3900 Trials and Counting: The Global Outlook on Genetic Medicines
Roughly 35% of trials conducted or in progress focus on monogenic (single gene mutation) like Rett syndrome, and over 50% of the trials are based in the US, with a steadily increasing trend towards more and more trials being conducted with every year that passes.
The landscape of genomic medicine has changed rapidly over the past decade, and even more in the past five years. A review article published over the summer in the Journal of Gene Medicine looks at the global landscape of clinical trials using genomic approaches like gene therapy, genome editing, and RNA silencing, starting with the first trial in 1990 where researchers treated a young girl with severe genetic immunodeficiency. In this piece, we’ll review the key findings most relevant to Rett syndrome.
What’s being treated?
Cancers are the most common indication for clinical trials using genetic medicines, accounting for almost 70% of trials initiated or completed over the last 35 years. A range of strategies have been used, most prominently CAR-T immunotherapy, which relies on editing T cells to better detect and attack cancerous cells. CAR-T trials mainly focus on non-tumor cancers like leukemias, although progress is being made with using CAR-T to attack solid tumors. Other approaches include inserting tumor suppressor genes and engineering viruses to attack tumor cells in solid cancers.
The next most common indication, accounting for about 13% of trials, is monogenic diseases, e.g. diseases like Rett syndrome that are caused by a mutation in a single gene. About a third of these trials have treated severe genetic immunodeficiency, hemophilia, or cystic fibrosis. For genome-editing specifically, sickle cell disease and beta thalassemia, another red blood cell disorder, have been the most common target after cancers.
A commonality between cancers like leukemias and lymphomas, immune disorders, sickle cell disease, beta thalassemia, and hemophilia is that the cells to be eliminated or modified are available through the blood or bone marrow, and therefore fairly easy for clinicians to access. Delivery to organs like the kidneys or brain is typically much trickier.
What genetic medicines have been approved so far?
We can loosely categorize approved medicines based on delivery method. At publication of the review in Summer 2024, genetic medicines delivered without viral vectors were the most common. Spinraza, an antisense oligonucleotide (ASO) therapy for spinal muscular atrophy (SMA) and Casgevy, A CRISPR-based genome editing therapy for sickle cell disease and beta thalassemia, are two medicines from this group that you may recognize. Most of the medicines in this group rely on using oligonucleotides or siRNA and are delivered by IV or through injection. Non-viral delivery has the advantage of avoiding the dangerous immune reactions that viral delivery can trigger, but typically only works with small therapeutic molecules.
Virally-delivered medicines are the next most common class. You may be familiar with Zolgensma, another SMA treatment, Luxterna, a treatment for genetic retinal dystrophy, or Kymriah, a CAR-T therapy used in patients with certain kinds of leukemia or lymphoma. Just like the highest percentage of clinical trials so far has been for cancers, a large percentage of the approved virally-delivered therapies (about 50%) are to treat cancers. The other 50% of trials are for monogenic disorders, with an overrepresentation of blood disorders, likely because of the ease of delivery.
How many trials have been held?
At the time the review was being drafted in 2023, 3900 trials had been undertaken in 46 countries. The number of trials approved or initiated has been growing over time. The first trial was approved in 1989, and the participant was treated in 1990. The number of trials per year slowly increased throughout the 1990s, then increasing to about 100 per year between 1999 and 2012. Since 2013, the trend has been an increasing number of trials, with a peak of 246 in 2020. This recent spike can be attributed in part to the expansion of the genomic medicine toolkit with not just the continual increase in scientific knowledge, but CRISPR (developed in 2012) and improved and novel delivery methods, like lipid nanoparticles (LNPs), viral vectors with new modifications, cell-penetrating peptides, and more.
Where are trials being held?
Trials have been conducted on every continent except Antarctica, with the United States (53%), China (17%), and the United Kingdom (6%) leading the way. This distribution largely reflects the amount of a nation’s overall spending on research and development. Between 2017 and 2023, the percentage of trials being conducted in Asia tripled, reaching 20%. This mainly reflects an increase in the number of trials reported from China, although it is worth noting that a high number of Chinese trials are registered but never report results or publish findings.
Another trend in the past few years is the increase in the number of trials taking place in multiple countries at once, more than doubling between 2017 and 2023. This may reflect the increased research into rare diseases, where accessing patient populations from multiple countries may be crucial for enrolling a sufficient number of trial participants.
What technologies could make a difference moving forward?
There is no doubt that CRISPR-based genome-editing technology has made it possible to create treatments for previously untreatable diseases. The CRISPR toolbox continues to expand, from base editing to CRISPR tools that modulate the epigenome rather than changing DNA sequences. RNA editing approaches also expand possibilities.
Viral-based delivery systems continue to be modified and refined for safety, efficacy, and effectively targeting different tissue types. The variety of viruses being used has also expanded possibilities for treatment of targeted cell types. Non-viral delivery systems have gotten more press in recent years, particularly LNPs, which are used in one approved ASO therapy, and have shown remarkable early results in ongoing clinical trials for two diseases whose pathology starts in the liver, where most LNPs naturally accumulate.
Delivery approaches that can penetrate the blood-brain barrier (BBB) to reach brain tissue are particularly interesting to Rett syndrome. Researchers are actively working on engineering AAV vectors with greater ability to cross the BBB, as well as combining AAV with cell-penetrating peptides (CPP) to better reach the brain.
Many individuals are hopeful about the ability of bioinformatics, artificial intelligence, and machine learning to advance the field of genetic medicine, but the utility remains to be seen. Stay tuned!
