Advancing Technologies To Enhance Engraftment In Cell Therapy For T1D

Overview

The goal of this funding opportunity is to advance technologies that support the engraftment of insulin-producing cells following transplantation at extrahepatic sites for T1D cell therapy.

Proposals eligible for consideration will focus on strategies addressing the various challenges encountered at alternative transplantation sites during the peri-transplant period due to inflammation, hypoxia, and poor vascularization to enhance survival, engraftment, and function of transplanted cells.

This program will award grants of up to $300,000 per year for 2 years according to the preliminary data available and scope of work proposed. Awards of increased scope may be considered following discussion with the scientific lead.

Proposals focused on advancing technologies into late preclinical and early clinical development will be prioritized.

Eligibility

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Application Details

Breakthrough T1D Request for Applications:
Advancing Technologies to Enhance
Engraftment in Cell Therapy for T1D
November 2024
Summary
• The goal of this funding opportunity is to advance technologies that support the
engraftment of insulin-producing cells following transplantation at extrahepatic sites
for T1D cell therapy.
• Proposals eligible for consideration will focus on strategies addressing the various
challenges encountered at alternative transplantation sites during the peri-transplant
period due to inflammation, hypoxia, and poor vascularization to enhance survival,
engraftment, and function of transplanted cells.
• This program will award grants of up to $300,000 per year for 2 years according to
the preliminary data available and scope of work proposed. Awards of increased
scope may be considered following discussion with the scientific lead.
• Proposals focused on advancing technologies into late preclinical and early clinical
development will be prioritized.
Funding Opportunity Description
Breakthrough T1D requests applications seeking support for preclinical and clinical research
projects aiming to accelerate the development of technologies and/or strategies focused on
enhancing the survival, engraftment, and function of insulin-producing cells following
transplantation at extrahepatic sites. While much progress has been made in the
development of alternative renewable sources of insulin-producing cells, several barriers
related to the site of implantation, cell delivery, survival and engraftment, and immune
protection must be surpassed before cell therapies to cure T1D are widely available.
Intrahepatic delivery of cells is currently the gold standard in beta cell replacement
therapies given the success of this approach in achieving diabetes reversal and insulin
independence. However, this approach is limited due to various constraints of the
intrahepatic site and alternative sites of implantation that may offer advantages to novel
islet cell therapy approaches are being explored. Through this initiative, Breakthrough T1D
aims to promote the advancement of technologies that address the challenges faced during
the peri-transplant period that limit the survival and engraftment of insulin-producing cells
transplanted at alternative sites. Breakthrough T1D will award grants up to $300,000 per
year for 2 years. Awards of increased scope may be considered following discussion with the
Breakthrough T1D scientific lead.
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Background
Breakthrough T1D is committed to advancing the development of beta cell replacement
therapies that can restore glycemic control and eliminate the need for exogenous insulin
administration in people with T1D. It has been shown that cadaveric pancreatic islet
transplantation is efficacious in improving glycemic control, preventing severe
hypoglycemia, reducing exogenous insulin requirements, and improving quality of life in
patients with medically unstable T1D. While alternative renewable sources of insulin
producing cells like human stem cell-derived islets have advanced into clinical trials, major
scientific and technical challenges in ensuring adequate survival and engraftment of cells
following implantation at alternative sites. In addition, strategies to overcome allogeneic
immune rejection and recurring autoimmunity are needed to ensure long-term graft
function without the undue side effects of chronic immunosuppression before beta cell
replacement can be widely implemented as a cure for T1D. The major barriers and progress
toward addressing these barriers are reviewed here (Grattoni et al. 2024, Nature Rev Endo).
Intrahepatic delivery of cells via infusion into the portal vein is currently the gold standard
in beta cell replacement therapies given the success of this approach in achieving improved
glycemic control, reduction in exogenous insulin requirements, and protecting against
severe hypoglycemia events. However, this approach is limited due to various challenges
such as the instant blood-mediated inflammatory reaction (IBMIR), which results in an
immediate loss of 50 to 60% of the graft, a relatively hypoxic environment, and increased
risk for portal thrombosis and hypertension. Moreover, this site may need to be further
explored for safety consideration as the development of genetically modified immune
evasive stem cell-products advances toward clinical application. As a result, alternative
sites of implantation that may offer advantages for hypoimmunogenic naked cells or other
immune protective strategies over intrahepatic delivery are being explored. Nevertheless,
these alternative sites have their own limitations, such as poor vascularity and hypoxia,
which limit the survival and engraftment of transplanted cells. Moreover, inflammation and
immune-mediated reactions, which may depend on the implantation site, can induce stress
in insulin-producing cells and lead to cell death. Lastly, methods to monitor the engraftment
process are lacking.
As such, Breakthrough T1D requests applications seeking support for preclinical and clinical
research projects aiming to advance the development of strategies and technologies to
enhance the survival, engraftment, and function of insulin-producing cells transplanted in
alternative sites. This funding opportunity focuses on strategies directly targeting the beta
cell graft and methods to modify or monitor the graft microenvironment. Proposals focused
on advancing technologies into late preclinical and early clinical development will be
prioritized.
Applicants seeking to further develop technologies to enhance engraftment are encouraged
to have preliminary data demonstrating in vivo engraftment in rodent models is enhanced
with survival lasting for a minimum of 30 days. Demonstration of physiologic glucose
response post engraftment is highly recommended via dynamic GSIS or glucose tolerance
tests.
Examples of research appropriate for this RFA include, but are not limited to:
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• The further development of strategies (e.g. scaffolds, hydrogels, cell delivery
devices) that ensure adequate oxygenation of the cell graft in vivo and accelerate
stable long-term vascularization and integration of the graft at alternative
transplantation sites.
• Strategies to improve insulin kinetics through better function of implanted beta cells,
with a focus on improved function and glycemic control over purely cell survival.
• Development of methods to quantify engraftment without invasive biopsy such as
validating biomarkers of engraftment (e.g., miRNA, prohormone ratios) or
developing blood vessel and oxygen imaging.
• Investigation of the relationship between engraftment propensity and various graft
features such as cell maturation/metabolism (mitochondrial state, respiration rate),
insulin-producing cell source, immunogenicity or site of implantation.
• Characterization of differential immune reactions and inflammation at various
extrahepatic sites to better inform immune protection strategies at alternative sites.
• Validation of novel target genes involved in promoting cell engraftment via small
molecule or pharmacologic treatment.
Examples of research not supported by this RFA include:
• Genetic modification of the transplanted beta cells.
• Approaches entailing the use of co-transplanted support cells (e.g., mesenchymal
stem/stromal cells or isolated microvessels) to promote vascularization or survival
and engraftment of transplanted beta cells.
• Delivery of therapeutics targeting beta cells that reduce beta cell stress and death
independent of vascularization or engraftment (e.g., GLP-1 pathway).
• The early preclinical development of immunoisolating encapsulation devices to
prevent immune rejection.
Eligibility
Applications may be submitted by domestic and foreign non-profit organization, public and
private, such as universities, colleges, hospitals and laboratories, units of state and local
governments and eligible agencies of the federal government, for-profit entities, or industry
collaborations with academia. Applicants must hold an MD, DMD, DVM, PhD, or equivalent
and have a faculty position or equivalent at a college, university, medical school, or other
research facility.
Please note that applications from for-profit entities or industry collaborations with
academia may be submitted in response to this RFA. Additional information will be
requested from for-profit entities if invited to submit a full proposal.
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There are no citizenship requirements for this program. To assure continued excellence and
diversity among applicants and awardees, Breakthrough T1D welcomes applications from all
qualified individuals and encourages applications from persons with disabilities, women, and
members of minority groups underrepresented in the sciences.
Funding Mechanism
In response to this announcement, Letters of Intent (LOI) can be submitted under the
following mechanism(s):
Strategic Research Agreements (SRAs)
Strategic Research Agreements are intended for support of research activities at non-for-
profit entities such as academic institutions. For SRAs, proposed budgets for projects should
not exceed $300,000.00 USD (including 10% indirect costs) per year for up to two (2)
years. The level of funding will vary depending on the scope and overall objectives of the
proposal. If your project budget and/or timeline exceeds this amount, please discuss with
Breakthrough T1D scientific staff prior to LOI submission. For more information on the
Strategic Research Agreement (SRA) grant mechanism please refer to our grant handbook.
Industry Discovery and Development Partnerships (IDDPs)
Breakthrough T1D’s Industry Discovery & Development Partnership (IDDP) funding
mechanism is intended for support of research activities at for-profit entities. IDDPs have
additional requirements and typically entail a modest royalty payback to Breakthrough T1D.
The level of funding will vary depending on the scope and overall objectives of the proposal.
Indirect costs are not permitted on IDDP applications. If you would like to submit an
Industry Discovery and Development Partnership (IDDP) project LOI to this RFA, please
contact Breakthrough T1D scientific staff (contact information below) to discuss prior to LOI
submission. For more information on the IDDP grant mechanism please check our grant
handbook.
Letter of Intent
Prospective applicants should submit an LOI (2 pages maximum) online via RMS360 to be
considered for a full proposal request. The LOI template provided in RMS360 must be used
to complete the application in order to be considered for a full proposal request.
Proposal
An approved LOI is required prior to the submission of a full proposal. Upon notification of a
request for a full proposal, the application must be completed using the templates provided
in RMS360. Proposal section templates in Microsoft Word, [10 pages maximum] should be
type-written, single-spaced, and in typeface no smaller than 10-point font and have no
more than six vertical lines per vertical inch. Margins, in all directions, must be at least ½
inch. Complete information should be included to permit a review of each application
without reference to previous applications.
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Note that all applications involving human subject research must include supplemental
information to address subject safety, study design, and investigational product information.
More details can be found in the Human Subject Research Guidelines section of the grant
handbook.
Breakthrough T1D follows the U.S. National Institutes of Health (NIH) guidelines for studies
including human subjects, including the Common Rule changes.
Review Criteria
Applications will be subjected to confidential external scientific review evaluated on the
following:
• Significance
• Relevance
• Approach
• Environment
• Resource sharing plan
Informational Webinar and Public Q&A
Breakthrough T1D will hold an announcement introduction meeting via Zoom on December
5th, 2024, from 1-2 pm Eastern Time to which all prospective applicants are invited.
Breakthrough T1D scientists will give an overview of the goals of this initiative, explain the
application process, and answer initial questions on applications.
Registration for Webinar (please register by December 4th, 2024):https://breakthrought1d-
org.zoom.us/webinar/register/WN_e8-
0raAnSemNVoUPiVJhsQ?_x_zm_rtaid=L8tBELCPSjSRsHgWiQfPlw.1730918707231.d81e467
131beb8da9bd289c713221795&_x_zm_rhtaid=210#/registration
Projected Timeline
Milestone Date
Informational Webinar and Q&A December 5th 2024
LOI Deadline January 10th 2025
Notification of LOI Outcome January 21st 2025
Full Proposal Deadline February 21st 2025
Award Notification July 2025
Earliest Anticipated Start October 2025
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Program Contacts
Strategic Fit and Scientific Inquires
Nicholas Mamrak, Ph.D.
Scientist, Research
Breakthrough T1D
nmamrak@breakthrought1d.org
Administrative Inquiries
Madhu Prakash
Program Administrator
Breakthrough T1D
mprakash@breakthrought1d.org
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