for the high manufacturing cost of producing the therapy. 

This makes such gene therapies affordable for few, limiting the number of people that could access it. When it comes to gene therapies, there’s no one-size-fits-all approach, making bespoke therapies promising. KJ’s story is a first; yet developing more of these therapies requires rethinking how collaboration occurs between doctors, researchers, regulatory agencies, and biotech companies. None of these stakeholders should be working in vacuums.

Having CRISPR become more widely spread will likely take decades. For me at least, writing this article helped me see that translation of CRISPR therapies is not solely reliant on outputting more research, or the FDA regulating treatments on a faster timeline. Instead, it’s heavily dependent on cross-functional collaboration, and developing a framework that makes such collaboration the norm.