Gene Manipulations for Hemoglobinopathies

Transfusion-dependent Thalassemia and Sickle Cell Disease are two of the most prevalent red cell disorders, affecting millions worldwide. These genetic conditions often result in severe complications, including chronic anemia, progressive organ damage, a poor quality of life, and significantly reduced life expectancy. While traditional treatments like packed red cell transfusions and iron chelation therapy offer temporary relief, they fail to provide a long-term solution.

Hematopoietic stem cell transplant has come a long way but still faces inherent challenges, such as the need for high-dose chemotherapy, serotherapy, and allogeneic donors, which increases the risks of graft failure and graft-versus-host disease as the HLA barrier widens. Additionally, long-term immune suppression heightens the risk of severe infections, making this method less ideal. In contrast, innovative approaches like autologous gene-corrected transplants are emerging as safer and more effective solutions, with reduced reliance on immune suppression and improved long-term outcomes.

It's a known fact that by increasing the production of fetal hemoglobin (HbF), the severity of both TDT and SCD can be alleviated. It could be a one stop solution for β-hemoglobin disorders, providing a permanent cure addressing the challenges post by HSCT.

Developmental pattern of globin gene in human life

Understanding hereditary persistence of fetal hemoglobin (HPFH):
We know that a number of people have a mutation which leads to high fetal hemoglobin levels in their blood, an entity known as hereditary persistence of fetal hemoglobin (HPFH). Different mutations lead to different forms of HPFH. All these patients with different forms of HPFH remain asymptomatic all of their lives.

Cellogen’s approach:
Recreating mutations mimicking HPFH (using either Lenti-viral vectors or CRISPR-Cas based gene manipulation) strategies. To achieve this, the team at Cellogen has designed different guide RNA’s (sgRNA) to target various regions of BCL11A to create mutations mimicking HPFH. Cellogen has developed a solid proof of concept in model cell lines and also human cells lines using both CD34 precursor cells from homozygous sickle and thalassemia major patients.

Cellogen approach for β-hemoglobin disorders

We systematically tested our hypothesis in four different preclinical cellular models

Proof of Concept:

We have shown that forced long-range chromatin interactions can be used to reactivate a developmentally silenced gene.
Our approach consistently produced higher HbF levels in all three cellular models we tested.
More efficient NHEJ-based generation of the beneficial HPFH genotype causes reactivation of HbF synthesis in patients' erythroid cells—“one-stop solution for β-hemoglobin disorders.”
Testing of edited patient-derived HSPCs in an in vivo preclinical mouse model for their engraftment potential has been initiated before taking it to the Phase 1 clinical trial.

1980

Discovery of Genetic Basis of Blood Disorders

Identification of mutations in the HBB gene as the cause of sickle cell anemia and thalassemia.

1990

Early Gene Therapy Attempts

First attempts at gene therapy using viral vectors to introduce functional copies of the HBB gene.
Challenges included immune responses and low efficiency of gene integration.

2002

Development of RNA Interference (RNAi)

RNAi used to silence genes involved in the disease process, an early tool for understanding gene function and disease mechanisms.

2012

CRISPR-Cas9 Breakthrough

Discovery of CRISPR-Cas9 as a precise and efficient tool for gene editing revolutionizes genetic research.
Researchers start exploring its potential to correct mutations in the HBB gene.

2017

First CRISPR Gene-Edited Human Trials

Clinical trials begin for sickle cell anemia and beta-thalassemia using CRISPR to either correct mutations or activate fetal hemoglobin (BCL11A gene editing).

2019

Success in Thalassemia Treatment Using Gene Therapy

Patients with severe beta-thalassemia show reduced dependence on blood transfusions after undergoing gene therapy using lentiviral vectors.

2020

First CRISPR Cure for Sickle Cell Anemia Reported

A patient with sickle cell anemia is treated using CRISPR-based therapy, leading to significant reduction in disease symptoms.
Clinical trials continue, expanding to more patients worldwide.

2021

FDA Grants Breakthrough Status to CRISPR-Based Therapies

Gene editing treatments for sickle cell anemia and thalassemia receive special designation for accelerated approval.

2023

Approval of Exa-cel (CRISPR Therapeutic)

Exa-cel (exagamglogene autotemcel), a CRISPR-based therapy, is approved for treating sickle cell disease and beta-thalassemia in multiple countries.
First commercially available gene-editing therapy for these conditions.

2024

Widespread Clinical Application

Gene therapies are now available in several regions, showing high success rates in curing or significantly reducing symptoms of blood disorders.
Research continues to improve accessibility, scalability, and affordability.

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Next 5-10 Years:

Potential for widespread adoption of gene therapies globally.
Expansion to treat other genetic blood disorders like Fanconi anemia and severe aplastic anemia.