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Innovative methodology creates a streamlined device for genetic treatment

Scientists, spearheaded by Professor Feng Zhang at MIT and the Broad Institute, altered a bacterial RNA-guided enzyme, enhancing its capabilities as a potent editor of human genetic material.

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Scientists, headed by Professor Feng Zhang at MIT and the Broad Institute, modify a miniature...
Scientists, headed by Professor Feng Zhang at MIT and the Broad Institute, modify a miniature RNA-guided enzyme originating from bacteria. This redesign enhances the enzyme's capabilities, making it an effective tool for editing the human genome.

Innovative methodology creates a streamlined device for genetic treatment

Scientists from the McGovern Institute for Brain Research at MIT and the Broad Institute of MIT and Harvard have engineered a compact RNA-guided enzyme for efficient editing of human DNA. Called NovaIscB, this protein can be tailored to make precise changes to the genetic code, regulate specific genes, or perform other editing tasks.

The team, led by Feng Zhang, the James and Patricia Poitras Professor of Neuroscience at MIT and a core member of the Broad Institute, discovered that NovaIscB, derived from a bacterial DNA cutter, is a third the size of its Cas9 counterpart. This compactness simplifies delivery to cells, making it a promising candidate for developing gene therapies to treat or prevent disease.

The study, published in Nature Biotechnology, shows that NovaIscB can effectively edit DNA targets in human cells. To achieve this, the researchers first identified an IscB that could be a good starting point, testing nearly 400 different enzymes found in bacteria. Ten of these were capable of editing DNA in human cells.

Even the most active of these enzymes needed optimization to make it a useful genome editing tool. The challenge was enhancing its activity, but only at the sequences specified by the RNA guide. If the enzyme became more active indiscriminately, it would cut DNA in unintended places.

To optimize IscB for human genome editing, the team leveraged information about bacterial IscBs' evolution and diversity. After making strategic changes to the original protein, guided by their understanding of how IscBs interact with both DNA and RNA guides, they generated a protein called NovaIscB. This was over 100 times more active in human cells than the IscB they started with, and demonstrated good specificity for its intended targets.

Kannan and Zhu, researchers involved in the project, noted that NovaIscB functions similarly to Cas9, making it easy to adapt existing tools designed for Cas9. With different modifications, they used NovaIscB to replace specific letters of the DNA code in human cells and to change the activity of targeted genes.

Importantly, the NovaIscB-based tools are compact enough to be packaged inside a single adeno-associated virus (AAV), allowing for efficient delivery via this commonly used method for safe gene therapy delivery. This contrasts with larger tools like those based on Cas9, which require more complex delivery strategies.

Demonstrating NovaIscB's potential for therapeutic use, the team created a tool called OMEGAoff, which adds chemical markers to DNA to repress specific genes. They used this system to effectively lower cholesterol levels in mice by repressing a gene associated with cholesterol regulation.

The researchers expect that NovaIscB can be used to target most human genes, making it a versatile tool for a wide range of gene therapies. They hope others will adopt their evolution-guided approach to rational protein engineering, as it can improve the systems they are trying to engineer.

This study was funded by the K. Lisa Yang and Hock E. Tan Center for Molecular Therapeutics at MIT, the Broad Institute Programmable Therapeutics Gift Donors, the Pershing Square Foundation, William Ackman, Neri Oxman, the Phillips family, and the J. and P. Poitras.

  1. The McGovern Institute for Brain Research at MIT and the Broad Institute have engineered a compact RNA-guided enzyme, NovaIscB, for efficient editing of human DNA.
  2. Scientists from these institutes, led by Feng Zhang, discovered that NovaIscB is a third the size of its Cas9 counterpart, which simplifies delivery to cells.
  3. The study on NovaIscB was published in the journal Nature Biotechnology, showcasing its ability to effectively edit DNA targets in human cells.
  4. To optimize IscB for human genome editing, the team leveraged information about bacterial IscBs' evolution and diversity.
  5. With different modifications, the team used NovaIscB to replace specific letters of the DNA code in human cells and change the activity of targeted genes.
  6. Demonstrating NovaIscB's potential for therapeutic use, the team created a tool called OMEGAoff, which represses specific genes and lowered cholesterol levels in mice.
  7. The researchers hope that NovaIscB can be used to target most human genes, making it a versatile tool for a wide range of gene therapies.
  8. The study was funded by various institutions, including the K. Lisa Yang and Hock E. Tan Center for Molecular Therapeutics at MIT, the Broad Institute Programmable Therapeutics Gift Donors, and the Pershing Square Foundation.
  9. As NovaIscB functions similarly to Cas9, it can be easily adapted to existing tools designed for Cas9, providing a promising solution for the field of neuroscience, biotech, and medical-conditions related to health-and-wellness.

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