FightAging!
1-28-18

Sometimes the old-fashioned, simple solution is more than sufficient for the task at hand. In today's open access review paper, researchers discuss the delivery and targeting of gene therapies to arthritic joint tissue via the simple expedient of injecting the therapeutic into the joint - the most modern of medical treatments married to a 150-year-old technology. And why not? The alternatives for targeting a therapy to a specific tissue are numerous, but all quite complicated and expensive: magnetic fields to guide metallic nanoparticles attached to the therapeutic; using seeker proteins that preferentially match the surface structure of a given cell type; DNA machinery that checks the internal state of a cell and only triggers the therapeutic if the local environment appears correct; and so forth.

First generation gene therapies are appearing in clinical trials in ever larger numbers, hundreds in recent years, though the term covers a wide range of what are arguably quite distinct approaches and endpoints. Very few of these use CRISPR today; most are older delivery technologies working their way through the last portions of a years-long development pipeline. That story will likely be very different a couple of years from now, given the enthusiasm with which the research community has embraced CRISPR. Today's candidate gene therapies largely have effects that are temporary, as the delivery mechanisms don't successfully transfer their cargo into a large number of cells. Of those that are affected, near all will be somatic cells, limited in their ability to replicate, and thus altered cell lineages in a tissue will die out in a matter of months at most.

Putting aside the more advanced, machine-like, and programmable gene therapy platforms, such as that pioneered by Oisin Biotechnologies, most present day gene therapies in trials are essentially a way to make some cells produce more of a specific protein for some period of time. Each is an indirect two-stage protein delivery system, in effect, using cells as a local manufactory. All cellular machinery is controlled by levels of specific proteins - the amount of a specific protein in circulation in the local environment is a switch, or a dial. The cell is a fantastically complicated collection of these switches and dials, most of which can affect numerous others, forming feedback loops and chains of cause and consequence. Directly altering the amount of a specific protein is better than the use of pharmaceuticals to achieve the same aim, given that even the best drugs have all sorts of side-effects, but it is still a crude approach to obtaining the desired end results. Changin g the amount of a protein will have all sorts of downstream effects that may or may not be helpful, in addition to the desired outcome. Future medical technologies will likely become more sophisticated in their control over cellular operations.

Though, ironically, these anti-arthritis gene therapies are conceptually quite crude. They target controlling mechanisms of inflammation in a fairly heavy handed way - following the well-established pharmaceutical industry path for inflammatory conditions, which is to suppress inflammation and the immune response rather than go further in search of the causes of the problem. Yes, there is inflammation, but why is there inflammation? Why not find and target that root cause? The arthritis research community will likely undergo a considerable rearrangement of priorities and leaders in the years ahead, if the results obtained in mice for arthritis and clearance of senescent cells translate into human patients. Senescent cells are one of the root causes of aging, and it appears that their accumulation, and their pro-inflammatory signaling, is a significant cause of at least some types of arthritis.

Gene Delivery to Joints by Intra-Articular Injection

With the exception of rheumatoid arthritis (RA) and related autoimmune conditions, disorders of joints tend to be local and usually affect a small number of joints - often only one. Such circumstances favor intra-articular therapies, where the therapeutic agent is delivered directly to the affected joint. Compared to systemic delivery, this reduces the likelihood of adverse events in non-target organs, maximizes the concentration of the therapeutic at the site of disease, and, by treating a joint instead of the whole body, lowers cost. Joints are discrete, enclosed cavities, and most are readily accessible to intra-articular injection, which is the delivery method of choice.

Although it is a straightforward matter to inject therapeutics into joints, the effectiveness of intra-articular therapy is greatly compromised by the rapidity and efficiency with which material leaves the synovial space. Small molecules diffuse out through the sub-synovial capillaries, while macromolecules and particles leave through the lymphatics. It is thus very difficult to achieve sustained, therapeutic concentrations of drugs in joints. The idea to use gene therapy for joint disorders arose in response to this problem. The original concept was to target gene delivery to the synovium for treating arthritis. This would lead to the sustained synovial synthesis of therapeutic gene products locally within joints. Such a strategy also obviates another problem for treating joints with biologics, namely the restricted access of proteins and other large molecules to the interior of the joint from the circulation.

Intra-articular injection of suspensions of genetically modified cells is unlikely to achieve long-term transgene expression because injected cells are cleared from joints within days to weeks. Persistent intra-articular expression following in vivo gene delivery was only achieved when the importance of the immune system in curtailing transgene expression was fully appreciated. This followed experiments in which vectors were injected into the knee joints of athymic rats. Under these conditions, transduction of the synovium was initially high, but transgene expression then fell as a result of synovial cell turnover, persisting at about 25% of the early level for the rest of the animals' life-span. Similarly extended periods of transgene expression are achieved when immunologically silent vectors are used to deliver autologous gene products in wild-type animals.

Proof of concept has now been achieved for both in vivo and ex vivo gene delivery using a variety of vectors, genes, and cells in several different animal models. There have been a small number of clinical trials for rheumatoid arthritis (RA) and osteoarthritis (OA) using retrovirus vectors for ex vivo gene delivery and adeno-associated virus (AAV) for in vivo delivery. AAV is of particular interest because, unlike other viral vectors, it is able to penetrate deep within articular cartilage and transduce chondrocytes in situ.

Although gene therapy for arthritis and related conditions has been discussed for more than 25 years, progress toward clinical application has been slow. Nevertheless, there have been several clinical trials, and the first product, Invossa, has just received marketing approval in Korea. Phase III human clinical trials of Invossa are projected to begin shortly in the United States. Its approval should stimulate interest in the entire field leading to more rapid development of genetic drugs for conditions that affect joints. Invossa targets OA by the injection of allogeneic chondrocytes that have been transduced with a retrovirus carrying transforming growth factor-β1 cDNA. Meanwhile, two additional Phase I trials are listed, both using AAV. One targets RA by transferring interferon-β, and the other targets OA by transferring interleukin-1 receptor antagonist. The field is thus gaining momentum and promises to improve the treatment of these common and debilitating diseases.