Compositions and methods for treating central nervous system injury
Inventors
Tomlinson, Stephen • ADKINS, DeAnna • Alawieh, Ali
Assignees
MUSC Foundation for Research and Development • US Department of Veterans Affairs
Publication Number
US-11007254-B2
Publication Date
2021-05-18
Expiration Date
2037-10-17
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
The present invention describes compositions and method for improving outcomes after injury to the central nervous system wherein complement signaling is activated. In one aspect, the method comprises administering to a subject a therapeutically effective amount of a therapeutic agent comprising a targeted inhibitor molecule comprising a targeting portion and an inhibitor portion, wherein the molecule inhibits complement, and wherein therapeutic agent is administered in combination with rehabilitation therapy or thrombolytic agent.
Core Innovation
The invention provides compositions and methods for improving outcomes after injury to the central nervous system where complement signaling is activated. The method comprises administering a therapeutically effective amount of a therapeutic agent comprising a targeted inhibitor molecule with both a targeting portion and an inhibitor portion, wherein the molecule inhibits complement. The therapeutic agent is administered in combination with rehabilitation therapy or a thrombolytic agent, aiming to reduce tissue damage and improve functional outcomes after injury.
The problem being solved is that ischemic stroke, traumatic brain injury, and spinal cord injury cause significant mortality and long-term disability. Following cerebral ischemia, reperfusion leads to secondary injury mediated by pathological processes including complement activation, which propagates ischemia reperfusion injury. Current treatments, like thrombolytic therapy, require immediate administration and are limited by a short treatment window. There remains an unmet need for improved treatment compositions and methods to treat stroke and other central nervous system injuries with extended therapeutic windows and reduced complications.
The invention addresses these needs by providing a targeted complement inhibition strategy that specifically delivers complement inhibitors to sites of complement activation, such as by utilizing an antibody or fragment that specifically binds to Annexin IV or phospholipids. This targeting avoids systemic complement inhibition and its associated risks, increasing bioavailability and efficacy. The invention also describes using the targeted inhibitor in combination with standard therapies, including thrombolytic agents and rehabilitation, to improve motor and cognitive recovery and survival after central nervous system injury.
Claims Coverage
The patent includes one independent method claim directed to treating central nervous system injury by administering a composition with a targeted inhibitor molecule and a thrombolytic agent, optionally combined with rehabilitation therapy. The inventive features pertain to the composition's specific targeting portions, complement inhibitors, and thrombolytic agents used.
Targeted inhibitor molecule comprising a targeting portion and a complement inhibitor
The method involves administering a composition comprising a targeted inhibitor molecule which includes a targeting portion (such as an antibody or fragment binding Annexin IV or a phospholipid) and a complement inhibitor portion.
Use of specific complement inhibitors
The complement inhibitor portion is selected from Factor H, DAF, MCP, CD59, Crry, MAp44, CR1, or fragments thereof.
Administration in combination with thrombolytic agents
The method comprises administering the targeted inhibitor composition together with a thrombolytic agent, which can be tissue plasminogen activator (t-PA), urokinase, anistreplase, ancrod, or brinase.
Optional addition of rehabilitation therapy
The method may further include providing rehabilitation therapy to the subject, including cognitive therapy and motor therapy, in combination with the compositions.
The claims cover methods of treating central nervous system injury by administering a therapeutically effective amount of composition comprising a targeted complement inhibitor molecule and a thrombolytic agent, optionally with rehabilitation therapy. The inventive features focus on the composition's targeting portion, complement inhibitor identity, thrombolytic agent combination, and rehabilitation adjunct.
Stated Advantages
Targeted complement inhibition reduces acute mechanisms of degeneration and infarct volume following stroke.
Combining targeted complement inhibitors with thrombolytic agents reduces treatment-associated hemorrhage and mortality.
The invention extends the therapeutic window for treatment of central nervous system injury beyond that of current therapies.
Targeted delivery avoids systemic immunosuppression and preserves complement’s homeostatic functions.
Use of targeted inhibitor enhances motor and cognitive recovery in combination with rehabilitation therapy.
Documented Applications
Treatment of ischemic stroke to reduce tissue damage, improve functional and cognitive recovery, and increase survival.
Treatment of traumatic brain injury for improved recovery outcomes.
Treatment of spinal cord injury to improve functional recovery.
Use as adjuvant therapy in combination with thrombolytic agents such as t-PA to improve stroke treatment efficacy and safety.
Use in combination with rehabilitation therapies (motor and cognitive) to augment recovery after central nervous system injury.
Interested in licensing this patent?