# Homologous Recombination Mediated Gene Correction for the Hemoglobinopathies

> **NIH NIH R01** · STANFORD UNIVERSITY · 2021 · $395,344

## Abstract

Project Summary
 Sickle cell disease is a genetic disorder that results in the production of a dysfunctional form of
hemoglobin. In the United States about 100,000 people have sickle cell disease and worldwide almost
300,000 affected children are born every year. b-thalassemia is also an inherited disorder that results in the
decreased synthesis or complete absence of the b-globin chains of hemoglobin. The estimated annual
incidence of b-thalassemia is 500,000 most commonly to parents from Mediterranean countries, North
Africa, the Middle East, India, Central Asia, and Southeast Asia. Both diseases are caused by mutations in
the b-globin (HBB) gene and can be cured by allogeneic hematopoietic stem cell transplantation (allo-HSCT
or provocatively called “allogeneic gene therapy”). The lack of available immunologically matched donors
and the significant morbid complications from allo-HSCT, however, means that allogeneic gene therapy has
only been used to treat a small fraction of the patients who could benefit. There are currently no other
definitive and curative approaches for either of these diseases.
 We have developed an alternative approach that has the potential to circumvent all of these issues
described. For sickle cell disease, the functional gene correction process we are developing uses
CRISPR/Cas9 to edit the HBB gene directly in patient’s own HSPCs by precisely correcting the sickling
point mutation. But b-thalassemia is caused by mutations throughout the gene. For this we will either
knock-in a wild-type cDNA into exon 1 of the HBB gene such that the cDNA utilizes the endogenous ATG
initiation codon or knock-in a full length HBB gene into HBA1. In this way the HBB gene will be expressed
using the endogenous initiation start codon and using all of the endogenous natural regulatory elements. By
knocking into HBA1 we will also simultaneously create a-thalassemia trait, a genotype that is known to
decrease the severity of b-thalassemia. In Aim 1- we will correct the sickle mutation in the endogenous
HBB gene using genome editing; in Aim 2 we focus on developing the knock-in strategy to allow expression
of the HBB cDNA in HSPCs from b-thalassemia patients. The final aim (Aim 3) is to use a series of
functional assays to test the overall toxicity of the optimized process and thereby determine the safety of the
genome editing process. As part of this grant we have assembled a team of co-Investigators and
consultants with expertise in creating a GMP compatible cell manufacturing process. Collectively our goal is
to develop reagents that optimize HBB gene correction thereby providing key IND enabling data to move
forward to first-in-human clinical phase I/II clinical trials for the b-hemoglobinopathies.
!

## Key facts

- **NIH application ID:** 10213813
- **Project number:** 5R01HL135607-04
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Matthew H Porteus
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $395,344
- **Award type:** 5
- **Project period:** 2018-08-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10213813

## Citation

> US National Institutes of Health, RePORTER application 10213813, Homologous Recombination Mediated Gene Correction for the Hemoglobinopathies (5R01HL135607-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10213813. Licensed CC0.

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