REQUEST FOR PROPOSALS

NEXT-GENERATION PRECLINICAL MODELS OF NEUROFIBROMATOSIS TYPE 1

January 11, 2023

 

The Gilbert Family Foundation (GFF) is pleased to announce a Request for Proposals (RFP) for developing innovative preclinical models of neurofibromatosis type 1 (NF1) disease that will enable more robust NF1 drug discovery and translation into human clinical trials.  The RFP places special emphasis on organoid, assembloid, and other in vitro 3D tissue and organ models, particularly those that may add depth to mechanistic studies and/or are tractable to drug screening.

GFF invites proposals for further developing and/or characterizing existing, or developing new, genetically engineered mouse (GEM) models of NF1.  Proposals comparing or referencing existing best-in-class GEM models with new NF1 organoid models and/or providing a robust reference to NF1 clinical parameters to validate the models are particularly encouraged.  Also of interest are proposals that harness the power of artificial intelligence (AI) and deep learning to identify new NF1 targets or interventional opportunities through systems analysis, or as a tool to assist the phenotypic characterization of the models, analyse image-based screening data or otherwise support and enable the goals of the RFP.

 

BACKGROUND

NF1 is an autosomal dominant, monogenic disorder that affects approximately 1 in every 3,000 individuals throughout the world.  Hallmark features of NF1 include multiple café au lait (light brown) skin spots, neurofibromas (small benign growths) on or under the skin, and tumors on nerves that can lead to disfigurement, blindness, and cancer.  NF1 can also result in cognitive disability, skeletal deformity, and cardiovascular complications.  The course of the disease is both unpredictable and variable among individuals.  Even within the same family, patients may experience vastly different symptoms with varying degrees of severity.

NF1 is caused by germline mutations in the neurofibromin 1 (NF1) gene, which encodes neurofibromin protein.  Neurofibromin is primarily characterized as a GTPase-activating protein, catalyzing the conversion of active Ras-GTP into inactive Ras-GDP and thereby negatively regulates Ras/MAPK pathway activity.  In NF1 disease, NF1 haploinsufficiency is thought to underlie vasculopathy and cognitive symptoms.  The remaining majority of NF1 clinical manifestations require a separate mutational event in the somatic NF1 allele (a ‘second hit’).  Tumor manifestations are typically benign; however, the accumulation of additional pathogenic mutations leads to progression to a more aggressive and/or malignant state.

GFF is a private nonprofit foundation founded by philanthropists Dan and Jennifer Gilbert.  GFF’s mission is to develop effective treatments and ultimately a cure for NF1.  At present, its major research initiatives include its (1) Gene Therapy Initiative, developing innovative therapies that address the underlying genetic abnormalities in NF1 patients, its (2) Vision Restoration Initiative, developing vision enhancement and restoration therapies in patients with NF1-associated optic pathway glioma, and its (3) Brain Tumor Initiative, focused on identifying and developing therapeutic strategies to effectively treat NF1-associated transformed gliomas.  GFF seeks bold ideas and high-risk, high-reward projects that have the potential to catapult NF1 drug discovery and development.

 

KEY REVIEW CRITERIA

The focus of this RFP is to stimulate the development of next-generation NF1 disease models that meet as many of the below three criteria as possible and innovation in analytical tools to enable more robust NF1 drug discovery.

  1. A model that serves as a new best-in-class or gold standard for any single or multiple manifestations of NF1.
  2. A new or enhanced model that is validated with respect to robust clinical criteria. Comparative clinical versus in vitro model studies are particularly encouraged.
  3. A model that is be adaptable for screening of potential therapeutics (low to medium throughput is acceptable).

The following are example focal points of proposals that are of interest.

  1. iPSC or patient-derived organoids models of NF1.
  2. Hybrid or assembloid models that may better recapitulate NF1 heterogeneity.
  3. Organoid models of NF1 pre-malignant tumors with emphasis on those that switch from pre-malignant to malignant tumors, including brain tumors and malignant peripheral nerve sheath tumors (MPNSTs). Studies focused on elucidating the mechanism of NF1 tumor progression and transformation as well as the effect of particular NF1 gene germline mutations are encouraged.
  4. In vitro 3D tissue models of NF1 optic pathway gliomas.
  5. In vitro 3D tissue models of NF1 MPNSTs.
  6. In vitro 3D tissue and organoid models of different stages of NF1 disease progression.
  7. In vitro 3D tissue and organoid models that enable the study of the timing, frequency, and mechanism of the ‘second hit’.
  8. In vitro 3D tissue and organoid models that capture aspects of the complex NF1 tumor environment such as the extracellular matrix and immune system.
  9. In vitro 3D tissue and organoid systems that model the response to existing drugs used to treat NF1 manifestations by recapitulating parameters extracted from clinical studies to demonstrate that the model is a robust preclinical model of human NF1 disease.
  10. Lab-on-a-chip or patient-on-a-chip approaches that have the potential to capture more than a single manifestation of NF1.
  11. Microfluidic-based NF1 lab-on-a-chip, patient-on-a-chip, and organ-on-a-chip models that are amenable to medium throughput phenotypic screening.
  12. NF1 genetically engineered murine (GEM) models, xenograft murine models, murine-derived organoids transplantation models, and patient-derived organoids transplantation models (PDOX).
  13. Characterization of and comparison between NF1 models, particularly organoids models, PDOX, and GEM models.
  14. AI and deep learning tools to further enable NF1 drug discovery, e.g., systems level analyses to identify NF1 drug targets, in silico drug screening, and AI and deep learning tools to assist the automated image analysis of NF1 organoid screening data.

 

TEAM SCIENCE AWARD

GFF awards for team science are designed to foster a collaborative research process amongst researchers with complementary expertise and capabilities who will work together to advance new therapeutic solutions for NF1.  Applying teams may consist of investigators from the same or different institution and may be international.  The designated Administrative PI is responsible for administrative leadership.  All PIs on the team share authority for scientific leadership.

Team science awards have a collaborative and multidisciplinary emphasis, involving meaningful collaboration between participants.  Applications therefore must include a description of the nature of and rationale for the proposed collaboration, the specific role of all PIs, and synergistic opportunities.

Evidence of prior productive collaborations between members of the team is also useful.

 

AWARD LENGTH AND BUDGET

GFF expects project timelines of up to 3 years with up to $400,000 per year in direct research costs.  GFF will allow indirect costs of up to 5% of the total direct research cost minus travel and equipment expenses.

GFF is committed to support exceptional research.  Research projects requiring supplemental funding for a critical step arising during the course of the project may receive additional budgetary support at the discretion of GFF.  Likewise, should it be determined that a research project will require more time than planned, GFF has the discretion to provide an award extension to continue the research after the initial 3-year funding period has been completed.

 

REVIEW AND SELECTION PROCESS

All proposals will undergo rigorous peer review by both GFF staff members and by an external panel comprised of experts in NF1, preclinical modeling, organoids and 3D tissue models, and/or AI and related analytical tools.  Applications will be evaluated according to the Key Review Criteria (above), scientific merit, and team synergies.  GFF will provide summaries of reviewer critiques and evaluations to full proposal applicants.  Based on peer review and GFF priorities, GFF will work with selected applicants to modify submitted project plans and/or budgets prior to award execution.

 

APPLICATION INSTRUCTIONS

The application process entails 2 stages.

  1. Letters of intent (LOIs) are due by 5:00 PM Eastern Time on March 3, 2023.
  2. For LOIs selected to advance, full-length proposals are due by 5:00 PM Eastern Time on May 5, 2023.

All applications must be submitted online via GFF’s application portal.  All forms and templates that must be completed as part of your application are available on the portal.  Applications include the following steps and components.

 

LETTER OF INTENT

All applicants must submit a LOI to GFF prior to submission of a full proposal.  The LOI application consists of the following components.  To submit your LOI, please input the requested components on the form at the bottom of this page.

  1. Project Title
  2. Applicant/PI Information: Team Science applications must identify one PI for administrative

purposes (the Administrative PI for the proposal).  This is the Applicant.

  1. Organization/Institution Information: This is the Administrative PI’s institution.
  2. Key Personnel Information: Identify other PIs and other key personnel on the team. All PIs share authority for project leadership. Please describe the nature of and rationale for the proposed collaboration, and the specific roles of each key personnel, including the Administrative PI.
  3. LOI: 1-page maximum that includes:
    1. description of the aims
    2. key milestones/activities within each aim
    3. timeline

 

FULL PROPOSAL APPLICATION

Full proposals will be invited from LOIs selected by GFF.  Applications include the following steps and components.

  1. Face Page. Using the GFF Research Grant Application Face Page Form, provide the project title, applicant/PI information, and organization/institution information. The GFF Research Grant Application Face Page Form will need to be signed by the applicant/PI and the institution’s Signing Official. Electronic signatures are acceptable.
  2. Key Personnel. Using the GFF Research Grant Application Key Personnel Form, list and provide the requested information for the PI and all individuals who will contribute in a substantive, meaningful way to the scientific development or execution of the project, whether or not salaries are requested.
  3. CV/Biosketch of Key Personnel. Attach a CV/biosketch for each key personnel using either the CV/Biographical Sketch Form provided on the GFF portal or the NIH biosketch format.
  4. Current and Pending Research Support for Key Personnel. Using the Current and Pending Support Form, list current and/or pending research support for all Key Personnel.  Any overlap of current or pending support with your application must be described and explained.
  5. Abstracts and Keywords. Provide a lay audience-friendly abstract and a technical abstract (2,000 characters maximum each). Please note that the lay abstract will become public if the application is selected for funding; therefore, it should not contain any proprietary information. Also, provide 3-6 keywords associated with your project.
  6. Project Description. Provide a description of the proposed project, 5-page maximum and inclusive of the following: Specific Aims, Background & Preliminary Data, Research Design and Methods (including a description of technical risks and mitigation), and Figures.  This must be formatted in Arial 11-point or Times New Roman 12-point font with no less than ½ inch margins.
  7. Collaboration and Synergy. Please describe the nature of and rationale for the proposed collaboration, the specific roles of each PI, and synergies.
  8. Literature References. Include a list of up to 20 references supporting the project description in addition to the 5-page project projection.
  9. Milestones. Complete the Milestone Chart to provide a detailed assessment of experimental timeline and dependences, as GFF requires a thorough understanding of parallel vs. sequential activities.  Add or remove rows as needed for your application.  Please note that grant funding will be milestone driven.
  10. Organizational Assurances. Attach IRB and IACUC approvals, if applicable.
  11. Budget and Justification. Please use the Excel file GFF Budget Workbook for Research Grants, provided separately, and instructions below to detail the application budget and respective
  12. Location of RFP. Please specify how you learned about this research grant opportunity, e.g., Email from GFF, GFF Website, GFF Social Media, Internet Search, Colleague, or Other.

 

TIMELINE

RFP release January 11, 2023
Deadline for LOIs March 3, 2023
Teams of selected LOIs invited to submit full length proposals March 17, 2023
Deadline for full proposals May 5, 2023
Peer and internal reviews complete June 23, 2023
Revisions and final research plans complete July 14, 2023
Award letters sent July 31, 2023
Projects commence October 16, 2023

*Timeline is subject to change at GFF’s discretion.

 

GFF CONTACTS

For questions regarding GFF and this RFP, please contact YooRi Kim, Scientific Officer, at YooRiKim@gilbertfamilyfoundation.org.

For technical support for proposal submissions, please contact Mar Paricio Sunyer, Grants and Operations Manager, at Info@gilbertfamilyfoundation.org or (313) 946-1584.

 

SUBMIT YOUR LOI HERE!