Arthritis is a common cause of disability worldwide, impacting over 300 million people. It causes chronic pain, stiffness, and loss of mobility in joints. The two most prevalent forms are osteoarthritis and rheumatoid arthritis. Currently, treatment options focus on managing symptoms through medications, physical therapy, exercise, and joint replacement surgery for severe cases. However, none target the underlying cause or provide a permanent cure. Gene editing offers promise as a targeted disease-modifying approach to treating arthritis in the future.
Osteoarthritis and rheumatoid arthritis both have genetic risk factors that contribute to disease development and progression. For example, variants in genes encoding cartilage and joint proteins like COL2A1 influence osteoarthritis risk. Genetic factors also impact the immune system pathways involved in rheumatoid arthritis pathology.[1] Gene editing tools aim to directly correct the DNA mutations that elevate arthritis risk or severity. This could halt the molecular processes leading to joint inflammation and damage from the start.
The CRISPR-Cas9 system has advanced the potential for gene editing in arthritis. CRISPR uses a Cas9 enzyme guided by RNA to make precise cuts in DNA. It allows targeted modification or correction of specific genes. In preclinical models, CRISPR has been tested for its ability to alter genes associated with arthritis. For example, editing the IL-1β gene reduced inflammatory responses and protected mice from developing arthritis when exposed to triggers like cigarette smoke.[2] Tweaking cartilage protein genes like COL2A1 repaired damage caused by mutations in animal studies as well.[3]
Other gene editing approaches under investigation include transcription activator-like effector nucleases (TALENs) and zinc-finger nucleases (ZFNs). TALENs and ZFNs cut DNA similarly to CRISPR-Cas9 but use different protein-DNA binding domains. Early research modified immune cells from rheumatoid arthritis patients using ZFNs, reducing their abnormal function and inflammatory cytokine production ex vivo.[4] These represent plausible first steps towards eventually delivering gene editing therapies directly into affected joints.
A major barrier to clinical application in arthritis patients stems from delivery challenges. Editing cells directly within joints requires developing targeted tools to access tissues without harm. Viral and non-viral vectors currently delivery gene editing machinery in animal studies but pose size limitations and safety questions for human use.[5] Alternatively, collecting and editing a patient’s own immune or cartilage-producing cells outside the body pre-clinically before returning them could avoid these hurdles. However, keeping edited cells functional long-term remains an obstacle.
Additional safety risks include off-target DNA changes and abnormal gene expression levels from editing. Precise control and validation techniques like homology-directed repair are important to minimize unwanted effects. Ethical issues also arise regarding permanent genetic alterations, though correcting disease-causing mutations could prove less controversial than other applications. Strong preclinical justification and oversight will be crucial as gene editing progresses towards arthritis clinical trials in the next decade.
Overall, gene editing offers a customized disease-modifying approach for arthritis by targeting root molecular causes rather than symptoms alone. Further research optimizing delivery, safety and effectiveness is still required. But successfully achieving even partial or transient effects through one-time edited cell therapies might provide long-lasting benefit compared to lifelong drug regimens. By addressing drivers of joint damage and dysfunction at the genetic level, this field holds promise to one day transform arthritis treatment.
References:
[1] Ivaska KK, et al. Genetics of osteoarthritis – Beyond primary osteoarthritis. Nat Rev Rheumatol. 2018;14(4):201-212.
[2] Wei Y, et al. CRISPR/Cas9-mediated editing of the Gdf5 gene in mice rescues a brachypodism phenotype. Development. 2017;144(20):3703-3713.
[3] Li J, et al. CRISPR-Cas9 Intronic Targeting Prevents Mismatch Repair-Mediated Rejection of Corrective Donor DNA. Mol Ther Nucleic Acids. 2019;16:606-617.
[4] Xue Y, et al. Targeted genome editing of the HPRT1 gene in rheumatoid arthritis patient T cells mediated by TALENs. Sci Rep. 2017;7(1):2319.
[5] Tian Y, et al. Delivery strategies of genome editing for the treatment of rheumatic diseases. J Cell Mol Med. 2020;24(23):13655-13666.