Given a suitable delivery system, one that localizes to the desired target tissues to a far greater degree than to all other undesirable off-target tissues, the big advantage of a gene therapy is it precisely achieves the manipulation desired. It dials up or dials down expression for selected genes, alters the amount of proteins produced from those genes, and thereby changes cell behavior as a consequence - and that is all it does. One doesn't have the endless concern about off-target effects that characterize small molecule drug development.
There are, of course, different challenges. Setting aside some adventurous technologies that won't be deployed in therapies any time soon, manipulating a few genes at a time is the present practical upper limit on gene therapy. Further, there is no viable delivery system for most target tissues in the body, if the goal is to maximize expression in a limited set of locations. Yes, a great many interesting technologies exist for use in animal studies, but the bounds of the possible are more limited when it comes to what is permitted in the clinic. Injecting a gene therapy vector into the bloodstream means that most of it will end up in the liver, lungs, and heart, and very little in lesser, smaller organs. Injecting a vector directly into tissue is prohibitively risky for most internal organs except in cases of very serious disease.
Another pressing issue is that there is no proven gene therapy vector that can produce months of expression. Too long an expression is as much of a problem as too short an expression when it comes to treating disease. The only options on the table are (a) permanent changes via integration into the genome, (b) non-integrating viral vectors such as AAV that produce expression that can last for years, (c) very short term expression changes via RNA therapies that might last a few days. In principle, plasmid delivery can produce expression that lasts for months, but no-one has yet robustly solved the very poor expression characteristics of plasmids once delivered into a cell. They just don't want to localize to the nucleus where they need to be in order to express.
Yet another problem: viral vectors are the most effective, but a given vector can be used once in a given individual. Thereafter the immune system will clear further doses before they can take effect. For some of the older vectors, a fraction of the population is already reactive to some variants, and must be screened out. In general, the immune system is the dose-limiting concern for most gene therapies. If it takes too much notice of a therapeutic, serious side-effects can result due to an inflammatory response. There are groups working towards ways to cloak vectors, but none are yet clinically approved, robust, and ready to be used for arbitrary therapies.
In summary, most of the challenges inherent in developing gene therapies revolve around delivery. The other hurdles are much less of a problem, and there are many groups working on solutions at various stages of development. What the industry is waiting for is a good delivery system that overcomes the issues noted above. That would enable a sudden blossoming of gene therapies.
A last point to made about gene therapies is that yes, they are the future of medicine when it comes to manipulating cellular pathways, in principle much more precise and capable than small molecules. Bigger effects are possible, with fewer side-effects. But if gene therapies are only used to adjust the operation of an aged metabolism, forcing a restoration of the expression of important regulatory and signaling genes to youthful levels, without addressing the underlying causes of those age-related changes in gene expression, then they are still only a compensatory therapy. The same limits apply here as for small molecule compensatory therapies: change one consequence of damage, and all the other consequences are still there. In a complex, interacting system, the benefits of such a strategy are necessarily limited.
Gene therapies and small molecule therapies can be rejuvenation therapies, repairing damage. They can be used to target deeper causes of aging. Senolytics, for example, are largely small molecule drugs that achieve the goal of selectively destroying senescent cells. The important thing is not the methodology but the goal, removal of a form of damage that is as close to the root causes of aging as possible, with many downstream consequences alleviated as a result. As today's short article notes, that is not what Rejuvenate Bio is doing. They are producing compensatory gene therapies, aiming at targets that allow a clear demonstration of superiority over small molecule strategies. But the upside remains limited by the underlying damage of aging, still there, still causing all of the other harms it is capable of.
"Today we think about aging as a dysregulation of genes and proteins that lead to age-related diseases, such as heart disease, obesity, diabetes, etc. When we talk about reversing aging - or, more accurately, the disease states associated with aging - we're talking about reregulating genes back to the healthy state people had when they were younger." Unlike most companies addressing the diseases associated with aging, Rejuvenate Bio tackles multiple cardiac, metabolic, and renal issues at once. "Based on the data we've seen from mice and dogs, we can reverse obesity, diabetes and heart disease."
Rejuvenate Bio has two therapies in its pipeline, RJB-01 and RJB-02, targeting the cardiac, metabolic and renal space. Both are delivered via adeno-associated viruses (AAV). The company expects RJB-01 to enter the clinic for humans in 2023, and also to be commercialized for animals that same year. RJB-01 targets overexpression of FGF21 and downregulation of TGFß1 via expression of sTGFßR2. Rejuvenate is developing it for heart failure. Research conducted by other companies shows that targeting these genes is also effective and safe for weight loss, diabetes, and tumor inhibition. The second therapy, RJB-02, is designed to treat osteoarthritis. It targets two genes - downregulation of TGFß1 via expression of sTGFßR2, and overexpression of αKlotho. The latter is associated with improving cognitive performance as well as protecting the heart and kidneys, and increasing insulin sensitivity.
Notably, the researchers combined two therapies into one to treat four age-related conditions. The results in mice showed "a 58% increase in heart function in ascending aortic constriction ensuing heart failure, a 38% reduction in α-smooth muscle actin (αSMA) expression, and a 75% reduction in renal medullary atrophy in mice subjected to unilateral ureteral obstruction, as well as a complete reversal of obesity and diabetes phenotypes in mice fed a constant high-fat diet. What's particularly exciting is that in mice, we showed we could halt progression of heart disease in its tracks despite the surgical tightening of the aorta." Similar results were seen in dogs, too.