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Enhanced pancreatic islet cell engraftment by treatment with serpin B1

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41DK127818-01A1
Agency Tracking Number: R41DK127818
Amount: $246,281.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: 200
Solicitation Number: PA20-265
Solicitation Year: 2020
Award Year: 2021
Award Start Date (Proposal Award Date): 2021-09-24
Award End Date (Contract End Date): 2022-08-31
Small Business Information
San Mateo, CA 94402-1129
United States
DUNS: 010286563
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (510) 412-9100
Business Contact
Phone: (650) 622-9702
Research Institution
BOSTON, MA 02215-5306
United States

 Domestic Nonprofit Research Organization

The number of people with diabetes worldwide is predicted to increase from 415 million in 2015 to 642 million
in 2040. The health care costs of treating diabetes accounts for 12% of the global health expenditure of which
Type 1 diabetes mellitus (T1DM) constitutes 10-15% of the disease burden (IDF World Atlas 2015). T1DM is
an autoimmune disease triggered by genetic and/or environmental factors in early childhood, resulting in T-cell
mediated destruction of insulin producing pancreatic β-cells causing life-threatening hyperglycemia.Pancreatic β-cell transplantation is a promising experimental therapy that reverses diabetes in both
animals and humans but is limited by the availability of donors and immune-mediated graft rejection and thus
used primarily to control diabetes in patients who do not respond well to insulin replacement therapy or who
develop severe complications. The discovery of new ways to induce tolerance without compromising a
patientandapos;s immune system would be a major step forward in allowing wider adoption of β-cell transplantation as
an effective therapy. One such protein displaying profound immunoregulatory effects is the human plasma
protein alpha 1-antitrypsin (AAT, serpin A1) which is currently in clinical trials to improve pancreatic islet
survival in patients undergoing renal transplantation, total pancreatectomy, or with difficult-to-control T1DM.Recently, the Kulkarni lab identified Serpin B1 (sB1) as a β-cell growth and survival factor. Serpin B1 is
structurally and functionally related to AAT, and like AAT, is an effective anti-inflammatory protease inhibitor
with immunoregulatory activities. However, sB1 also induces β-cell proliferation in vitro, promotes the
neogenesis of insulin + cells in pancreatic ductal lining epithelia in vivo, induces immuno-tolerance by altering
the Th17/Treg ratio in vivo and inhibits programmed cell death pathways not regulated by AAT. Independently,
the Pemberton lab discovered that the protease inhibitory activity of sB1 can be rapidly inactivated by reactive
oxygen and nitrogen (ROS/RNS) species and has formulated the protein with N-acetylcysteine to protect
against this inactivation and mitigate the oxidative stress-induced inflammation, and pro-coagulant activities
that islets are subject to during transplantation. We have demonstrated this formulation to prevent and treat
new onset diabetes in the NOD mouse via mechanisms directly relevant to islet cell transplantation.Thus, we propose that sB1 will restore and maintain euglycemia in syngeneic (C57BL/6) and
xenogeneic (NOD-SCID) mouse models of islet transplantation by protecting functional marginal β-cell
masses against oxidative stress, IBMIR and inflammation while inducing their proliferation and
enhancing immune tolerance by altering the Th17/Treg ratio.The proposed research in phase I will focus on producing highly purified active recombinant proteins
and providing proof-of-principle in animal models of β-cell transplantation. The outcome of these studies will
guide the design of future efficacy studies in animals and humans.PROJECT NARRATIVE
This proposal aims to establish proof-of-concept in an animal model that the protein serpin B1 (sB1) can
improve transplanted pancreatic islet cell engraftment, survival and function by inducing immune tolerance and
enhancing the survival and proliferation of insulin + β-cells. The academic partner discovered sB1 is a growth
and survival factor for β-islet cells while the small business partner and others have proven it to be a regulator
of multiple inflammatory and programmed cell death pathways in vitro and in vivo. The small business partner
discovered that sB1 is subject to inactivation by ROS/RNS and is developing and evaluating ROS/RNS
resistant sB1andapos;s as novel therapies to treat inflammatory and autoimmune diseases and jointly with the
academic partner will test if sB1 can enhance transplanted β-cell survival and engraftment to improve
transplant outcomes in patients with poorly controlled T1DM.

* Information listed above is at the time of submission. *

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