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

> **NIH NIH K08** · STANFORD UNIVERSITY · 2022 · $54,000

## 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.

## Key facts

- **NIH application ID:** 10440217
- **Project number:** 3K08NS102398-05S1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Natalia Gomez-Ospina
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $54,000
- **Award type:** 3
- **Project period:** 2017-07-15 → 2023-02-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10440217

## Citation

> US National Institutes of Health, RePORTER application 10440217, Correction of Mucopolysaccharidosis type 1: Targeting safe harbor loci using genome editing (3K08NS102398-05S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10440217. Licensed CC0.

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