July 23, 2024

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Gene therapy pioneers bet on in vivo gene therapy: Larger gene fragments?

Gene therapy pioneers bet on in vivo gene therapy: Larger gene fragments?

Gene therapy pioneers bet on in vivo gene therapy: larger gene fragments?

Insert larger fragments? Gene therapy pioneers bet on in vivo gene therapy, and is expected to submit its first clinical application next year

After launching G2 Bio Companies, a gene therapy biotechnology company, and a non-profit organization that provides services for rare diseases, Jim Wilson’s other gene editing company iCURE recently completed a $50 million Series A financing and officially went out of the hidden mode . This round of financing was led by well-known life science investment institutions Versant and Aobo Capital.

iCURE has obtained 13 pipelines from Wilson’s laboratory authorization, several of which use gene insertion and replacement methods to replace defective genes with healthy genes, and perform gene editing in patients, which may solve hundreds of mutations at once. .

On the same day, iCURE also announced a partnership with a biotech company, Precision BioSciences (hereinafter referred to as “Precision Bio”, Nasdaq: 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. After evaluating different gene editing technologies and platforms, we believe that using the ARCUS platform will quickly bring several drug candidates to the clinic.” Chief Executive Officer of iCURE Officer Joe Truitt said.

Gene therapy pioneers bet on in vivo gene therapy: larger gene fragments?

Figure | Joseph Truitt, CEO of iCURE

It is relatively difficult to accurately insert large-segment genes into the genome. How will iCURE overcome it?

More suitable for neonatal treatment?

iCURE is derived from the Latin “iecur” of “liver”, “We added an e to the end of the word, which means cure.” Its CEO Joseph Truitt said. Since the establishment of iCURE, Truitt has been hired as CEO. Prior to this, he worked for Achillion Pharmaceuticals (acquired by Alex Brother) for 11 years and served as CEO.

The University of Pennsylvania and Wilson jointly hold shares in iCURE. According to the agreement between iCURE and the University of Pennsylvania, Wilson Laboratory will conduct pre-clinical research and manufacturing, and toxicological experiments on the pipeline selected by iCURE. When it enters the new drug application stage, iCURE will take over and conduct clinical development. If approved, it will proceed. commercialize.

Precision Bio also acquired a share of iCURE. If iCURE uses the products developed by ARCUS to enter the market, the former will also receive milestone payments and sales expenses. Cindy Atwell, its business development director, expressed satisfaction with the cooperation, “iCURE clinical trial results will also provide validation of the technology for therapies using ARCUS.” The company is currently cooperating with Eli Lilly to conduct gene knockout trials through internal research. .

According to Truitt, iCURE is the result of an informal meeting between Versant managing director Tom Woiwode and Wilson two years ago. Versant is one of Passage Bio’s original investors, Passage Bio is a now-listed gene therapy company founded by Wilson. Versant has also invested in companies such as CRISPR Therapeutics and Graphite Bio.

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 one of the studies, Wilson stated that gene insertion is most suitable as a neonatal treatment. “Newborns have rapidly dividing liver cells, which are necessary for gene editing therapy, while adult livers divide relatively slowly,” Truitt explained.

In this way, Wilson has conducted research on familial hypercholesterolemia and ornithine transcarbamylase deficiency. His animal data excited Woiwode, which prompted Versant to contact another investor in Passage Bio OrbiMed. Together, they promoted the establishment of iCURE.

The company has obtained 13 pipelines from Wilson’s laboratory license, several of which are the use of gene insertion to treat rare liver diseases, and have licensed ARCUS from Precision Bio for 4 liver indications. In exchange, iCURE will advance Precision Bio’s PCSK9 therapy into the first phase of testing for familial hypercholesterolemia.

The big challenge surrounding “knock-in” genes is that the target cell needs to divide. “But this is not a problem for these projects, because the target population is newborns with metabolic diseases.” Wilson said.

Submit the first clinical application next year

In fact, Wilson and Precision Bio have already cooperated.

For the past 5 years, Wilson and his team have been studying the mechanism of cutting the liver cell genome in vivo and then inserting normal genes. Since he was a postdoctoral fellow in the laboratory in the late 1980s, Wilson has believed that the liver is an important target for gene therapy. “Because the root of many diseases lies in the liver.” Wilson once said.

Wilson and his team tried various gene editing tools, including CRISPR, but had little success until they used Precision Bio’s technology. This 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 perform high-intensity and specific cleavage in cellular DNA.

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

In 2018, Wilson and Precision Bio collaborated and used the latter’s ARCUS platform to develop an in vivo gene editing platform. In the same year, an article published in Nature Biotechnology showed that ARCUS can knock out the cholesterol-regulating gene PCSK9 in monkeys. In February of this year, Wilson published a paper on Molecular Therapy, describing three years of data, showing that PCSK9 protein was reduced by 85%, while low-density lipoprotein cholesterol levels were reduced by 56%. It is also worth noting that the one-time treatment continues to prove to be 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 expect to submit an application to start clinical testing of candidates for familial hypercholesterolemia in early 2022. At the same time, iCURE will also select indications from the University of Pennsylvania. Truitt said, “The two diseases the company is focusing on are phenylketonuria and ornithine transcarbamylase deficiency. The other two will be selected in the future.”

The delivery tool for 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. “As far as the collaboration with iCURE is concerned, nothing I hear on the committee will affect the preclinical plan,” Wilson said.

It is reported that this round of funds will support the company until early 2023, and a large part of it will be used in manufacturing. Truitt also bluntly stated that the cooperation with Wilson put iCURE far ahead of the first round of funds raised by most startups.


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Gene therapy pioneers bet on in vivo gene therapy: larger gene fragments?

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