A Novel Office-Based Injectable to Treat Duchenne-Related Fibrosis
Abstract
With progression of Duchenne Muscular Dystrophy (DMD), articular joints in limbs contract or tighten (freeze), causing significant challenges in mobility and basic daily functioning. As muscle function around joints becomes increasingly impaired, the reduced use of these joints causes them to become increasingly stiff, making it painful and difficult to flex, move, or use these joints in a natural manner. Ultimately, some joints (especially ankle, knee, and hip, and later shoulder, elbow, wrist, and all digits) can become completely rigid as the structures in and around the joints accumulate an incapacitating excess of fibrotic or connective tissue. Current treatments for contracted or frozen joints arising from DMD typically address symptom relief; these treatments include physical therapy, serial casting, and bracing. Several approaches aim to prevent joint contracture from occurring, such as botulinum toxin treatment to diminish muscle-associated contracture and corticosteroids aimed at improving muscle function. Overall, these presently available treatment modalities do not address the underlying cause of rigidity, which is the fibrotic tissue accumulation in and around the joints; therefore, their success is limited. Surgical options include manipulation under anesthesia, and muscle, tendon, and joint resection surgeries. For many patients, surgical approaches are fraught with risks such as further damage to the joint structures, and many individuals with DMD are not strong candidates for surgery given the intubation and ventilation that is required. The overall health and quality of life for those with DMD will be greatly enhanced by a non-operative drug treatment that safely eliminates and staves off joint contractures, while delivering the drug only to the joints and avoiding side effects throughout the rest of the body – a common occurrence for drugs taken by mouth. Ortholevo has identified human relaxin-2, a member of the insulin family of hormones, as a potential novel injectable treatment for frozen joints arising from DMD. As a naturally occurring hormone in males and females, relaxin-2 is present at significantly higher levels in women in the third trimester of pregnancy, where it allows the normally stiff pelvic ligaments to become softer in preparation for child birth. Additionally, relaxin-2 plays an ongoing role in the breaking down of fibrotic tissues arising naturally. We have conducted a substantial amount of preliminary work to demonstrate the effectiveness of a sustained-release drug formulation of relaxin-2 in reversing joint contracture in a rat model. The sustained release formulation is administered in a site-specific manner (directly to the joint tissues), allowing for one injection session to restore proper functioning at the whole-joint level, as well as at the microscopic tissue level, supporting its potential as an easy-to-administer and effective therapy. Relaxin-2’s natural presence in the body, as well as its Phase III investigation by other companies for treating fibrotic tissue in heart disease (Novartis) and scleroderma (Genentech), support the safety profile of this therapeutic hormone. The proposed project is well aligned with the stated Translational Research Partnership Award Focus Areas (Novel interventions and drug/biologic delivery technologies to improve quality of life, with respect to orthopaedics and skeletal muscle; and expansion of existing preclinical translational data in support of a specific therapeutic development path). This proposal will enable us to build on our successes to date in order to: 1. Transfer our relaxin-2 production methods to a contract development and manufacturing organization to prepare for preclinical and clinical studies; 2. Transfer our proprietary sustained-release drug formulation technology to a contract development and manufacturing organization to establish product specification and sterilization and shelf-stability protocols; and
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110720
Entities
People
- Ara Nazarian
Organizations
- Beth Israel Deaconess Medical Center
- United States Army