Beginning genetic interventions in infants (BEGIN)

The advancements in genomic medicine have significantly accelerated over the past decade. However, their translation into clinical practice have been slow, and the precise treatment options are essentially nonexistent. The formulation of effective therapies is obstructed by the vast diversity of genetic diseases and the limited number of patients diagnosed with any specific genetic condition. Furthermore, the inefficiency often encountered in diagnostic workups leads to delayed diagnoses for children, rendering it difficult to test interventions effectively at an appropriate stage of their condition. There exists an urgent necessity to bridge the disparities between the prompt identification of patients who are likely to have a genetic disease, the delineation of a precise genetic diagnosis, and the development of effective precision therapies. This project is centered on the Neonatal Intensive Care Unit (NICU) and establishes a framework for an innovative approach to addressing its challenges by integrating rapid turnaround diagnostics with expedited gene-targeted therapies. Within this model, we will provide rapid genome sequencing to patients in the NICU, where many severe childhood genetic conditions initially present—approximately 20% of all admissions—thus offering the opportunity for early diagnosis, prior to irreversible disease progression. Furthermore, we will leverage our VIGOR network and collaborate with comprehensive sequencing facilities, such as GeneDx, to identify NICU cases that exhibit specific types of mutations and conditions that qualify them for patient- customized antisense oligonucleotides (ASOs) therapies. These ASOs are modular therapeutic agents composed of snippets of synthetic DNA or RNA, ranging from 15-30 nucleotides, which can be flexibly tailored to modulate specific gene-splicing patterns or target genes for degradation. Our previous work has demonstrated the feasibility of developing ASOs as a platform for precision treatment in several genetic conditions. This proposal lays the groundwork for the implementation of precision medicine within the NICU. We will focus on identifying opportunities to use ASOs to treat NICU infants with various rare genetic disorders due to the pharmacological advantages conferred by ASOs. In Aim 1, we will conduct rapid genome sequencing on a cohort of NICU infants with rare genetic conditions and implement a systematic algorithm to identify pathogenic variants amenable to ASO intervention sourced from diverse resources. In Aim 2, we will establish a biorepository to preserve biospecimens and assess their ASO amenability through RNA sequencing, subsequently referring them to laboratories and non-profit organizations for the advancement of ASO-based therapeutic modalities. In Aim 3, we will survey the families and healthcare providers regarding this precision NICU care model. This initiative will address the pressing necessity for translational genomic medicine for infants suffering from severe genetic disorders and will provide a widely applicable framework for linking rapid genetic diagnosis to rapid precision therapy across other populations as well. Project Number: 1R01HG014337-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Human Genome Research Institute (NHGRI) | Principal Investigator: PANKAJ AGRAWAL (+1 co-PI) | Institution: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE, CORAL GABLES, FL | Award Amount: $3,151,302 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 MGG-W (51)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11291997