While the medical world is melting down from the absolute apocalypse that is RFK Jr., it’s good to celebrate that (at least for now) medical progress continues to march on. Recently published in the NEJM is a case report of a breakthrough that we may look back on as a milestone in medicine. Patient-Specific In Vivo Gene Editing to Treat a Rare Genetic Disease.
This represents the culmination of one of the promises of the CRISPR revolution – specific gene therapy in living individuals. I wrote in November 2023 about the first FDA approved CRISPR therapies, for sickle cell disease and thalassemia. These are both blood diseases which can be treated by removing bone marrow from the patient, altering the cells with CRISPR, then putting it back. The specific gene edit is general, not specific to the individual patient, and is targeted against cells that can be removed and then replaced. The new case report contains two new and very significant details – targeting an organ that cannot be removed and so has to be treated in vivo, and a patient-specific mutation.
For review, CRISPR stands for clustered regularly interspaced palindromic repeats. It is a system taken from bacteria which evolved as a bacterial immune system, to remove foreign bits of DNA from invading viruses. Researchers earned a Nobel prize for turning this system into a fast, efficient, and relatively cheap gene-editing system. It is so good (and the technology itself continues to improve) that it reinvigorated the field of gene therapy. Scientists have also discovered another similar system in bacteria, TIGR, which may be even better than CRISPR.
CRISPR promised to accelerate genetic research and potentially provide treatments for genetic diseases, as well as make genetic engineering more precise and affordable. The sickle-cell and thalassemia treatments were a milestone, the first FDA-approve CRISPR therapies. And now we have another.
This innovation occurred at Children’s Hospital of Philadelphia (CHOP) and Penn Medicine. The patient, known as KJ, was born with a rare urea cycle disorder, a mutation in the enzyme carbamoyl phosphate synthetase 1 (CPS1). This enzyme, mostly active in the liver, alters ammonia so that it enters the urea cycle, which eventually churns out urea which can be eliminated in the kidney. Without a functional CPS1 ammonia cannot be converted to urea, and so it builds up in the blood. Ammonia is relative toxic, it can impair brain function and even permanently damage the brain, as well as cause death. About 50% of children born with CPS1 deficiency die of their disease.
Treatment is very difficult, partly because ammonia mainly comes from the metabolism of protein. So infants have to be placed on a low protein diet, which impairs their development and ability to thrive. They also need to be placed on drugs that scavenge nitrogen and help reduce ammonia levels in the blood. Eventually they need a liver transplant, and the lifelong treatment that comes with it, but this can only be done when they are old enough. Many do not survive are have significant impairment by that time.
When KJ was born his doctors decided to see if it were possible to treat him with CRISPR gene editing. The main hurdle was designing and creating a CRISPR treatment in time. It took six months, which is incredibly fast and could not have been done with older gene-editing systems. The other challenge was getting the bespoke CRISPR to the liver cells. For this they used lipid nanoparticles as vectors, another recent technology that allows for delivering something as large as CRISPR in vivo.
Vectors are a serious challenge to gene-editing therapies in vivo. We have several viral vectors we can use, but they all have their risks and limitations. Lipid nanoparticles have proven to be an amazing technology, not only for CRISPR delivery but drug delivery as well.
KJ received his three infusions of lipid nanoparticles full of CRISPR specifically designed for his mutation – in February, March and April of this year, starting at 7 months of age. The results have been extremely promising. First, there have been no significant side effects. KJ has been able to increase his protein intake, which is critical for his development and survival. The dose of his nitrogen-scavenging drug has also been decreased to half.
KJ will need long term follow up and lifelong monitoring. But he has a much better shot at a healthy life than any previous time in human history. Depending on how he does he may get further infusions. It also remains to be seen whether or not he will still need a liver transplant. The primary variables are the percentage of his liver cells that received the gene editing, and how long they survive. Liver cells are generally replaced every 200-300 days. Also, the treatment was not aimed at altering liver stem cells, but there are stem cells in the liver and so they could have been affected. Therefore the duration of the treatment effect remains a big question.
At the very least this treatment gives KJ a better chance at surviving long enough to get a liver transplant without permanent damage.
This case opens the door for the millions of people who have individual genetic mutations. This is a critical proof of concept – we can engineer CRISPR in a short time frame, we can deliver it with lipid nanoparticles to at least some organs in the body, and these treatments can have the desired effect on a sufficient percentage of cells to make a significant clinical difference.
All of this was only possible because of federal funding of medical research. The NIH, for example, funds the Somatic Cell Genome Editing Consortium, which did the basic research that allowed for KJs treatment to become a reality. Not only the research itself, but the doctors and the labs that conduct the research, and eventually created KJs treatment.
The NIH is the greatest engine of biomedical research in the world, but now this entire infrastructure is being dismantled before our eyes due to reckless management and defunding. Pausing grants, removing funding, and threatening universities who do the research will hamper medical innovation for years, perhaps decades.
Meanwhile, we are on the precipice of a revolution in gene therapy that promises to transform many areas of medicine, not to mention many other medical breakthroughs at every stage of development.
If you are not outraged by this, then that is because you don’t know that you should be.
