CRISPR/Cas9 from the NIH image library, found on Flickr
Over the past four weeks, I’ve discussed numerous aspects of gene therapy in an attempt to convey my excitement for this field moving forward. The convergence of numerous advances in basic biology (as described here and here) and clinical trials (as explained here and here) has placed gene therapy back in the driver’s seat as one of the most promising technologies in the cellular therapy and regenerative medicine spaces.
As of January 2020, the U.S. Food and Drug Administration (FDA) had approved four gene therapy products and the previous FDA commissioner, Scott Gottlieb, estimated that between 10 and 20 gene and cell therapies would be approved annually until 2025. It’s clear this field is only going to get more exciting.
As the results of trials role in, it is evident that some therapies are more effective than others, but the critical thing is that the safety of the trials so far has been leaps and bounds better than the original trials. This is not to say that all gene therapy products are safe, and the utmost caution must be taken when considering whether it is the correct approach for a given set of patients.
As the number of trials increase, a more accurate assessment of the risks and the associated costs of gene therapy approaches will become apparent. This will prompt some interesting areas for further analysis and discussion, including which vectors work best and whether new technologies will be incorporated into the clinical landscape.
Battle of the vectors
With the number of trials and approved therapies rapidly growing, the number of patients receiving gene therapy has obviously exploded as well. This should allow us to begin to put some bigger numbers together to establish which vectors work for which gene therapies (it almost certainly will not be a one-size fits all solution!).
One major outcome would be to allow researchers to state more confidently whether adeno-associated viruses (AAVs) or lentiviruses will be best suited for a particular application. At this stage, this is not an argument for me to weigh in on without considerably more research since it is one of the biggest areas of intellectual property and profit generation for companies in the gene therapy space. Last November, Boston Consulting Group published an excellent summary entitled “From Lab to Marketplace, Succeeding With Gene Therapies,” which captures many of the challenges facing businesses trying to get a foothold in this area. This article is well worth a read for anybody interested in that adventure.
The next generation of therapies
One of the biggest questions on people’s minds in the last few years has been whether or not gene editing using CRISPR/Cas9 will thrive in the clinical setting. In the laboratory research setting, the CRISPR/Cas9 technology (a rapid, accurate, and inexpensive form of gene editing) has already revolutionized how gene targeting is performed to assess the function of specific mutations in cells. In particular, it is highly effective for interrupting gene function.
Less efficient and less effective are attempts to introduce highly specific single genetic base pair changes (the kind often required for gene therapy), although the process has been shown to work quite well in some situations. Heidi Ledford at Nature has written a great summary article on the hopes and promises of CRISPR editing for gene therapy and CRISPR edited cells have already been shown to be well-tolerated in patients who received gene edited T cells for cancer therapy (although they ultimately did not cure the patients of their cancers).
Final thoughts
Overall, I hope that Signals readers have enjoyed this small focused series on the recent advances in gene therapy using blood stem cells. Being at the basic science end of things with our own laboratory’s research has an obvious impact on where I see the fun and exciting advances that might lead to the big changes in the successful future of gene therapies.
This is in sharp contrast to the thousands of people nearer the clinical delivery side that are dedicated to adding the final touches on such therapies and initiating carefully controlled and monitored clinical trials with unenviable amounts of paperwork and regulatory mechanisms.
Both sides deserve a substantial pat on the back for not giving up on gene therapy after a very rocky clinical start. At the end of the day, we must remind ourselves that successful translation of scientific discoveries, especially in such complicated areas as genetic engineering of human cells, takes years and legions of people to accomplish. In this case, the cream has certainly risen to the top and I’m excited to see what the next 5-10 years will bring!
David Kent
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