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2024-2025 Grants2024-2025 Grant period is now OPEN!
Pre-Proposals are due on April 30th, by 11:59 pm (EST) Click here for the pre-proposal form When invited, full proposals are due August 15th, 2023 by 11:59 pm (EST)
Applicants with pre-proposals that have been selected for the full proposal round will have received an email with instructions.
For funding period 2022-23, CAAT granted two grants.
- Christine E. Bear, Research Institute of the Hospital for Sick Children
Title: Modeling the safety of CFTR gene editing in patient-specific organoids
- Riccardo Barrile, University of Cincinnati
Title: A Sensor-Powered Blood-Vessel on-Chip for Deciphering of COVID-19-Vaccine Induced Thrombosis and De-risking Future Antibody Therapies
Christine E. Bear, Cystic Fibrosis is one of the most common genetic diseases: one in 25 North Americans carry a mutant version of the CFTR gene. The genetic cause of CF was discovered over 30 years ago, but it is only recently that this knowledge has led to the development of new drugs to treat some CF patients. These precision drugs can be effective for individual patients but are costly (>$300,000/year/patient), must be taken for life and are available only to patients harboring specific CF mutations. The effect of decades of daily drug therapy remain unknown, and not all patients, even with the relevant mutations, appear to benefit from treatment. Further, rare, disease-causing variants in the CF gene will not be corrected by existing drugs. Novel and powerful strategies for gene editing to correct disease-causing mutations have become available and are currently being tested for efficacy and safety in animal models of disease. We will employ funding from the Alan and Helen Goldberg In-Vitro Toxicology Grant to develop an analytical pipeline for organoids differentiated from iPSCs that have been edited by CRISPR-Cas9 to repair specific CF-causing mutations. Given the propensity CF patients to develop colorectal cancers, we will first test colonic organoids differentiated from patient-derived iPSCs to determine if this inherent risk is recapitulated in the organoid model. We will then use this platform to conduct a “proof-of-concept” study of cancer risk when a CF-causing nonsense mutation is “repaired using CRISPR-Based base editing. This work will be enabled by the established data base and bioresource existing at SickKids Hospital called CFIT (the Program for Individualized CF Therapies). Significance: Our studies will develop methods for identifying risk associated with CFTR mutation editing in relevant, patient derived tissue organoids thereby reducing the need for studying safety in rodents. Once established, this pipeline will be used in preclinical safety trials for CRISPR based gene editing beyond Cystic Fibrosis to apply to a diverse range of genetic diseases. Riccardo Barrile, Advances in vaccine technology are crucial to limit and prevent infectious diseases around the world, which still account for around 40% of all recorded deaths globally. Over the past decade, the scientific community and the vaccine industry have been asked to respond urgently to epidemics caused by pathogenic agents such as H1N1 influenza, Ebola, Zika, and now the severe acute respiratory syndrome coronavirus (SARS-CoV-2 or Covid19).T o address the growing need of vaccines, pharmaceutical a nd biotech companies have been investing heavily in developing novel technologies and manufacturing platforms that can be readily adapted to new pathogens. Despite the remarkable progresses made int he last decade, however, methods for safety evaluation of novel vaccine candidates haven to kept the pace with the rapid advances in vaccine technology. Better alternatives to current immune-toxicity toxicology methods are urgently needed to improve the current paradigms of translating preclinical data to the clinic and for developing of safer and more effective vaccines.
The recent increase in unanticipated thrombotic events (also referred as “vaccine induced thrombotic thrombocytopenia” or VITT) associated with vaccination against Covid19, has highlighted the safety risks associated with he development of vaccines and the limited predictor power of current toxicology models. While mechanisms underpinning VITT remain poorly understood, a growing body of evidence suggest an Off-target interaction of some not-yet-identified component of the vaccine with existing human blood-factors. Unfortunately, the current lack of translational models of drug-induced thrombosis represents a major roadblock to identify the molecular mechanisms underlying VITT as well as for assessing of putative risk-factors present in existing adenoviral vaccines and other biotherapeutics.
This project will bring together a multidisciplinary team of investigators, including a tissue engineer, an electrochemical engineer, and a virologist whose, complementary expertise is critical for the success of this project. We will leverage the ability of a sensor-powered Blood vessel-Chips device of recapitulating the 3D architecture and dynamic microenvironment of a human blood-vessel, to decipher the molecular mechanisms of VITT in Covid19-vaccines with the long-term goal of providing a validated translational platform designed for de-risking future vaccine development.
This project will result in a unique platform for dissecting the complex series of signaling events underlying VITT and a promising alternative method to current animal testing.
General Award Information:The grants program (http://caat.jhsph.edu/programs/grants) is a centerpiece of our work, providing initial funding for scientists to develop alternatives to the use of animals in biomedical research and product safety testing. To date, the center has funded over 300 grants (including renewals) for a total of more than $6 million. The Johns Hopkins Center for Alternatives to Animal Testing (CAAT) is soliciting projects that focus on the implementation of the NAS Report: Toxicity Testing in the 21st Century: A Vision and a Strategy in the following areas: - Proposals Relating to Toxicology: Maximum grant amount is $40,000. The objective should be to significantly reduce or replace laboratory animals. Examples of acceptable projects could include: providing mechanistic understanding of in vitro responses to toxicants in human cells, development of AOPs, or conducting systematic reviews. Consideration should be given to the translation of this new method to evaluate/predict health outcomes.
- Proposals relating to Refinement are awarded through a different funding mechanism: See Science-Based Refinement Awards – funded separately.
Although relatively small individually, these grants offer critical seed money that allows researchers to demonstrate the value of a particular area of study so they can gain support from the NIH and other sources. We have a stringent, peer-reviewed process for selecting the recipients of these grants. This process consists of sending each application to at least two to three experts in the field from academic, industrial, and government institutions. These reviewers evaluate the applications with regard to scientific merit, budget appropriateness, suitability to CAAT's mission, and expertise of the investigators. They also assign a priority score based on the scoring system used by the NIH. At the CAAT annual advisory board meeting, these applications are reviewed by board members. Board members constitute the voting contingent for the grant applications and assign priority scores in a secret ballot format based upon a synopsis of the outside reviews and the board reviewers. The applications are then ranked in order of priority score and those that receive fundable scores are awarded funds based upon availability of money for the fiscal year. We continue to monitor the long-term progress of the Research Grant Program by requiring our grant recipients to submit copies of publications resulting from the work supported by CAAT grant funds. We maintain a list of publications and an archive of journal reprints. Grants Program Coordinator: Fenna Sillé (fsille1@jhu.edu) | 
