Catabolism eventually predominates over anabolism to such an extent that severe cartilage erosions and bone marrow lesions / remodeling manifest in clinical osteoarthritis.
Joint inflammation is also a key mechanism in OA,[9] and a number of pro-inflammatory cytokines, particularly IL-1, have been implicated in pathophysiology,[10][11] human genetics,[12] and animal models of disease.
[19] Gene Augmentation approaches aim to replicate the success of anabolic protein therapies by delivering the genetic instructions for these factors in the form of single injection treatments.
For this purpose, genes may be inserted into delivery vectors and administered to target cells to augment or replace defective genetic material.
This "cloaking" often requires the use of additional genetic manipulation, such as the insertion of a CD47 gene to express a "don't eat me" signal on the surface of the cells to make them hypoimmune.
Genetically modified cell therapies for the treatment of osteoarthritis are currently strictly investigated and their safety and effectiveness claims have not been reviewed by the FDA.
[25][26] It is characterized by the progressive loss of normal structure and function of articular cartilage, the smooth tissue covering the end of the moving bones.
[25][27] Since the degeneration of cartilage is not naturally reversible, it will continue to progress, eventually resulting in the need for joint replacement as a potential terminal intervention.
[25] The growing number of people suffering from osteoarthritis and the potential of some gene therapy approaches, attracts a great deal of attention to the development of genetic medicines for the treatment of this chronic disease.
[1][29] Viral vectors are the most widely used gene delivery method as they have evolved to do this job with a high degree of efficiency and specificity.
The combination of their evolutionary origin and broad use, makes viral vectors highly effective at delivering genetic cargo to cells, and significantly reduces the risks associated with using this delivery method.
When administered systemically, or in high doses, viral vectors may induce an inflammatory response, which can cause minor side effects such as edema or serious ones like multisystem organ failure.
[31][1][32] Furthermore, the durability of therapeutic transgene expression appears to be such, that a single injection therapy may be sufficient to reverse progression of a disease.
[34] Non-viral methods involve complexing therapeutic DNA to various macromolecules including cationic lipids and liposomes, polymers, polyamines and polyethylenimine, and nanoparticles.
Since the joint capsule is relatively well contained, intra-articular injections are highly successful at delivering the therapeutic gene therapy locally to the target cell types.
Although prior approaches with recombinant proteins have shown mixed results, gene therapy remains a promising avenue for IL-1 inhibition.
[47] A therapeutic gene with potential to counteract the effect of Interleukin-1,[48] the Interleukin 1 receptor antagonist (IL-1Ra), is currently being evaluated in early clinical trials with several delivery vectors including AAV and Adenovirus.
Finally, FGF18 was able to reduce pain (WOMAC) and clinically meaningful symptom progression, in both the full trial population and the high-risk subgroup.
Most efficient methods of gene transfer to cartilage have involved in vivo strategies delivering AAVs directly to joints via intra-articular injection.
[14][1][18] The major purpose of gene delivery is to alter the lining of the joint in a way that enables them to serve as an endogenous source of therapeutic molecules that can diffuse and influence the metabolism of adjacent tissues such as cartilage.
Also, since osteoarthritis is the disease of cartilage tissues, treating the synovium is an indirect approach and may be complicated by lack of therapeutic activity.