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crispr cas azd7648 gene editing damage

CRISPR Cas Gene Editing Side Effect Exposed: AZD7648 Damages Genome

ETH Zürich researchers examining the effects of AZD7648 in CRISPR-Cas gene editing and identifying genome damage

Introduction

The field of genome editing using diverse CRISPR-Cas complexes has seen remarkable advancements in recent years, with numerous laboratories globally striving to bring these tools to clinical application.

CRISPR-Cas technology enables precise and targeted editing of genetic materials, paving the way for gene therapies to combat inherited diseases, tackle cancer, and develop resilient crops.

The Basics of CRISPR-Cas9 and Gene Editing

What is CRISPR-Cas9?

CRISPR-Cas9, often referred to as genetic scissors, is the most prevalent tool in global genetic research, designed to precisely cut double-stranded DNA at target sites for modification. In contrast, emerging methods avoid such double-strand cuts.

DNA Repair Mechanisms: Rapid vs. Precise

The DNA cut triggers two inherent cellular repair mechanisms:

  • Rapid imprecise repair: Quickly reconnects DNA ends but may lead to errors.
  • Slower, precise repair: Requires a template for a accurate repair, which is not always activated.

Homology-Directed Repair: The Preferred Method

The slower mechanism, known as homology-directed repair (HDR), is preferred by researchers for its ability to accurately integrate specific DNA segments into target gene regions, offering versatility in repairing diverse disease-associated genes.

Jacob Corn, Professor of Genome Biology at ETH Zürich, states, "Theoretically, it holds the potential to cure any disease."

Enhancing Gene Therapy with AZD7648

Introduction to AZD7648

Researchers have recently introduced AZD7648, a molecule that inhibits rapid repair mechanisms, compelling cells to adopt homology-directed repair. This method aims to enhance the efficiency of gene therapies. Early results appeared exceptionally promising—perhaps overly so, as subsequent findings revealed.

The Discovery of Side Effects

Corn's research team has identified significant side effects associated with AZD7648. Their findings are detailed in Nature Biotechnology.

Major Shifts in Genetic Sequences

Unexpected Genetic Alterations

While AZD7648 enhances precise repair for accurate gene editing via the CRISPR-Cas9 system, it unexpectedly caused extensive genetic alterations in some cells at targeted sites.

ETH researchers discovered that the alterations involved

  • The deletion of thousands of DNA bases.
  • In some cases, entire chromosome arms, rendering the genome unstable and the outcomes unpredictable.

Detailed Findings and Concerns

Grégoire Cullot, a postdoctoral fellow in Corn's group and lead author, explained, "While the edited sections of the genome appeared accurate and precise, broader analysis revealed extensive genetic changes not apparent in the immediate vicinity of the edits."

AZD7648 increases the frequency of megabase-scale deletions.

The Extent of Damage and Research Im plications

Understanding the Damage

The researchers were taken aback by the extent of the negative effects. They believe that their current understanding of the damage is incom plete, as they only examined  partial sections of the genome, not the whole.

Need for Com prehensive Testing

To fully understand the extent and potential impact of the damage, new tests, methodologies, and regulations are essential.

Investigating the Issues Further

How the Problem Was Identified

So, how did the ETH researchers identify the issue? In previous studies, they demonstrated the exceptional effectiveness and precision of CRISPR-Cas9 gene editing with the addition of AZD7648. "This raised our concerns, prompting us to investigate further," states Corn.

Analysis Beyond the Edited Site

The ETH researchers examined not just the DNA sequence around the edited site but also the broader genetic context. They identified significant, harmful side effects associated with the use of AZD7648.

Implications for the Future

This study is the first to document these side effects. Other research teams have examined them as well and corroborate the ETH researchers' findings. They also plan to share their results. "We are the first to acknowledge that not everything is perfect," says Corn.

This represents a significant setback for use, as we, like man other researchers, had anticipated using the new technique to fast-track gene therapy advancements.

The Start of a New Chapter in Gene Editing

Corn points out that this is merely the beginning of further progress in gene editing with CRISPR-Cas techniques. "Every new technology faces its share of difficulties, and a single setback does not spell defeat," he adds.

In the future, it might be feasible to avoid risks by using a combination of substances, rather than a single moleucle, to encourage HDR. "Numerous potential candidates exist. Our next step is to determine which substances should be included in the mix to prevent genomic damage," says Corn.

CRISPR-Cas in Clinical Practice: A Success Story

CRISPR-Cas-based gene therapies have already shown success in clinical setting. For instance, a hundred patients with sickle cell anemia have been treated with these therapies in recent years, without the use of AZD7648.

Corn states, "All patients have been considered cured, with no reported side effects. I'm confident that gene therapies like this will become widely accepted. The key is determining the most effective approach and ensuring its safety for as many patients as possible."

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