Disease Roundup: Sickle Cell Disease

In this disease-oriented roundup, we take a look at clinical-stage gene-editing approaches to sickle cell disease, which affects millions of people worldwide and is the most common inherited blood disorder in the United States.

By: Karen O'Hanlon Cohrt - Dec. 30, 2020

Earlier this month, Vertex Pharmaceuticals and CRISPR Therapeutics gave hopes to millions of people worldwide with the news that their jointly-developed CRISPR-engineered cell therapy CTX001 led to consistent and sustained health improvements in a handful of patients with severe sickle cell disease (SCD) or beta-thalassemia.

While CTX001 has the potential to cure the millions of people suffering from these inherited blood diseases that implicate haemoglobin, clinical testing is not yet complete and CTX001 is not the only candidate in the race.

In this roundup, we take a look at gene-editing approaches to one of these diseases, SCD, which is the most common inherited blood disorder in the U.S.

Gene Editing - A Cure For Sickle Cell Disease

SCD is a group of diseases that are characterised by defective adult haemoglobin, and it belongs to a larger family of autosomal-recessive blood disorders known as the haemoglobinopathies (See Fact Box).

A number of treatments exist to manage the symptoms and complications of SCD but none of these are curative. Hydroxyurea was the first medication to obtain FDA approval for SCD (1997). It is an anti-cancer agent that promotes the production of foetal haemoglobin by a poorly understood mechanism and is widely used today despite side effects. Recently-approved treatments include Endari (2017), which increases L-glutamine levels in the blood triggering a cascade of events that reduces oxidative stress in sickled cells, allowing them to retain some function, Oxbryta (2019), which prevents defective haemoglobin from aggregating, thus ameriolating the symptoms of SCD, and Adakveo (2019), a monoclonal antibody that blocks P-selectin, thus lessening the inflammation associated with SCD.

Fortuantely for the millions of SCD sufferers worldwide, decades of research to unravel the genetic pathways involved in regulating haemoglobin production has opened doors for gene-editing approaches that aim to cure the disease. There are currently 3 clinical-stage candidates in development, all of which aim to restore foetal haemoglobin (HbF) expression through gene-editing of patient-derived cells.

Schematic of HbF induction. Gene editing can be used to disrupt the BCL11A erythroid enhancer,...
Schematic of HbF induction. Gene editing can be used to disrupt the BCL11A erythroid enhancer, resulting in reconfiguration of the globin gene cluster to reactivate HbF expression. From: Lettre & Bauer, Lancet (2016). 10.1016/S0140-6736(15)01341-0.

1. CTX001: Vertex Pharmaceuticals, US and CRISPR Therapeutics, U.S.

CTX001 is developed using CRISPR technology. Specifically, CRISPR-Cas9 is used to delete the BCL11A in a patient’s own haematopoietic stem cells (HSPCs) ex vivo, and the engineered cells are then transplanted back into the patient where they express HbF to restore healthy red blood cell levels.

Phase 1/2 clinical testing is still ongoing for CTX001 and it is anticipated to be a one-time curative therapy for both SCD (and beta-thalassemia). You can read our earlier coverage on CTX001 here.

2. BIVV003: Sanofi, France

BIVV003 is an ex vivo-engineered autologous HSPC therapy that is designed to express HbF through BCL11A disruption. In contrast to CTX001, BIVV003 is edited using a zinc finger nuclease (ZFN) mRNA that targets the BCL11A locus.

The candidate is being developed as a one-time treatment for severe SCD, and is currently undergoing evaluation in a phase 1/2 study in < 10 adult participants with severe SCD. The study will evaluate its safety, tolerability, and efficacy of autologous HSPC transplantation using BIVV003. BIVV003 is developed using Californian Sangamo Therapeutics proprietary ZFN technology.

At last year’s American Society of Hematology Annual Meeting, Sangamo presented results from ex vivo studies of BIVV003 that showed efficiency BCL11A disruption in both alleles, increased HbF expression and reduced sickling in red blood cells isolated from non-treated SCD patients. As of yet, no clinical data has been shared for BIVV003.

3. OTQ923 and HIX763: Novartis, Switzerland

Switzerland-based Novartis Pharmaceuticals recently initiated an open label, non-randomised, first-in-patient, phase 1/2, proof-of-concept study to follow patients for two years after transplantation of one of two ex vivo CRISPR-edited autologous haematopoietic stem and progenitor cell experimental therapies.

The experimental therapies are OTQ923 and HIX763, both of which are designed to reduce the biologic activity of the B-cell lymphoma/leukaemia 11A protein (BCL11A), increasing fetal haemoglobin (HbF) and reducing complications of sickle cell disease.

The study will be split into distinct sections that will individually assess the candidate therapies in adults and children. OTQ923 and HIX763 are CRISPR-edited haematopoietic stem cells that are developed using CRISPR/Cas9 RNA guides identified through collaboration between Novartis and Intellia Therapeutics. The trial is currently in the recruitment stage for a total of 20 participants and the expected completion date is in November 2023.

We strive to keep you updated with clinical and pre-clinical news from the CRISPR Medicine field. For a complete overview of current gene editing clinical trials, check out CRISPR Medicine News' Clinical Trials Database.

FACT BOX: Sickle Cell Disease (SCD) and Foetal Haemoglobin

SCD results from mutations in the beta globin gene, HBB, and is associated with a range of symptoms and life-life complications. Daily treatment is limited to symptom control, dietary intervention and pain management. While a bone marrow transplant from a healthy matched donor has traditionally been the only (albeit slight) hope of a cure for the haemoglobinopathies, gene-editing technology unleashes the possibility to cure a patient using their own cells. The key to this approach is foetal haemoglobin (HbF).

HbF is highly expressed and critical during foetal development, but then rapidly suppressed early in life. Extensive research on the molecular mechanisms of the haemoglobinopathies revealed that the B-cell lymphoma/leukaemia 11A gene, BCL11A, is a negative regulator of HbF expression, and that its disruption could restore HbF expression and reverse SCD in mice by compensating for the lack of functional adult haemoglobin.

Since the discovery of this so-called haemoglobin switch, reactivation of HbF expression has emerged as a dominating therapeutic strategy for SCD (as well as beta-thalassemia).


HashtagArticleHashtagex-vivoHashtagBeta-ThalassemiaHashtagSickle Cell Disease, SCDHashtagBlood diseaseHashtagCRISPR-CasHashtagZFN - Zinc finger nucleasesHashtagClinical

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