Chapter 115
Curing Rare Diseases — 4
Although this was a huge step forward for genome editing to provide medical treatment, there are two fundamental limitations of this first approved strategy. It’s a disruptive knockout of a gene, not fixing the underlying genetic defect, because it relies on CRISPR-Cas 9, or CRISPR 1.0. Also, the patient must go through a long, grueling process because the editing is done in cells outside the body (ex vivo). The future of genome editing will move to in vivo, in the patient’s body, ideally with a one-and-done shot like I touched on for familial hypercholesterolemia that uses base editing, not Cas-9. Indeed, a clinical trial of base editing of sickle cell disease to fix the single base pair mutation is underway. Even pills are being developed to avoid the need for shots. One pill that epigenetically targets the same BCL11A gene has been shown to be effective in mice and monkey models of sickle cell disease.
When CRISPR got FDA approval for sickle cell disease, a gene therapy called Lyfgenia was approved for the same disease. While the terms gene editing and gene therapy are often used interchangeably, they are two very different strategies.
When I asked my friend Fyodor Urnov, a pioneer in gene editing, to explain the difference to me, he said, “Imagine you have a car with a flat tire. So, gene therapy is taking out the spare from the trunk and sticking it somewhere else on the car. So now the car has a fifth wheel and hoping it runs. And believe it or not, that actually works. Gene editing is fixing the flat.”
The metaphor speaks well to the fact that gene therapy is a gene addition, unlike genome editing, which disrupts or fixes a specific gene. It does not correct the underlying defect and has traditionally relied on an engineered virus delivery system, such as the adenovirus or lentivirus vectors.
About fifteen different gene therapies were approved in the years before CRISPR’s Casgevy, beginning in 2012 with the European Medicines Agency approval of Glybera for lipoprotein lipase deficiency, and by the FDA in 2017 with Kymriah and Yescarta to genetically engineer T cells in people with lymphoma, and Luxturna for a rare genetic eye disease, Leber’s congenital amaurosis. The approvals have greatly expanded since to spinal muscular atrophy, hemophilia A and B, beta-thalassemia, Duchenne muscular dystrophy, severe combined immunodeficiency (“bubble boy disease”), metachromatic leukodystrophy, dystrophic epidermolysis bullosa, and several others. Single-injection gene therapy to restore hearing in children with autosomal recessive deafness 9 has been demonstrated without adverse side effects, which could be the start of using gene therapy to prevent or treat a wide array of hearing loss conditions including presbycusis (hearing loss with advanced age). Ongoing clinical trials for central nervous system conditions are targeting amyotrophic lateral sclerosis, Parkinson’s disease, and Huntington’s disease.