Curing Rare Diseases — 10

Which brings us to a familiar therapeutic channel. Engineering the gut microbiome has enormous potential for modulating our immune response and inflammation throughout the body. There are many ways to manipulate the gut microbiome, from the most primitive of fecal transplant, to perhaps the most advanced using gene editors, that design or change the function of bacteria and other microbial residents in our gut. One example of several companies is a bacterial strain to break down oxalate in the gut, to reduce the development of kidney stones (most commonly caused by calcium oxalate). Theoretically, it would be possible to get gut microbes to secrete anti-inflammatory compounds, or block ones that promote inflammation, or tackle antibiotic resistance. The first successful editing of gut bacteria (Escherichia coli and Klebsiella pneumoniae) was accomplished with base editors and an engineered bacteriophage (a virus that infects bacteria) that achieved over 90 percent editing efficiency after a single dose in mice. The first microbiome editing project undertaken by Jennifer Doudna and UC Berkeley’s Innovative Genomics Institute is childhood asthma, for which a culprit bacteria is known, but an approach to specifically edit it with a pill or oral administration is not. It will be challenging but may be possible. In the meantime, editing the gut microbiome of cows, targeting archaea single-cell organisms that produce the methane, will likely be an earlier application that could, if highly effective and durable, dramatically reduce greenhouse gas emissions.

Figure 8.4. Epigenetic editing. Modulating the expression of a gene (on or off) by an “effector” protein that adds or removes chemical tags on DNA and histone proteins. Adapted from Jocelyn Kaiser, “Better than CRISPR? Another way to fix gene problems may be safer and more versatile,” Science News, June 1, 2022, https://www.science.org/content/article/better-crispr-another-way-fix-gene-problems-may-be-safer-and-more-versatile.

We turn back to editing DNA, but now it’s not in the cell nucleus; it’s in the mitochondria (mtDNA). There are nearly one hundred disease-causing mtDNA mutations that are maternally inherited, affecting about one in five thousand individuals. Getting into the mitochondria is tricky because of their double membranes, but with adapted nucleases and editors, increasing success is being reported in lab studies. In theory, mitochondrial editing has potential relevance in medicine for the pivotal role this organelle plays in the aging process. For now, it is contemplated to be the preferred approach to mitochondrial genetic disorders compared with replacement therapy that requires a donor maternal egg to substitute the mitochondrial genome for the biologic mother’s (thus delivering a “three-parent baby”). This takes us to germline (egg, sperm, embryo) instead of somatic (body cell) editing, which, as we know, has a special peril.