Supplementing Deficiencies vs. Gene Editing

Abstract：This article explores two primary approaches in gene therapy: supplementing deficiencies and gene editing. The supplementing deficiencies method involves introducing a corrected gene sequence to compensate for a faulty gene, but it faces risks of uncontrolled DNA insertion, potentially causing new health issues. Gene editing, on the other hand, modifies the genome directly but poses concerns about off-target effects. While both approaches show promise, gene editing holds greater long-term potential for precise corrections. Advanced techniques like base editing and prime editing, pioneered by Dr. David Liu's lab, offer higher precision without cutting DNA strands, paving the way for safer and more effective treatments.

When comparing the two primary approaches in gene therapy—supplementing deficiencies and gene editing—which one holds greater potential?

It's difficult to give a definitive answer, as both approaches still face systemic technical challenges.

The "supplementing deficiencies" approach involves introducing a correct gene sequence into a patient's genome to compensate for a faulty gene. However, the process of inserting DNA into the genome is currently uncontrolled. Viral vectors can insert multiple copies of the gene at unpredictable locations, potentially disrupting important genes and leading to unintended health risks. For example, while Lyfgenia has been approved, clinical trials observed blood cancer cases, prompting the FDA to issue a black-box warning for doctors and patients.

Gene editing, on the other hand, faces the issue of "off-target" effects, where unintended parts of the genome may be edited. Although Casgevy has not shown such risks in clinical trials so far, long-term monitoring is essential as the therapy scales.

Moreover, neither approach can yet be considered a definitive, targeted cure. In supplementing deficiencies, the defective beta-globin gene continues to function alongside the inserted corrected copy, possibly still producing faulty hemoglobin. In gene editing, while reactivating fetal hemoglobin (as Casgevy does) can mitigate symptoms, its oxygen-binding properties differ from adult hemoglobin, raising concerns about unforeseen side effects.

Looking forward, gene editing holds greater long-term potential due to its ability to directly modify and correct pathogenic gene sequences—a goal traditional gene supplementation struggles to achieve. Two promising strategies are emerging for precise genome editing:

1. CRISPR-Based Precision Repair Using Donor DNA Templates:CRISPR/Cas9 can cut DNA, and cells can use a provided DNA template to repair the break with the correct sequence. If both the editing tool and the corrected sequence are delivered together, the faulty gene could be corrected accurately. Companies like Graphite Bio are exploring this approach for beta-globin gene correction.

2. Advanced Gene Editing Tools: Base Editing and Prime Editing:Base editing and prime editing, developed by Dr. David Liu's Harvard lab, offer an even more precise approach.

• Base Editing: Introduced in 2016, it modifies single nucleotides without cutting the DNA. For example, the cytosine base editor (CBE) can convert cytosine (C) to thymine (T) without breaking the DNA strand, while the adenine base editor (ABE) can convert adenine (A) to guanine (G). Together, these tools allow four of the twelve possible DNA base conversions.

• Prime Editing: Introduced in 2019, prime editing uses a modified CRISPR/Cas9 paired with a reverse transcriptase enzyme. This method can directly replace entire sequences of DNA without inducing double-strand breaks, enabling all twelve base conversions and more complex modifications such as insertions and deletions.

These advanced technologies have significantly expanded the precision of gene editing, beyond what CRISPR/Cas9 initially offered. Liu's companies, BEAM Therapeutics and Prime Medicine, are actively advancing this field toward therapeutic applications.

Despite both Lyfgenia and Casgevy being approved for sickle cell disease treatment, the market reaction revealed clear favoritism toward gene editing technologies. Bluebird Bio, which developed Lyfgenia using the supplementing deficiencies approach, saw a 40% drop in its stock price on approval day, reflecting market confidence in gene editing's superior long-term potential.

However, significant technical challenges remain. Improving editing efficiency, reducing off-target effects, and achieving multi-gene edits are critical next steps. Delivering gene editing tools precisely to the target cells and tissues also needs refinement. Furthermore, clinical complexities, high treatment costs (often exceeding millions of dollars), and the narrow focus on rare monogenic diseases highlight the need for broader, more accessible applications.

In the future, the evolution of gene editing will likely focus on lower costs, broader accessibility, and effective treatments for complex, multifactorial diseases, pushing the boundaries of modern medicine.