Combinatorial Helper-Dependent Adenoviral Gene Therapy for Post-Traumatic Osteoarthritis
Abstract
Osteoarthritis (OA) is a common clinical condition with a prevalence of 32 million individuals in the U.S. More than 80% of those over the age of 55 have radiographic evidence of OA. Among those individuals, 30% present with significant pain or disabilities. Post-traumatic injury is the cause attributed in 12% of the patients who suffer from OA. This equates to 3.8 million individuals in the United States and corresponds to an annual expenditure of $3.06 billion for post-traumatic arthritis. This is especially relevant for our military as traumatic joint injuries occur at a higher prevalence and such traumatic injuries are a major predisposing factor for OA and pain. However, current treatment of osteoarthritis is limited to lifestyle modification, analgesics and invasive procedures such as joint replacement surgery in severe cases. The mechanism and important biological players in OA still remain largely unknown. Hence, the studies proposed here should have broad implications both for basic research and clinical treatments in OA. First, we aim to identify the most efficient gene therapy approach to joint cells (both synovium and cartilage) for transferring genes. Second, we will test molecules that have cartilage protective and anti-inflammatory functions during OA development. Finally, we plan to evaluate a gene therapy approach in a large animal horse model of post-traumatic OA, which may best model the possible outcomes of human clinical trials. Our specific approach is to deliver combinations of genes that will protect cartilage as well as block inflammation only when inflammation is present to delay OA progression. This research will lead to the commercialization of novel, more efficient and long-lasting new treatments for OA. Our proposed approach uses a highly modified version of the adenovirus called helper-dependent or gutted adenovirus. We, and others, have shown that this version of the virus is highly effective in delivering therapeutic genes. Importantly, it stimulates the patient immune system much less than early generation adenoviruses. Also, because it is gutted, it can accommodate many genes of different sizes, thereby making it unique among different vectors for delivering combination therapies. In addition, the safety of adenoviruses is well established with thousands of individuals receiving these viruses as gene therapy vectors in the context of cancer therapy and vaccines, while our approach of direct injection into the joint space provides additional safety with low chance of systemic exposure. These safety advantages are important for treating a long-term chronic disease like OA. Finally, from the perspective of widespread access, adenoviruses can be produced easily at high concentrations at low cost. Unlike other viral vectors, large-scale production has been well established, for example, in the generation of the COVID vaccine by Johnson and Johnson and others. This is also important for treating a common disease like OA. From a commercialization perspective, we have already licensed our single IL-1RA targeted anti-inflammatory therapy to our commercial partner GeneQuine Biotherapeutics, which in collaboration with us performed the key feasibility horse OA study that led to the sublicense to Flexion Therapeutics. Flexion is now performing a first-in-human phase 1 study that has so far shown good safety in age-related osteoarthritis, paving the way for phase 2 and 3 pivotal studies of this helper-dependent adenovirus monotherapy. As part of this, both Flexion and GeneQuine have established the production infrastructure to make Good Manufacturing Practice-grade human vector for clinical trial and subsequent clinical use. Finally, we have also licensed our PRG4 cartilage protective therapy to GeneQuine, and they are well positioned to work with us to move the monotherapy and combinatorial approach to clinical trial and clinical use if our proposed studies are successful. We see this therap
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210372
Entities
People
- Brendan Lee
Organizations
- Baylor College of Medicine
- United States Army