# Circuit-Specific Delivery of Large Cargo Across the Nervous Systems of Adult Mammals and Embryos via Novel Engineered Systemic Vectors

> **NIH NIH DP1** · CALIFORNIA INSTITUTE OF TECHNOLOGY · 2020 · $1,172,500

## Abstract

Viviana Gradinaru, Caltech
With the advent of technologies such as CRISPR/Cas9, genome engineering for both
basic research and therapeutic applications is becoming reality. An outstanding challenge
is the mean to safely and efficiently transfer large genomes to desired cells across life
span. We have developed an in vivo Cre-based selection platform (CREATE) for
identifying adeno-associated viruses (AAVs) that efficiently transduce genetically defined
populations. We used CREATE to select for viruses that transduce the brain after
intravascular delivery and found a vector that nonspecifically transduces most cells across
the adult brain. Since the restrictive nature of the blood brain barrier presents a major
impediment toward treating CNS disorders our discovery has the potential to enable
exciting advances in gene editing/replacement via CRISPR-Cas or RNA interference to
restore diseased CNS circuits if the needed level of efficiency and specificity can be
engineered for diseased targets.
We plan to enable such efforts by creating viral-based solutions to non-invasive whole-
brain large cargo delivery across the blood-brain barrier from embryo to adult by:
1. Generating AAVs for cell-type and region specific gene delivery across the blood-brain-
barrier, noninvasively via the bloodstream in the adult rodent for neurodegeneration
applications.
2. Generate AAVs capable of transducing the developing brain in utero with a simple
systemic injection to the pregnant dam for neurodevelopment research and therapy.
3. Increase the packaging capability of AAVs by about 2-fold to enable delivery of large
genomes for gene therapy and research.
4. Enable non-invasive circuit specific deep brain modulation by the use of systemic
vectors and genetically encoded activity modulators (e.g. by chemogenetics or others in
development now).
Longer term we plan, in our laboratory and also with collaborators, to contribute our
neurotechnologies (including, in addition to viral vectors, tissue clearing and optogenetic
control and imaging) towards elucidating maladaptive neural circuits that contribute to
brain pathology in neurodegeneration and neurodevelopment.

## Key facts

- **NIH application ID:** 10004187
- **Project number:** 5DP1NS111369-03
- **Recipient organization:** CALIFORNIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Viviana Gradinaru
- **Activity code:** DP1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,172,500
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10004187

## Citation

> US National Institutes of Health, RePORTER application 10004187, Circuit-Specific Delivery of Large Cargo Across the Nervous Systems of Adult Mammals and Embryos via Novel Engineered Systemic Vectors (5DP1NS111369-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10004187. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*