CRISPR

Scientists engineer CRISPR enzymes that evade the immune system

adicorat — Thu, 09 Jan 2025 14:00:00 +0000

Scientists engineer CRISPR enzymes that evade the immune system

By Allessandra DiCorato January 9, 2025

Scientists engineer CRISPR enzymes that evade the immune system

The new genome-editing tools could lead to safer, more efficient gene therapies.

By Allessandra DiCorato

January 9, 2025

Credit: Natalie Velez, 映画传媒 Communications

The core components of CRISPR-based genome-editing therapies are bacterial proteins called nucleases that can stimulate unwanted immune responses in people, increasing the chances of side effects and making these therapies potentially less effective.

Researchers at the 映画传媒 of MIT and Harvard and Cyrus Biotechnology have now engineered two CRISPR nucleases, Cas9 and Cas12, to mask them from the immune system. The team identified protein sequences on each nuclease that trigger the immune system and used computational modeling to design new versions that evade immune recognition. The engineered enzymes had similar gene-editing efficiency and reduced immune responses compared to standard nucleases in mice.

Appearing today in Nature Communications, the findings could help pave the way for safer, more efficient gene therapies. The study was led by Feng Zhang, a core institute member at the 映画传媒 and an Investigator at the McGovern Institute for Brain Research at MIT.

鈥淎s CRISPR therapies enter the clinic, there is a growing need to ensure that these tools are as safe as possible, and this work tackles one aspect of that challenge,鈥� said Zhang, who is also a co-director of the K. Lisa Yang and Hock E. Tan Center for Molecular Therapeutics, the James and Patricia Poitras Professor of Neuroscience, and a professor at MIT. He is an Investigator at the Howard Hughes Medical Institute.

Rumya Raghavan, a graduate student in Zhang鈥檚 lab when the study began, and Mirco Julian Friedrich, a postdoctoral scholar in Zhang鈥檚 lab, were co-first authors on the study.

鈥淧eople have known for a while that Cas9 causes an immune response, but we wanted to pinpoint which parts of the protein were being recognized by the immune system and then engineer the proteins to get rid of those parts while retaining its function,鈥� said Raghavan.

鈥淥ur goal was to use this information to create not only a safer therapy, but one that is potentially even more effective because it is not being eliminated by the immune system before it can do its job,鈥� added Friedrich.

In search of immune triggers

Many CRISPR-based therapies use nucleases derived from bacteria. About 80 percent of people have pre-existing immunity to these proteins through everyday exposure to these bacteria, but scientists didn鈥檛 know which parts of the nucleases the immune system recognized.

To find out, Zhang鈥檚 team used a specialized type of mass spectrometry to identify and analyze the Cas9 and Cas 12 protein fragments recognized by immune cells. For each of two nucleases 鈥� Cas9 from Streptococcus pyogenes and Cas12 from Staphylococcus aureus 鈥� they identified three short sequences, about eight amino acids long, that evoked an immune response. They then partnered with Cyrus Biotechnology, a company co-founded by University of Washington biochemist David Baker that develops structure-based computational tools to design proteins that evade the immune response. After Zhang鈥檚 team identified immunogenic sequences in Cas9 and Cas12, Cyrus used these computational approaches to design versions of the nucleases that did not include the immune-triggering sequences.

Zhang鈥檚 lab used prediction software to validate that the new nucleases were less likely to trigger immune responses. Next, the team engineered a panel of new nucleases informed by these predictions and tested the most promising candidates in human cells and in mice that were genetically modified to bear key components of the human immune system. In both cases, they found that the engineered enzymes resulted in significantly reduced immune responses compared to the original nucleases, but still cut DNA at the same efficiency.

Minimally immunogenic nucleases are just one part of safer gene therapies, Zhang鈥檚 team says. In the future, they hope their methods may also help scientists design delivery vehicles to evade the immune system.

Funding

This work was supported in part by the Federal Ministry of Education and Research (BMBF) and the Ministry of Science Baden-W眉rttemberg within the framework of the Excellence Strategy of the Federal and State Governments of Germany, Deutsche Jos茅 Carreras Leuk盲mie-Stiftung, the Howard Hughes Medical Institute, the Poitras Center for Psychiatric Disorders Research at MIT, the Hock E. Tan and K. Lisa Yang Center for Autism Research at MIT, and the K. Lisa Yang and Hock E. Tan Molecular Therapeutics Center at MIT.

Paper cited

Raghavan R, Friedrich MJ, et al. Rational engineering of minimally invasive immunogenic nucleases for gene therapy. Nature Communications. Online January 2, 2025. DOI: 10.1038/s41467-024-55522-1.

Tags:

CRISPR

Feng Zhang

Some CRISPR screens may be missing cancer drug targets

adicorat — Fri, 14 Jun 2024 13:00:00 +0000

Scientists engineer CRISPR enzymes that evade the immune system

By Allessandra DiCorato January 9, 2025

Scientists engineer CRISPR enzymes that evade the immune system

The new genome-editing tools could lead to safer, more efficient gene therapies.

By Allessandra DiCorato

January 9, 2025

Credit: Natalie Velez, 映画传媒 Communications

Rumya Raghavan, a graduate student in Zhang鈥檚 lab when the study began, and Mirco Julian Friedrich, a postdoctoral scholar in Zhang鈥檚 lab, were co-first authors on the study.

In search of immune triggers

Funding

Paper cited

Raghavan R, Friedrich MJ, et al. Rational engineering of minimally invasive immunogenic nucleases for gene therapy. Nature Communications. Online January 2, 2025. DOI: 10.1038/s41467-024-55522-1.

Tags:

CRISPR

Feng Zhang

Study reveals links between blood vessel biology and heart disease risk

tulrich@broadinstitute.org — Wed, 07 Feb 2024 16:50:22 +0000

Scientists engineer CRISPR enzymes that evade the immune system

By Allessandra DiCorato January 9, 2025

Scientists engineer CRISPR enzymes that evade the immune system

The new genome-editing tools could lead to safer, more efficient gene therapies.

By Allessandra DiCorato

January 9, 2025

Credit: Natalie Velez, 映画传媒 Communications

Rumya Raghavan, a graduate student in Zhang鈥檚 lab when the study began, and Mirco Julian Friedrich, a postdoctoral scholar in Zhang鈥檚 lab, were co-first authors on the study.

In search of immune triggers

Funding

Paper cited

Raghavan R, Friedrich MJ, et al. Rational engineering of minimally invasive immunogenic nucleases for gene therapy. Nature Communications. Online January 2, 2025. DOI: 10.1038/s41467-024-55522-1.

Tags:

CRISPR

Feng Zhang

Search algorithm reveals nearly 200 new kinds of CRISPR systems

adicorat — Thu, 23 Nov 2023 19:00:00 +0000

Scientists engineer CRISPR enzymes that evade the immune system

By Allessandra DiCorato January 9, 2025

Scientists engineer CRISPR enzymes that evade the immune system

The new genome-editing tools could lead to safer, more efficient gene therapies.

By Allessandra DiCorato

January 9, 2025

Credit: Natalie Velez, 映画传媒 Communications

Rumya Raghavan, a graduate student in Zhang鈥檚 lab when the study began, and Mirco Julian Friedrich, a postdoctoral scholar in Zhang鈥檚 lab, were co-first authors on the study.

In search of immune triggers

Funding

Paper cited

Raghavan R, Friedrich MJ, et al. Rational engineering of minimally invasive immunogenic nucleases for gene therapy. Nature Communications. Online January 2, 2025. DOI: 10.1038/s41467-024-55522-1.

Tags:

CRISPR

Feng Zhang

Researchers uncover new CRISPR-like system in animals that can edit the human genome

leah@broadinstitute.org — Wed, 28 Jun 2023 15:00:11 +0000

Scientists engineer CRISPR enzymes that evade the immune system

By Allessandra DiCorato January 9, 2025

Scientists engineer CRISPR enzymes that evade the immune system

The new genome-editing tools could lead to safer, more efficient gene therapies.

By Allessandra DiCorato

January 9, 2025

Credit: Natalie Velez, 映画传媒 Communications

Rumya Raghavan, a graduate student in Zhang鈥檚 lab when the study began, and Mirco Julian Friedrich, a postdoctoral scholar in Zhang鈥檚 lab, were co-first authors on the study.

In search of immune triggers

Funding

Paper cited

Raghavan R, Friedrich MJ, et al. Rational engineering of minimally invasive immunogenic nucleases for gene therapy. Nature Communications. Online January 2, 2025. DOI: 10.1038/s41467-024-55522-1.

Tags:

CRISPR

Feng Zhang

Prime editing shows proof of concept for treating sickle cell disease

kzusi@broadinstitute.org — Mon, 17 Apr 2023 15:53:54 +0000

Scientists engineer CRISPR enzymes that evade the immune system

By Allessandra DiCorato January 9, 2025

Scientists engineer CRISPR enzymes that evade the immune system

The new genome-editing tools could lead to safer, more efficient gene therapies.

By Allessandra DiCorato

January 9, 2025

Credit: Natalie Velez, 映画传媒 Communications

Rumya Raghavan, a graduate student in Zhang鈥檚 lab when the study began, and Mirco Julian Friedrich, a postdoctoral scholar in Zhang鈥檚 lab, were co-first authors on the study.

In search of immune triggers

Funding

Paper cited

Raghavan R, Friedrich MJ, et al. Rational engineering of minimally invasive immunogenic nucleases for gene therapy. Nature Communications. Online January 2, 2025. DOI: 10.1038/s41467-024-55522-1.

Tags:

CRISPR

Feng Zhang

Scientists unveil the functional landscape of essential genes

tulrich@broadinstitute.org — Mon, 07 Nov 2022 16:05:51 +0000

Scientists engineer CRISPR enzymes that evade the immune system

By Allessandra DiCorato January 9, 2025

Scientists engineer CRISPR enzymes that evade the immune system

The new genome-editing tools could lead to safer, more efficient gene therapies.

By Allessandra DiCorato

January 9, 2025

Credit: Natalie Velez, 映画传媒 Communications

Rumya Raghavan, a graduate student in Zhang鈥檚 lab when the study began, and Mirco Julian Friedrich, a postdoctoral scholar in Zhang鈥檚 lab, were co-first authors on the study.

In search of immune triggers

Funding

Paper cited

Raghavan R, Friedrich MJ, et al. Rational engineering of minimally invasive immunogenic nucleases for gene therapy. Nature Communications. Online January 2, 2025. DOI: 10.1038/s41467-024-55522-1.

Tags:

CRISPR

Feng Zhang

映画传媒 Discovery Center in Cambridge opens to the public this October

kzusi@broadinstitute.org — Mon, 19 Sep 2022 14:53:09 +0000

Scientists engineer CRISPR enzymes that evade the immune system

By Allessandra DiCorato January 9, 2025

Scientists engineer CRISPR enzymes that evade the immune system

The new genome-editing tools could lead to safer, more efficient gene therapies.

By Allessandra DiCorato

January 9, 2025

Credit: Natalie Velez, 映画传媒 Communications

Rumya Raghavan, a graduate student in Zhang鈥檚 lab when the study began, and Mirco Julian Friedrich, a postdoctoral scholar in Zhang鈥檚 lab, were co-first authors on the study.

In search of immune triggers

Funding

Paper cited

Raghavan R, Friedrich MJ, et al. Rational engineering of minimally invasive immunogenic nucleases for gene therapy. Nature Communications. Online January 2, 2025. DOI: 10.1038/s41467-024-55522-1.

Tags:

CRISPR

Feng Zhang

Researchers use CRISPR to build melanoma models from scratch using human cells

adicorat — Thu, 28 Apr 2022 18:01:31 +0000

Scientists engineer CRISPR enzymes that evade the immune system

By Allessandra DiCorato January 9, 2025

Scientists engineer CRISPR enzymes that evade the immune system

The new genome-editing tools could lead to safer, more efficient gene therapies.

By Allessandra DiCorato

January 9, 2025

Credit: Natalie Velez, 映画传媒 Communications

Rumya Raghavan, a graduate student in Zhang鈥檚 lab when the study began, and Mirco Julian Friedrich, a postdoctoral scholar in Zhang鈥檚 lab, were co-first authors on the study.

In search of immune triggers

Funding

Paper cited

Raghavan R, Friedrich MJ, et al. Rational engineering of minimally invasive immunogenic nucleases for gene therapy. Nature Communications. Online January 2, 2025. DOI: 10.1038/s41467-024-55522-1.

Tags:

CRISPR

Feng Zhang

New programmable gene editing proteins found outside of CRISPR systems

kzusi@broadinstitute.org — Thu, 09 Sep 2021 23:14:59 +0000

Scientists engineer CRISPR enzymes that evade the immune system

By Allessandra DiCorato January 9, 2025

Scientists engineer CRISPR enzymes that evade the immune system

The new genome-editing tools could lead to safer, more efficient gene therapies.

By Allessandra DiCorato

January 9, 2025

Credit: Natalie Velez, 映画传媒 Communications

Rumya Raghavan, a graduate student in Zhang鈥檚 lab when the study began, and Mirco Julian Friedrich, a postdoctoral scholar in Zhang鈥檚 lab, were co-first authors on the study.

In search of immune triggers

Funding

Paper cited

Raghavan R, Friedrich MJ, et al. Rational engineering of minimally invasive immunogenic nucleases for gene therapy. Nature Communications. Online January 2, 2025. DOI: 10.1038/s41467-024-55522-1.

Tags:

CRISPR

Feng Zhang