Birds’ junk DNA enables UC Berkeley to unlock safe human gene therapy

Birds’ junk DNA enables UC Berkeley to unlock safe human gene therapy

Birds’ junk DNA enables UC Berkeley to unlock safe human gene therapy

CRISPR-Cas9 therapy has recently gained approval for treating sickle cell disease by knocking out specific genes. However, one restriction remains: it cannot presently introduce genes into the human genome to replace faulty or dangerous ones.

This challenge may persist even for other genetic diseases, in which just blocking or editing a gene using CRISPR may not be enough to address the consequences of the underlying genetic mutation. Researchers believe to completely resolve the problem, a corrective gene must be added to the DNA.

This is where the novel method known as Precise RNA-mediated INsertion of Transgenes (PRINT) comes in. 

While CRISPR-Cas technology has been a game-changer in gene editing, PRINT complements its capabilities by focusing on inserting genes into the genome. 

University of California Berkeley researchers have found a way to use a bird retrotransposon — a type of junk DNA. 

PRINT would complement CRISPR-Cas technology

Retrotransposons are a kind of transposable element—DNA sequences capable of moving or jumping around within a genome. These elements play a role in the evolution of organisms by contributing to genetic diversity.

The retrotransposon uses reverse transcription. During this procedure, the DNA element is first converted into RNA. The RNA is then reverse-transcribed, or replicated, into DNA in the genome.

As per the press release, this is a “self-serving cycle that clutters the genome with retrotransposon DNA. About 40% of the human genome is made up of this “selfish” new DNA, though most of the genes are disabled, so-called junk DNA.” 

According to the researchers, this approach can insert new genes into a safe region within the genome. Crucially, this safe insertion is specially designed to prevent any disruption of key genes or trigger cancer. 

“PRINT would complement the recognized ability of CRISPR-Cas technology to disable genes, make point mutations, and insert short segments of DNA,” mentioned the authors. 

Birds’ junk DNA enables UC Berkeley to unlock safe human gene therapy

The new PRINT technology

The PRINT technology, created by Professor Kathleen Collins and her colleagues, involves inserting fresh DNA into a cell using delivery techniques. 

The approach requires the utilization of two critical RNA components.

The first RNA encodes the R2 protein, a key player in the retrotransposon’s functionality. This protein contains a nickase, an enzyme that attaches to and nicks double-stranded DNA. Also, it carries out reverse transcriptase, which is responsible for creating the DNA copy of RNA.

The second RNA acts as the template for inserting transgene DNA, which includes gene expression control elements. Together, these components form a “transgene cassette” that the R2 protein adeptly inserts into the genome.

The technique allows precise insertion

“A CRISPR-Cas9-based approach can fix a mutant nucleotide or insert a little patch of DNA — sequence fixing. Or you can just knock out a gene function by site-specific mutagenesis,” said Collins in the press release.

Collins further explained: “We’re not knocking out a gene function. We’re not fixing an endogenous gene mutation. We’re taking a complementary approach, which is to put into the genome an autonomously expressed gene that makes an active protein —to add back a functional gene as a deficit bypass. It’s transgene supplementation instead of mutation reversal. To fix loss-of-function diseases that arise from a panoply of individual mutations of the same gene, this is great.”

Unlike previous approaches employing human viral vectors, where genes are inserted randomly, risking disruptions to vital processes and possible cancer risks, PRINT’s methodology assures a more exact and regulated insertion.

This technique efficiently holds tremendous promise for developing safer, more targeted gene therapies.

Source: Interesting Engineering

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Birds’ junk DNA enables UC Berkeley to unlock safe human gene therapy

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