Chapter 112
Curing Rare Diseases — 1
You might ask why a book on health span would include a chapter about rare diseases. It’s because our current approaches to curing rare diseases will play an increasing role in managing common diseases. The most consequential life science breakthrough of our era is genome editing, which is already being applied for patients with cancer and heart disease. That’s just the beginning. At the very least, your children or grandchildren may undergo some form of genome editing during their lifetime. But before we can fast-forward to ponder the future, let’s get grounded. Here and now, the big picture is that “rare” diseases, cumulatively, are common.
Six percent of the world’s population suffers from about ten thousand rare diseases, which equates to well over four hundred million people. The vast majority of the diseases, more than 80 percent, have a genetic basis. According to the European Union, a rare disease is one that affects less than one in two thousand individuals, and an ultra-rare disease has a prevalence of less than one in fifty thousand people. The US FDA categorizes a rare disease as occurring in less than one in two hundred thousand people. The term hyper-rare has been applied to prevalence of less than one in one hundred million. So, there’s clearly a wide range of terms and definitions that span several orders of magnitude. But even conservative estimates of the cumulative proportion of those affected by diseases most people have never heard of is between 3.5 and 5.9 percent. More than one in twenty? That’s a lot.
Let’s run through an example of how a new approach for a rare genetic disorder may ultimately affect an extremely common disease. Homozygous familial hypercholesterolemia, with a prevalence estimated at no more than one in three hundred thousand, results from two copies of genes with mutations that markedly elevate LDL cholesterol levels (three genes—PCSK9, the LDL receptor, and ApoB—account for most cases). This genetic disorder leads to LDL cholesterol levels over 400 mg/dl, at least fourfold the normal range. Without early diagnosis and aggressive therapy, premature coronary artery disease and death can occur. People with one copy of the gene are heterozygotes or carriers, comprising 1 in 250 people. That’s relatively common, well below the threshold of 1 in 2,000 for the European Union definition of a rare disease. We currently have an array of treatments to get the LDL cholesterol down, which, without treatment, is usually >190 mg/dl in adults or >160 mg/dl in children. Those lifelong treatments are statins, ezetimibe, PCSK9 antibodies or inhibitors, and bempedoic acid. Sometimes they are not tolerated well, with significant side effects, or do not adequately reduce the LDL cholesterol level. What if there was a one-shot CRISPR gene editing treatment that would markedly lower the LDL levels for life?
After a single injection by vein of a mRNA nanoparticle package, containing a CRISPR base editor that knocks out the PCSK9 gene, there was substantial and durable reduction of LDL cholesterol in monkeys. That led to the first clinical testing in New Zealand, and soon thereafter the FDA gave a green light for the company Verve Therapeutics to proceed in people with heterozygous (not homozygous) familial hypercholesterolemia, which has, in clinical trials, provided very encouraging results. While it’s still early to know for sure, we can envision—if it works and is safe—that people with a high risk of coronary artery disease and heart attacks, a disease that kills about seven hundred thousand Americans each year and is the number one killer worldwide, would be potential candidates to get genome editing. That illustrates how a new approach to an ultra-rare genetic disorder could be ultra-relevant.