# Correction of Mucopolysaccharidosis type 1: Targeting safe harbor loci using genome editing

> **NIH NIH K08** · STANFORD UNIVERSITY · 2020 · $196,236

## Abstract

Abstract
Mucopolysaccharidosis type 1 (MPSI) is one of approximately 50 genetic disorders collectively known as
lysosomal storage diseases (LSDs). Like many LSDs, MPSI presents with progressive neurologic and
systemic manifestations, and like most LSDs it lacks effective treatments. Current interventions for MPSI
include allogeneic hematopoietic stem cell transplantation (allo-HSCT) and enzyme replacement therapy
(ERT). Both can slow the progression of the disease, but their therapeutic impact is limited, particularly on the
neurologic and musculoskeletal systems. I propose a novel approach that overcomes the limitations of ERT
and allo-HSCT by genetically engineering the patient’s own hematopoietic system to express high levels of the
missing enzyme (IDUA). Specifically, CRISPR/Cas9 will be used to introduce IDUA into the CCR5 safe harbor
locus in human hematopoietic stem and progenitor cells (HSCPs). A safe harbor approach can achieve high
and sustained levels of enzyme expression, and is an adaptable platform for other lysosomal enzymes. The
feasibility of this approach is supported by the preliminary data, describing an efficient method to target IDUA
to the CCR5 locus in HSPCs. I show that the targeted cells secrete high levels of enzyme, differentiate into
multiple hematopoietic lineages, and are capable of short-term engraftment in immunocompromised mice. The
specific aims are designed to ascertain the potential of these cells to safely and effectively alleviate the MPSI
symptoms. This will be tested in our newly established MPSI mouse model, designed for human cell
engraftment by 1) measuring biochemical and multi-systemic phenotype improvement after transplantation, 2)
establishing the stem cell potential and multi-lineage differentiation capacity of the modified cells, and 3)
unbiasedly searching for off-target sites of our CRISPR/Cas9 methodology. Successful completion of the
proposed studies will have strong impact on the management of MPSI, and establish a new paradigm for
delivering therapeutic proteins for the treatment of non-hematological and neurological diseases, including
other LSDs.
 My ultimate goal is to become an independent physician-scientist who helps advance our treatments for
diseases, like the LSDs, with unmet clinical needs. My clinical training as a medical geneticist and my basic
science background in genetics, biochemistry, and molecular neurobiology, make me ideally suited to
contribute in the area. The training plan outlined in this application will permit me to develop additional needed
expertise, including: 1) genome-editing technologies, 2) hematopoietic stem cell biology and transplantation, 3)
bioinformatics, 4) neuropathology, and 5) the practice of translational research. With this additional training,
and career and scientific guidance from my advisory committee, I believe I can accomplish my goal.

## Key facts

- **NIH application ID:** 9934291
- **Project number:** 5K08NS102398-04
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Natalia Gomez-Ospina
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $196,236
- **Award type:** 5
- **Project period:** 2017-07-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934291

## Citation

> US National Institutes of Health, RePORTER application 9934291, Correction of Mucopolysaccharidosis type 1: Targeting safe harbor loci using genome editing (5K08NS102398-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9934291. Licensed CC0.

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