# Curing Sickle Cell Disease with CRISPR-Cas9 genome editing

> **NIH NIH OT2** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $476,994

## Abstract

Sickle Cell Disease (SCD) is a devastating recessive genetic disorder, afflicting ~100,000 Americans (3),
~6000 Californians, and hundreds of thousands more worldwide (4). It typically shortens lifespan by
decades even with optimal medical care. SCD is caused by a single mutation in the ß-globin gene; gene
editing can directly correct the mutation. We have developed an autologous stem cell product that uses a
CRISPR/Cas9 nuclease to stimulate repair of the sickle mutation in blood stem cells. Editing reproducibly
yields levels of correction that, based on clinical experience, will be sufficient for a curative effect. We
propose to complete preclinical development of this therapy, leading to an IND application for an early
phase clinical trial in adults with severe SCD. We held a pre-IND meeting on October 30, 2018, and
request CIRM funding for the following activities to support IND submission as discussed with the FDA:
1. Demonstrate the capacity to manufacture final cell product under GMP conditions at clinical scale.
We will generate at least 3 clinical-scale lots under cGMP that meet all release criteria, in plerixaformobilized
HSPCs. We will also complete a drug product stability study. These reports will complete the
CMC section of the IND.
2. Complete a rigorous genotoxicity assessment. A murine xenograft model that supports human
hematopoietic cells will be used to perform a toxicology study on final cell product manufactured under
cGMP conditions. After long-term engraftment, mice will be assessed for evidence of malignant human
cells using histopathology, flow cytometry, and genomic readouts. (pre-IND Question 8).
3. Complete additional preclinical studies to establish product safety and potency. An exhaustive
interrogation for off-target genomic modifications with the final manufacturing reagents will address
potential genotoxicity. We will also assess large deletions and translocations at the HBB on-target site,
the nature and potential impact of HBB mutations induced by the editing procedure, and evidence of
clonal expansion that could reflect early-stage neoplastic progression (pre-IND Questions 5,11).
4. Draft and file an IND with a final clinical trial design. We will generate a final clinical protocol, consent
form, and data and safety management plan to support the IND for a Phase I clinical trial of safety and
feasibility in adults with severe SCD. We will submit these for required regulatory (e.g. IRB, IBC, NIH
RAC) review, pending final approval of IND.
This therapy has the potential to transform the care of SCD by producing a curative treatment that is
applicable to any SCD patient and safer than allogeneic hematopoietic stem cell transplantation (HSCT),
thus making it possible to prevent complications of SCD before they have done irreversible damage.

## Key facts

- **NIH application ID:** 10264257
- **Project number:** 3OT2HL151319-01S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Mark C Walters
- **Activity code:** OT2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $476,994
- **Award type:** 3
- **Project period:** 2019-06-12 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10264257

## Citation

> US National Institutes of Health, RePORTER application 10264257, Curing Sickle Cell Disease with CRISPR-Cas9 genome editing (3OT2HL151319-01S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10264257. Licensed CC0.

---

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