Advances and Setbacks in CRISPR Genome Editing and Base Editing for Tyrosinemia

By Caitlin Seida from In The Cloud Copy

CRISPR-Cas9, often called just CRISPR, is a technique used to quickly edit DNA to alter gene functions. Think of it like the “cut, copy, and paste” techniques used on computer editing software, but for the human body. For those living with the autosomal recessive disorder tyrosinemia, CRISPR could spell relief from the condition — and the future, albeit the far future, may see doctors able to edit away the conditions that activate tyrosinemia in the body.

What is CRISPR?

First discovered in 1987 by a team of Japanese biotechnologists at Osaka University, the understanding of the science behind CRISPR took decades to understand. It wasn’t until 2017, however, that the powerful gene editing technique was given the greenlight for trial use in humans, and March of 2020 before the first human was given an in vivo treatment with the CIRSPR-Cas9 technique successfully.

Because it’s a patented breakthrough with ethical implications, CRISPR technology is largely unheard of outside of scientific communities. Cutting strands of DNA and replacing them with correct segments can have unpredictable effects on the cells. Editing the same gene 10 different times can yield 10 different results, often because of mis-targeting or improper application.

What is Base Editing?

A more refined approach to CRISPR-Cas9 techniques, called base editing, allows scientists to simply re-code the errant DNA sequence without cutting. Think of it like using a pencil eraser on the miscoded parts of the human genome so you can then write in the correct ones. This approach has been successfully demonstrated on animals, but not humans.  With human genome editing still in its relative infancy, there’s potential for growth — if the problems can be worked out.

Like the CRISPR techniques and technology it piggybacks on, base editing is still being studied for why some edits yield unexpected results, and how that can be corrected for use in human gene therapy.

Gene Therapy and Tyrosinemia

The first use of base editing and CRISPR technology on autosomal recessive tyrosinemia was carried out in 2018 by a joint team of doctors and scientists at the University of Pennsylvania and the Children’s Hospital of Philadelphia. The study, which used fetal mice as subjects, injected the base editing CRISPR directly into the vitelline vein to see if edits could be made on the liver, rather than anywhere else.

The study proved successful, with the edits appearing in the livers of baby mice and not in analogous areas. There was an approximately 2 percent error rate for genes corrected with base editing, compared to 40 percent with those that used traditional CRISPR technology.  This study showed the potential of CRISPR base editing technology on fetuses with tyrosinemia in utero.

Further Advances

Correcting the genes responsible for tyrosinemia in utero is valuable, as the disorder begins attacking the liver several months before birth. But can the technology be used for adults living with tyrosinemia?

2019 saw further advances in base editing technology, specifically adenine base editing (ABE) techniques, which use adenosine as the conveyance for edits as opposed to cytosine. Using adult mice, researchers used ABE to correct CRISPR spliced mutations and stimulate fumarylacetoacetate hydrolase (FAH) containing liver cells. FAH is the enzyme lacking in livers of individuals with tyrosinemia, which allows the body to break down amino acids.

What’s Next

It’s hard to say what’s next for the use of CRISPR-Cas9, base editing and adenine base editing as it relates to tyrosinemia. While cellular and animal models have shown successful use of these gene therapy techniques and technology, there’s still a long way to go in perfecting the techniques to have smaller margins of error. There’s an even longer journey for scientists and doctors to perfect them for use in humans, and possible ethical and legal battles complicating the matters. While people with tyrosinemia won’t see the rewards of base editing research any time soon, the rapid advances in the field hold promise.

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