Ever since Watson and Crick ended their seminal Nature paper in 1953 by saying that: "It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material," James Watson & Francis Crick, "Molecular Structure of Nucleic Acids; A Structure for Deoxyribose Nucleic Acid," Nature 171: 737-38 (April 25, 1953), it has been envisioned that identification of genetic mutations causing disease would someday provide a way to repair them to achieve a cure. Those hopes have only increased over the years since then, particularly in light of the ever-increasing genetic information that arose from cloning specific human genes in the late 1970's and the 1980's and even more so with the crowning achievement of the Human Genome Project at the turn of the century. Unfortunately, these hopes have not been fulfilled, in large part due to failures in successful introduction of unmutated genes into appropriate cells in patients suffering from genetic diseases. The causes for these failures are many, ranging from delivery of intact genetic constructs into these cells to stable insertion of the genes into the genome at a chromosomal location capable of efficient transcription under circumstances that did not result in inappropriate or disease-causing) expression of endogenous genes.
On October 31st, the U.S. Food and Drug Administration's Cellular, Tissue, and Gene Therapies Advisory Committee announced its recommendation that exagamglogene autotemcel (exa-cel) is safe for clinical use. This drug is the subject of biologics license application (BLA) 125787 from Vertex Pharmaceuticals, Inc. in collaboration with CRISPR Therapeutics (Zug, Switzerland) and provides for the first time gene therapy for sickle cell anemia. Sickle cell anemia was the first known human disease associated with a genetic polymorphism (an A→T single nucleotide polymorphism, or SNP), resulting in the substitution of a valine residue (encoded by a GTG codon) for a glutamic acid residue (encoded by a GAG codon) in the beta chain of human hemoglobin.* The Advisory Committee's announcement followed the FDA's earlier announcement on October 27th that exagamglogene autotemcel is effective, having 29 of 30 patients stay pain-free for 18 months.
The CRISPR-mediated effect on sickle cell disease from exa-cel is mediated by targeting the binding site of an inhibitor (BCL11a) of the gamma-globulin gene, which results in fetal globin expression that alleviates the symptoms of the disease. While there remains the possibility in some patients for "off-target" effects (some of which have been predicted by scanning human genomic DNA for such targets), the expected frequencies are low (1.6% according to David Altshuler MD, Vertex's Chief Science Officer). Scot Wolfe, PhD (UMass Chan Medical School), a member of the FDA advisory committee, voiced the sentiment that:
We don't want to let perfect be the enemy of the good. At some point we have to try things out in patients. There is a huge unmet need for sickle cell disease. It's important to advance therapies. I certainly think that this is one of them.
The FDA is scheduled to decide whether to approve the drug at a meeting scheduled for December 8th.
* The work, by Linus Pauling and colleagues at Cal Tech was published in the November 25, 1949 issue of the journal Science, about three and a half years before Watson and Crick deciphered the structure of DNA.
