Robust verification of genetic variant-associated candidate off-target sites
Active Cooperative Agreement Awarded Last action
- Award ID
- U01AI191210
- Recipient
-
The Children's Hospital Corporation UEI Z1L9F1MM1RY3
- Awarding agency
-
National Institute of Allergy and Infectious Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $2,531,877
Award facts
- Assistance listing
- 93.310 Trans-NIH Research Support
- Completion date 49% complete
- Funding agency
- Office of the Director National Institutes of Health, Department of Health and Human Services
- Place of performance
- Boston, MA 02115, USA
Award details come from USAspending.gov.
Description
- Abstract
- Therapeutic genome editing holds immense promise for treating genetic diseases, but off-target effects remain a critical safety concern, particularly when considering human genetic diversity. Most existing methods for identifying off-target sites do not account for genetic variants, potentially missing important risks for individual patients. We have developed crisprme, a computational tool that nominates off-target sites based on genetic variants, and absolve-SEQ, an experimental method to verify these sites in relevant cellular contexts. This proposal aims to optimize and integrate these approaches into a comprehensive pipeline for assessing variant- associated off-target risks in genome editing therapeutics to support IND applications. Aim 1 focuses on optimizing crisprme by incorporating larger variant datasets, integrating advanced prediction tools, and developing standardized protocols for off-target nomination. We will extend the search space to include genetic variants from the all of US research program and implement a risk assessment framework that considers functional annotations and cancer-related somatic mutations. Aim 2 will optimize the absolve-SEQ experimental methodology and analysis pipeline. We will improve vector design, plasmid fidelity, and transduction protocols to enhance sensitivity and scalability. The analysis pipeline will be refined to provide robust statistical modeling of editing outcomes across various editing modalities, including nucleases, base editors, and prime editors. Throughout the project, we will collaborate with scge consortium members to generate benchmark datasets for lead grnas being explored for clinical development. We will work to extend the methods to diverse cell types and tissues relevant to in vivo gene therapy of the liver, eye, and central nervous system. The deliverables will include standardized software modules, sops, and comprehensive data packages suitable for regulatory submissions. Our user-friendly software tools and interactive reports will facilitate the translation of genome editing therapeutics, meeting the highest standards required for supporting IND-submissions. This work will significantly advance our ability to assess off-target risks in genome editing therapies, accounting for genetic diversity and potentially accelerating the clinical translation of these promising treatments. By contributing valuable tools, datasets, and expertise to the scge consortium and the broader gene editing community, we aim to foster collaborative progress in developing safe and effective genome editing therapeutics suitable for diverse patient populations.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $1,675,364 | |
| Original award | $856,513 |
Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| The General Hospital Corporation | $254,530 |
Quick answers
Who received award U01AI191210?
U01AI191210 was awarded to The Children's Hospital Corporation by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on May 19, 2025.
How much is award U01AI191210 worth?
$2,531,877 has been obligated on U01AI191210.
Which agency awarded U01AI191210?
National Institute of Allergy and Infectious Diseases (National Institutes of Health) awarded U01AI191210, with funding from Office of the Director (National Institutes of Health).
On GovTribe
See this award's full record
- Every transaction and subaward
- The recipient's other awards and teaming partners
- Similar grant awards
- Ask GovTribe AI about this award