[R21] Efficacy of Sustained Anti-inflammatory Delivery in a Naturally Occurring Cruciate Ligament Injury Model
Ente: National Institute of Arthritis and Musculoskeletal and Skin Diseases
Scadenza: 2027-08-31
Importo max: $389,737
Paese: US
Descrizione
Abstract
From mouse to man, traumatic injuries to the joint cause inflammation and, when the instigating injury remains
uncorrected, persistent inflammation culminates in irreversible degradation of all joint structures. In companion
animals, such as dogs, cranial cruciate ligament (CCL) disease is one of the most common causes of lameness
and is the leading cause of degenerative changes in the stifle joint. A number of therapies have been developed
to treat inflammation associated with persistent joint pain, including direct joint injections of non-steroidal anti-
inflammatories and intra-articular (IA) glucocorticoid and systemically delivered biologic therapies, among others.
However, most IA therapeutics are rapidly cleared from the joint via the synovium within 24-48 hours. To sustain
drug delivery in the mechanically loaded joint, our team recently developed a novel delivery system based on
PLGA microparticles that are designed to rupture under specific mechanical loading parameters (MAMCs). Our
data show that biologic therapies (including receptor antagonists, such as IL-1Ra) can be encapsulated at high
efficiency and release active factors through both mechanically induced rupture and/or passive degradation of
the MAMCs. When injected into a minipig synovial joint, MAMCs were well tolerated and progressively released
their contents over a two-week period. While promising, this technology has not yet been extensively evaluated
in a naturally occurring spontaneous injury model. In this proposal, we will first (in Aim 1) develop MAMCs
delivering either the clinical formulation of IL-1Ra (AnakinraTM) or IL-6 receptor inhibitor (ActemraTM) and assess
this technology in client-owned canines subsequent to presentation of CCL injury. We will evaluate and compare
the safety and efficacy of IA IL-1Ra or IL-6 receptor inhibitor MAMCs to IA delivery of the same factors delivered
free (unencapsulated) soluble form. In these dogs, as well as humans with ACL injuries, several weeks generally
pass between the timing of knee injury and the surgical repair, during which time inflammatory factors are present
in the joint. In Aim 2, we will test the hypothesis that quelling inflammation via the sustained release of anti-
inflammatory therapeutics after injury, but before surgical repair, will improve patient recovery after surgery when
compared to IA delivery of unencapsulated soluble IL-1Ra or IL-6 receptor inhibitor. Successful completion of
this study will advance a new technology towards human clinical implementation and validate, for the first time,
the safety and therapeutic efficacy of MAMC-delivered IL-1Ra and IL-6 receptor inhibitor in client owned canines.
These data will set the stage for subsequent larger and longer lasting preclinical evaluation, as well as application
of this drug delivery system in other injury scenarios in which quelling inflammation improves long term outcomes.
Istituzione: UNIVERSITY OF PENNSYLVANIA
PI: Kimberly A Agnello
Progetto: 1R21AR087081-01A1
Settori: National Institute of Arthritis and Musculoskeletal and Skin Diseases
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