The term “rare disease” is, in a way, a misnomer. Yes, each rare disease is rare on an individual basis; depending on the country, they’re usually defined as diseases affecting less than 1 in 2,000 people in the population. If you consider the entire population of people with rare diseases, though, having a rare disease starts to become not-so-rare: in the U.S., 1 in 10 people has a rare disease. This adds up to 30 million people in the U.S., and 400 million worldwide with a rare disease.
It’s time that we start to consider this group underserved, when they constitute such a significant fraction of the overall population and have comparatively much fewer resources allocated towards addressing their ailments. Since each disease by itself is rare, we tend to assume there’s no cure, or at least not one that could be incentivized to be done at cost. And in fact, 95% of these diseases do not have an FDA-approved treatment. For those that do, patient financial burden is horrendous, due to the small market of patients for whom the specific treatment was developed. However, what if it were possible to have a generalized treatment that could be applicable to a large portion of these rare diseases?
To answer this question, we must examine the pathogenesis of these rare diseases for commonalities. As it turns out, many of them share (very broadly) similar origins, in the sense that an estimated 85% of them are genetic. The question then becomes if we can develop effective, accessible genome editing therapies, which could then be precisely tailored to specific genes or conditions with relative ease. To that, I’d pose that advancements in this area might not be as far away as we think.
Figure 1: Generic mechanism of CRISPR-Cas9 gene editing. (Image: Costa et al., 2017)
As some may know, I currently engage in research in the Doudna Lab at the Innovative Genomics Institute, a partnership between UC Berkeley and UCSF. Dr. Jennifer Doudna earned the 2020 Nobel Prize in Chemistry for her discovery of CRISPR-Cas9, an enzyme derived from bacteria that could be harnessed as a tool for gene editing. It was a major leap forward in the gene-editing field due to its remarkable specificity. Its specificity comes from something called a guide RNA, which the Cas9 can use to tell it where to go. Consisting of a nucleic acid code just like DNA, this guide RNA can hybridize (pair with) a particular DNA sequence that corresponds to it. Once it gets stuck on its matching sequence, the Cas9 enzyme will know precisely where to make a cut in the genome that allows us to edit.
This system seems like it fits the desired model quite well for the treatment of rare, genetic diseases: a general strategy (the Cas9 enzyme to make cuts in the genome), yet highly modifiable and tailorable to each individual case (the specificity of the guide RNA for telling where to cut). And in fact, with clinical trials already underway for CRISPR-based therapies, there may be hope that one day, even the rarest genetic illnesses can be cured affordably. However, there are countless additional considerations that come with a novel field of science, which could probably each warrant their own post. I’ll briefly summarize some of the biological issues here:
Tissue specificity: every cell in your body contains all of your genes, but the expression of those genes is highly dependent on the tissue. For example, a neuron in the brain has all the DNA instructions to function like a liver cell, but those genes are “turned off” for the neuron, because you don’t want to have a liver cell in the brain. Therefore, almost always, a genetic condition impacts a particular tissue, and we would want editing to only occur in that tissue.
Genome specificity: though the guide RNA is highly specific, there can occasionally be “off-target” edits made in the genome, which is certainly a safety consideration to minimize.
Delivery: many issues fall under the umbrella of delivery, which is basically trying to answer the question of “how can we get the gene-editing machinery to the right tissue, then into each cell, then into the nucleus of each cell?”
Immune response: since the genome editing machinery originated in bacteria, we may be programmed to recognize it as foreign to the body, and launch a harmful immune response against it. This is similar to the issue of transplant rejection, and the need to “match” a recipient to an appropriate donor.
Clinical strategy: can the treatment be done in vivo (that is, in the living individual), ex vivo (in cells outside the body to be transplanted in), before birth, etc.?
The issue that always concerns me most with new drug treatments, though, is accessibility. Especially for something as powerful as gene editing to prevent rare diseases at birth, newly discovered treatments can have the capacity to either relieve or intensify health disparities. However, I am hopeful that the latter won’t be the case with CRISPR-based therapies for a few reasons. First, I feel it could be difficult for one or a few pharmaceutical companies to control the whole market for any given rare genetic disease. Cas9 is so programmable and modifiable, and ordering a custom guide RNA is quite cheap and easy. Second, I sure hope we would all realize how incredibly unethical the alternative would be. To literally select out individuals with unfortunate genes from the population, purely on the basis of their inability to afford treatment, is an absurd proposition which would only magnify health inequity and downstream social issues.
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