Chapter 120
Curing Rare Diseases — 9
As Fyodor Urnov, a pioneer in the field, who coined the term genome editing, and professor at the UC Berkeley Innovation Genomics Institute, told me, the lung, muscle, and spine will be the next three organ systems deemed approachable. CRISPR-ing the spine is especially noteworthy as a treatment for chronic pain by blocking the spinal neurons from transmitting the pain signal. The new editing frontiers won’t stop there. Genome editing in utero has started. Eventually it will be possible for the gene-edited brain to self-edit unfavorable alleles like APOE4, but that’s still years away. And one day all this will be done by a pill rather than an injection. That’s just a matter of time and building on drug delivery innovations.
BEYOND DNA EDITING
Most of what has been discussed to this point pertains to DNA editing, but the same principles apply to RNA, microbiome, epigenetic, and mitochondrial editing. RNA editing has several advantages because it doesn’t change proteins, the effect is short-lived, and the transience, lack of permanent impact, may offset concerns about off-target effects. RNA editing has been approved by the FDA for treating Stargardt disease, a rare eye disease that causes macular degeneration and loss of vison. It is being pursued to treat alpha-1antitrypsin deficiency and as a treatment of liver (hepatocellular) cancer. Here, again, what was envisioned for rare disease treatment may have much broader applicability to alter the RNA sequence in cancer that leads to cell death of tumor cells.
Considering the results in animal models, editing the epigenome (fig. 8.4) is now drawing considerable attention. Like RNA editing, it does not change a protein directly; rather, it controls the regulation of a gene, the on-off switch, and it’s temporary. It’s a hit-and-run approach. The term gene tuning has been applied because, like adjusting dial settings on a soundboard, epigenome marks can be modified to harmonize the expression of multiple genes at once, not just turn them on or off. The putative enhanced safety profile is alluring, as are the results of mouse studies for cholesterol lowering, Alzheimer’s, Huntington’s disease, Dravet syndrome (a rare inherited form of obesity), modulating a pain perception gene, and permeating the brains of mice to silence neuron-killing prions. But many of these studies used AAV as the ferry, which undermines the objective of a transient effect. Other cargo techniques are being explored. Intranasal delivery of exosomes, loaded with an epigenetic editor, was successful for reducing expression of beta-amyloid production in brains of mice. Epigenetic silencing of the PCSK9 gene in mice led to marked and durable cholesterol lowering with nanoparticles, which augurs well for avoidance of AAV delivery. With a full atlas of twenty-eight million methylation changes across cell types, a new company (Moonwalk Therapeutics) plans to edit methylation sites to treat chronic disease and modulate the aging process. Other companies formed to edit the epigenome are focused on treating liver cells in patients with hepatitis B or cancer. Clearly, these are ambitious programs that, if successful, would have transformative impact well beyond rare genetic disorders.