Two Approaches in the Field of Gene Therapy

Abstract：This blog explores two primary approaches in the field of gene therapy, as demonstrated by the recently approved drugs Lyfgenia and Casgevy. The first approach, gene supplementation, involves introducing a corrected gene into a patient's cells to compensate for a genetic defect, as seen with Lyfgenia and Zynteglo for blood disorders. The second approach, gene editing, modifies the patient's DNA directly to disrupt disease-causing genes or reactivate beneficial genes, exemplified by Casgevy using CRISPR technology. These therapies mark significant advancements in genetic medicine, offering promising treatment options for inherited diseases like sickle cell disease and beta-thalassemia.

In this blog, we will focus on two primary approaches currently used in the field of gene therapy, exemplified by the recently approved gene therapies: Lyfgenia by Bluebird Bio and Casgevy by Vertex Pharmaceuticals.

Approach One: Gene Supplementation

The first approach, often referred to as "gene supplementation," aims to compensate for a genetic deficiency by introducing a corrected version of the defective gene into the patient's cells. Most approved gene therapies to date fall into this category.

Take Lyfgenia, for example. Bluebird Bio, the developer, has previously received approval for three gene therapies, all based on this supplementation strategy.

Among them, Skysona was approved in 2022 for the treatment of cerebral adrenoleukodystrophy (CALD), a rare genetic disorder caused by mutations in the ABCD1 gene. Skysona delivers a functional ABCD1 gene into the patient’s hematopoietic stem cells using a lentiviral vector, correcting the genetic defect.

This treatment requires a complex process: stem cells must be extracted from the patient, cultured, and infected with the lentiviral vector carrying the corrected gene. After verifying successful gene transfer, the modified cells are reinfused into the patient. This multi-week treatment comes with a staggering cost of $3 million.

Bluebird Bio’s other two therapies, Zynteglo (approved in 2022 for beta-thalassemia) and Lyfgenia (approved in 2023 for sickle cell disease), follow a similar approach. Both use lentiviral vectors to deliver a functional beta-globin gene to correct the underlying genetic mutations. Like Skysona, they require personalized treatment and lengthy procedures, with similarly high costs.

Approach Two: Gene Editing

The second approach is gene editing, which involves directly modifying the patient's DNA sequence to treat the disease. Casgevy, the other recently approved gene therapy, is the world’s first officially approved gene editing drug.

Gene editing has gained global attention, primarily through CRISPR technology, which allows precise targeting and modification of specific DNA sequences.

The first-generation gene editing tool, Zinc Finger Nuclease (ZFN), was invented in 1996, followed by the second-generation TALEN (Transcription Activator-Like Effector Nuclease) in 2010. Both tools rely on a combination of two components: a sequence-recognition module and a DNA-cleaving module.

CRISPR/Cas9, developed in 2012, significantly improved editing precision and ease of use, becoming a transformative technology in gene therapy. The inventors of CRISPR/Cas9 were awarded the Nobel Prize in Chemistry in 2020.

The idea of using gene editing to correct DNA errors sounds promising—delivering the tool into a patient’s cells to repair faulty genes. However, despite CRISPR’s efficiency, achieving precise DNA corrections remains extremely challenging due to low modification efficiency.

How Gene Editing Therapies Work

Currently, gene editing therapies work in surprisingly straightforward ways.

1. Disrupting Faulty Genes:

   
   

   If a disease is caused by a malfunctioning gene, gene editing can disrupt the gene to prevent it from producing defective proteins.

   
   

   For example, in 2021, the New England Journal of Medicine published data on a gene editing therapy, NTLA-2001, targeting transthyretin amyloidosis (ATTR). This rare disease is caused by mutations in the TTR gene, leading to protein aggregation that damages cells. NTLA-2001 disrupts the TTR gene in liver cells using CRISPR technology, preventing the production of defective proteins and slowing disease progression.

2. Inactivating Repressors to Restore Function:

   
   

   Casgevy, on the other hand, works through a more complex "double-negative equals positive" mechanism.

   
   

   Sickle cell disease and beta-thalassemia result from mutations in the beta-globin gene, which leads to defective hemoglobin. Hemoglobin in fetuses, however, relies on a different subunit called gamma-globin, which is suppressed after birth by a protein called BCL11A.

   
   

   Casgevy uses CRISPR to disable the BCL11A gene, reactivating the gamma-globin gene to restore fetal hemoglobin production. This effectively compensates for the dysfunctional beta-globin, alleviating disease symptoms.

Summary of Gene Editing Approaches

Currently, gene editing therapies do not precisely repair genetic errors but focus on disrupting gene function to treat diseases.

• Approach One: Disable a disease-causing gene, as seen in NTLA-2001.

• Approach Two: Disable a repressor gene to reactivate a beneficial gene, as seen in Casgevy.

These groundbreaking therapies, despite challenges, mark a significant step forward in genetic medicine and offer hope for treating a range of genetic disorders in the future.