Targeted Rapamycin Micelle (TRaM) as a Therapeutic and for Solid Organ Transplant

Description:

Technology: TRaMs are a novel therapeutic tool for immunosuppression during solid organ transplantation that encompasses a pH sensitive, self-assembling nanocarrier with encapsulated rapamycin and a targeting moiety for endothelial cells. TRaMs internalize more rapidly than non-targeted RaMs, suppress biomarkers of EC inflammation and reduce MHC expression in vitro. Also, in a co-culture model where T cells are pre-sensitized to mouse cardiac endothelial cells (MCECs), TRaM therapy (100 ng ml-1) significantly reduced IL-8 (data not shown) and IFN- (Figure 1-left) compared to controls.

In addition, TRaMs (TR) are superior to free rapamycin (FR) in reducing intimal thickening of aortic allografts 28 days post-transplant in a mouse model. In Figure 2 (right) aortic allografts were harvested and placed in UW solution containing 100 and 1000 ng ml-1 of TR or FR. The intimal expansion was significantly less in the 1000 ng ml-1 TR group compared to the FR group at 28 days. TRaMs have also been shown to be safe in preliminary porcine testing. Overall, this dosing method can likely be provided to the patient prior to a transplant and/or given directly to the donor tissue prior to transplantation to achieve immunosuppression with limited side effects.

 

Overview: Conventional immunosuppression globally reduces the immunological response by dampening the entire immune system to protect the newly grafted organ. However, side effects such as infections, cancers, and metabolic derangements are among the list of complications that organ transplant recipients suffer while on the necessary organ saving immunosuppressant medications. Furthermore, these therapies have little impact on the cascade induced during IRI. While significant advancements have been made with the design and efficacy of newer immunosuppressive medications, many carry high systemic risk profiles.

 

Recent studies have shown that treatment of ECs in vitro with the mTOR inhibitor rapamycin, an immunosuppressive drug used clinically, can render ECs tolerogenic. Pre-treatment of EC with rapamycin reduced proliferation of allo-reactive memory T cells, reduced cytokine production, reduced EC activation, and further promoted the differentiation of T regulatory cells in an EC/T cell co-culture system. These elegant studies demonstrate that pre-operative rapamycin therapy provides protection from EC-mediated immune injury.

 

A potential way to circumvent the systemic side effects of immunotherapeutics like rapamycin and protect the organ graft is to develop strategies to specifically deliver these medications directly to the endothelium of grafted tissues to reduce local injury, inflammation, allopresentation, and the harmful side effects associated with their systemic counterparts.

 

We have capitalized on these unique findings and have developed a bioengineering solution to deliver rapamycin to the donor organ ECs through endothelial Targeted Rapamycin Micelles (TRaM). 

 

Applications: Pretreatment solution for transplant organ and a therapeutic given to a patient prior to transplant

Advantages: Alleviate the side effects of systemic rapamycin delivery by selective suppression of the immune response

Key Words: Organ transplant, transplantation, nanoparticle, micelle, endothelial cells, cytokines, reperfusion injury, rapamycin, preservation solution, organ storage, immunosuppression

 

Publication: Nadig, Satish N., et al. "Immunosuppressive nano-therapeutic micelles downregulate endothelial cell inflammation and immunogenicity." RSC Advances 5.54 (2015): 43552-43562.

 

Inventors: Ann-Marie Broome, Suraj Dixit, Satish Nadig, & Carl Atkinson

Patent Status:       US 15/107,536; EP 3094314; PCT/US2016/39315

MUSC-FRD Technology ID: P1446; P1577

 

Licensing Status: This technology is currently licensed to MUSC startup, ToleRaM. Please contact the FRD to be put in touch with ToleRaM

 

Patent Information:
Category(s):
Therapeutic
For Information, Contact:
Troy Huth
Sr Licensing Manager
MUSC Foundation for Research Development
huth@musc.edu
Inventors:
AnN-Marie Broome
Suraj Dixit
Satish Nadig
Carl Atkinson
Keywords:
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