The actual biggest challenge for CRISPR that seldom gets talked about
When CRISPR emerged in 2012, the headlines promised a cure for all genetic diseases. Yet today, despite being one of the most rapidly developed new therapeutic modalities, CRISPR is only used to treat a few dozen of the 7000+ known genetic diseases. Why?
Ask experts in gene editing, and most will point to two familiar culprits: delivery to target tissues and the precise control of editing outcomes. While these are significant hurdles, the truth is they are red herrings—relatively straightforward issues to describe and for which technological solutions are actively being developed.
But a deeper, less-discussed challenge lurks beneath the surface: the immense genetic diversity within what we label a single genetic disease. Many genetic disorders aren’t caused by a single, uniform mutation but by hundreds or thousands of unique subtypes. This complexity means that the precision of CRISPR could paradoxically require the development of countless tailored therapies, each targeting a specific mutation variant. To put some numbers to that there are estimated to be roughly 7000 genetic diseases and from the Human Gene Mutation Database (HGMD) there are an estimated 300,000 mutations associated with these diseases. This is probably underestimated in both cases, but with this simple analysis, each genetic disease would require 40 different drugs. In the current environment, developing just one of those drugs might take half a billion dollars, and only a handful of patients could benefit from it. Putting aside the logistics of developing this many specific drugs, a company would need to charge $10M+ per treatment just to break even.
Example of Limb-Girdle Muscular Dystrophy
Take Limb-Girdle Muscular Dystrophy (LGMD) as an example. LGMD is a group of genetic disorders that cause progressive weakness and wasting of the muscles around the hips and
shoulders—the areas known as the limb girdles. People with LGMD often experience difficulty walking, climbing stairs, and lifting objects due to the gradual degeneration of these muscles. LGMD, as a broad category, is already a rare disease, affecting about 1:50,000-1:100,000 people. However, it’s not a single disease but a group of disorders caused by mutations that present similarly. LGMD is divided across at least 30 subtypes based on the gene it impacts (Fig 2). If that wasn’t challenging enough, the mutations within a given gene, for example, Calpain 3, are spread almost evenly across the length of the gene with very few hot spots (Fig 3). Let’s conservatively say that 50 different gene editing guides would be required to fix the entire length of the gene. After taking the 30+ causative genes and the distribution of mutations in those genes into account, the previous 1:50,000 has now turned into 1:10,000,000, or ~30 patients in the US.
Possible solutions
It’s not all doom and gloom, though. Researchers and biotech companies are exploring strategies to overcome this genetic complexity. Three stand out and are gaining traction: protective alleles, large insertions, and platform approvals.
- Protective Alleles
Instead of targeting each harmful mutation individually, scientists are looking at enhancing or introducing protective alleles—versions of genes that can counteract the effects of harmful mutations. Promoting these beneficial genes makes it possible to provide a broad-spectrum therapeutic effect across multiple genetic variations of a disease. This is the basis for our lead program at Mammoth, where we’re targeting a gene called APOC3 that, when knocked out, can protect patients from high triglycerides largely independently of the genetic basis. - Large Insertions
Some newer gene editing technologies could allow larger DNA sequences to be inserted into the genome (e.g., CRISPR transposases, recombinases, RT editing, Bridge RNAs, etc.). This capability can enable the replacement of entire faulty genes with functional ones, effectively bypassing the need to target specific mutations. This method holds promise for diseases caused by large deletions or complex mutations that are hard to correct with traditional gene editing. Many of these tools are still very early in their development, and each has its own challenges, but they could end up making more diseases addressable as they mature. - Regulatory innovation (e.g. Platform Approvals)
Regulatory bodies are beginning to recognize the need for more flexible approval processes. Platform approvals would allow a single CRISPR-based system to be approved for multiple uses, streamlining the path to market for therapies targeting different mutations within the same disease category. Similarly, basket and platform trails also present an opportunity to bundle more drugs together under a streamlined regulatory process. These approaches could significantly reduce development time and costs, making it economically viable to treat rare genetic variants. Changes in regulatory policies move forward with caution, so I don’t expect this to develop overnight, but CRISPR is uniquely poised to be able to be a fit for platform approvals. Apart from regulatory evolution, this will also likely require a tremendous data science effort to predict the behavior of new drug candidates.
Looking Ahead
The road to conquering genetic diseases is undeniably complex, but the evolution of gene editing technology offers a beacon of hope. By acknowledging the true scope of the challenge—the genetic heterogeneity within diseases—we can better direct our efforts and resources. As we continue to explore these solutions, the goal remains clear: to bring safe, effective, accessible treatments to all patients, regardless of the uniqueness of their genetic makeup. Likely the solution will be some combination of genetics, technology, and regulation.
I’m a big believer that correcting the underlying cause of disease (genetics) is the future of medicine and of improving our species’ health span. I think this is the biggest problem that we as a field should focus on. In subsequent posts, I plan on exploring these potential solutions in more detail. Stay tuned!