Splenic Modulation of SHP-2 Activity as a Therapeutic Option for Systemic Lupus Erythematosus - PROJECT SUMMARY
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder characterized by a loss of tolerance
to multiple endogenous antigens, for which there is no cure. Current therapeutic options for SLE patients involve
a variety of non-specific immunosuppressive or anti-inflammatory agents that have significant associated side
effects and are often inadequate. There is thus a great unmet need to develop curative therapies for this disease.
In SLE, tissue injury is often mediated by aberrant expression of immunoregulatory signaling proteins. In
particular, Src homology region 2 domain-containing phosphatase-2 (SHP-2) has been shown to enhance
disease-active T cell proliferation and promote downstream cytokine production, each of which are innately tied
to the pathophysiology of the disease. The importance of this phosphatase in the promotion of SLE has been
further demonstrated by its inhibition, wherein systemic treatment normalized many of the symptoms of the
disease concomitant with an extension of lifespan. Yet, SHP-2 is expressed throughout the body, thus the
potential for off-target effects from systemic therapies is great. The spleen is the largest secondary lymphoid
organ and an active regulator of the immune response, with a structure designed to increase the likelihood of
rare interactions between cells, in particular cognate lymphocytes and antigen-presenting cells. While the spleen
is not considered a target organ in SLE, it is an active site for autoantibody generation and the accumulation of
pathogenic cells, including DNTCs, which are trafficked throughout the body to elicit the observed multi-organ
damage. We thus hypothesize that the localization of therapeutics to the spleen, in particular modulators of
SHP-2, may be sufficient to enable a systemic therapeutic effect. To accomplish this, we propose to utilize
engineered senescent red blood cell mimetic nanohybrids to specifically deliver small molecule inhibitors or
oligonucleotide-based therapeutics to the splenic milieu. If successful, the generated materials may potentiate
the discovery of novel therapeutic options for the treatment of SLE with the capacity for increased specificity and
decreased side effects.
