Pioneers of gene therapy bet on in vivo gene therapy of "larger gene fragments"?

Insert large fragments? The pioneers of gene therapy bet on in vivo gene therapy and are expected to submit their first clinical application next year

Jim Wilson’s other gene editing company, iCURE, recently completed a $50 million Series A financing and officially stepped out of the hidden mode

iCURE has obtained 13 pipelines authorized by Wilson's laboratory, several of which use gene insertion and replacement methods to replace defective genes with healthy genes and perform gene editing on patients, which may solve hundreds of mutations at a time

On the same day, iCURE also announced a collaboration with the biotechnology company Precision BioSciences (hereinafter referred to as "Precision Bio", Nasdaq code: DTIL) to use the latter's ARCUS genome editing platform to develop allogeneic CAR-T and in vivo gene therapy

"The purpose of creating iCURE is to focus on genetic diseases with significant unmet needs

Joseph Truitt , CEO of iCURE

It is more difficult to accurately insert large fragments of genes into the genome

More suitable for neonatal treatment?

iCURE comes from "iecur" in the Latin "liver".

The University of Pennsylvania and Wilson jointly hold shares in iCURE

Precision Bio also acquired shares in iCURE

According to Truitt, iCURE is the result of an informal meeting between Versant managing director Tom Woiwode and Wilson two years ago

For the past many years, Wilson has been conducting research on gene editing, with special attention to neonatal diseases where gene therapy does not work

In this way, Wilson conducted studies on familial hypercholesterolemia and ornithine transcarbamylase deficiency

The company has obtained 13 pipelines licensed by Wilson Laboratories, several of which use gene insertion to treat rare liver diseases, and has obtained ARCUS licenses from Precision Bio for 4 liver indications

The biggest challenge of "knock-in" genes is that the target cell needs to divide

Submit your first clinical application next year

In fact, Wilson and Precision Bio have already collaborated

For the past 5 years, Wilson and his team have been studying the mechanism of cutting the liver cell genome in the body and then inserting normal genes

Wilson and his team tried a variety of gene editing tools, including CRISPR, but with little success until they used Precision Bio's technology
.
The North Carolina-based biotechnology company has developed a platform called ARCUS
.

ARCUS is a unique, proprietary and multifunctional genome editing platform
.
Its attributes include specificity and the ability to perform various effective edits (knock-in, knock-out and repair) to achieve a series of therapeutic edits
.
The platform is based on a natural genome editing enzyme called I-CreI, which evolved from Chlamydomonas and is a homing endonuclease that can cut cellular DNA with high intensity and specificity
.

Homing endonuclease is a very rare endonuclease, and the DNA sequence they can recognize is larger than that of traditional restriction endonucleases
.
Compared with other enzymes in gene editing research, I-CreI enzyme has only 364 amino acids and can be used to insert, delete or edit DNA
.
This also means that the I-Crel enzyme is easier to pass through AAV
.

In 2018, Wilson cooperated with Precision Bio to develop an in vivo gene editing platform using the latter's ARCUS platform
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In the same year, an article published in the journal Nature Biotechnology showed that ARCUS can knock out the cholesterol-regulating gene PCSK9 in monkeys
.
In February of this year, Wilson published a Molecular Therapy paper, describing three years of data, PCSK9 protein decreased by 85%, low-density lipoprotein cholesterol levels decreased by 56%
.
It is also worth noting that the one-time treatment continues to be proven safe, with no reports of adverse reactions
.

This laid the foundation for the cooperation between iCURE and Precision Bio
.
The startup will use ARCUS to knock in healthy genes or gene insertions
.

Both parties hope to submit an application to start clinical trials of candidates for familial hypercholesterolemia in early 2022
.
At the same time, iCURE will select indicators from the University of Pennsylvania
.
Truitt said: "The two diseases the company is concerned about are phenylketonuria and ornithine transformylase deficiency
.
The other two will be selected in the future
.
"

The delivery tool of this technology also uses AAV
.
Last week, due to the toxicity and safety issues of AAV gene therapy, the FDA advisory committee convened a meeting to make recommendations on animal and human trials of the therapy
.

During the two-day meeting, Wilson participated in two meetings and stated that the results of the meeting would not affect iCURE
.
"In terms of cooperation with iCURE, what I heard on the committee will not affect the preclinical plan," Wilson said
.

It is reported that this round of funds will support the company until early 2023, a large part of which will be used in manufacturing
.
Truitt also stated frankly that the cooperation with Wilson put iCURE far ahead of the first round of financing of most start-ups
.