On the third day of the JP Morgan Healthcare Conference, Arbor Biotechnologies and Vertex Pharmaceuticals announced their expansion into reverse transcription-based in vivo gene medicines. Vertex can now use Arbor’s precision editing technology for up to three diseases.
In 2018, the two companies began working together on gene-editing therapies. Vertex gave Arbor his $30 million-plus upfront payment, and Arbor gave Vertex her Cas13d RNA-modifying enzyme for CRISPR gene editing to help treat Vertex’s cystic fibrosis (CF). provided. The two businesses will reunite in 2021 to work at a whole new level – a billion dollar scale – to develop new cell therapies for diseases such as diabetes and hemoglobinopathies. Arbor received an undisclosed upfront cash payment. Potential milestone payments totaling $1.2 billion across up to seven programs.
“Today we announced the expansion of one of our collaborations with Vertex to precision editing with reverse transcriptase (RT)-based editing, which is great for the company,” said Devyn Smith, CEO of Arbor. He said: gen edge.
“We continue to have great relationships with them and great partners. This is exciting as it is the first partnership announced in the precision editing space across the industry. is showing.”
Under the terms of the agreement, Arbor will be eligible for payment upon the achievement of certain research, development, regulatory and commercial milestones. Vertex will also pay tiered royalties on future net sales of products from this partnership.
Some Healthy Competition (and Controversy)
Arbor isn’t the only iron Vertex has in the gene therapy fire. was This cooperation created exagamglogene autotemcel (exa-cel) (previously he was called CTX001). – Her Cas9 gene editing therapy showing promising results in patients with sickle cell disease (SCD) and transfusion-dependent beta-thalassemia (TDT). (Vertex pledged her $105 million up front to her CRISPR, which includes her $75 million in cash and her $30 million equity investment.)
In April 2021, Vertex increased its investment in CRISPR Therapeutics by another $900 million. The revised contract shows Vertex’s confidence in his exa-cel, which said in September 2022 the FDA continued to review exa-cel for potential treatment of his SCD and TDT. Supported by Vertex announcement. Last week on January 9th, CRISPR Therapeutics tweeted that in December 2022 he completed his SCD and TDT exa-cel regulatory submissions using his Vertex in the EU and UK. .
Almost a year before ExaCell’s announcement, Vertex signed another CRISPR gene-editing agreement with Mammoth Biosciences, co-founded by Jennifer Doudna. In October 2021, Vertex announced he would pay her Mammoth $41 million up front, up to $650 million. The focus of this collaboration is on her Mammoth CRISPR system, which is about one-third smaller than the well-known CRISPR-Cas9 enzyme.
Arbor does not disclose much information about RT editing techniques. The best-known application of RT in precision genome editing is that of Prime Medicine, which has licensed its Prime Editing technology from David Liu’s lab at the Broad Institute. (Liu is a co-founder of Prime Medicine.) Prime Editing is summarized in two components, a Cas9 nickase fused to a modified reverse transcriptase and a multifunctional Prime Editing guide RNA (pegRNA), and Prime Medicine has developed both I own a patent on .
Arbor recently published a paper on nuclease technology. the research paper Nature Communications (McGaw et al., 2022) describe an engineered Cas12i2 (called ABR-001) as a platform for genome editing, but they do not appear to publish data on precision RT-editing technology.
When asked about Arbor’s RT technology, Smith played his card close to his chest. “RT-editing is based, at least in part, on Arbor’s proprietary nuclease fused to reverse transcriptase and a guide RNA (gRNA) fused to a template sequence encoding the desired genetic modification,” he says. “Early studies have shown that our proprietary RT-editing system can incorporate targeted genetic modifications into targeted genomic sites.”
This applies not only to Arbor, but also to Tessera Therapeutics, which developed an RT editing system called RNA Gene Writing. Tessera’s technology appears to be rooted in a novel mechanism based on retrotransposons encoding RTs, particularly group II intron-like RTs in bacteria, which function in host DNA repair. At the JP Morgan conference, Tessera reported some advanced data in this area using his RNA gene writing platform. Notably, clinically relevant levels of in vivo rewriting in the genome of non-human primate hepatocytes after a single dose. Michael Severino, CEO of Tessera and CEO partner of Flagship Pioneering, said:
The RNA gene writing program also demonstrated clinically relevant levels of in vitro rewriting in the genome of hematopoietic stem cells (HSCs). [corrected HSCs] Severino, formerly vice chairman and president of R&D and corporate strategy at AbbVie and senior vice president of global development and chief medical officer at Amgen, said: “We are able to almost completely normalize hemoglobin production from 100% sickle cells and untreated cells from sickle cell donor patients, to the point where 98% of the hemoglobin produced is normal.” It’s in culture, but our ultimate goal is in vivo.”
Arbor was co-founded by Feng Zhang, David Walt, David Scott, and Winston Yan as a bioinformatics company primarily developing a proprietary therapeutic pipeline. “Our two major programs are wholly owned by us and we plan to file the first of his INDs later this year,” Smith said. “[Our strategy is to] Establish leadership and ownership in liver and central nervous system (CNS) diseases. Both have very different risk-return profiles and have serious and significant unmet needs in the field of genetic diseases that could benefit from compilation. “
For the liver, Arbor utilizes lipid nanoparticles (LNPs) and previously announced a partnership with Acuitas to gain access to some of its LNP technology for delivery. Regarding the CNS, Smith said much of the focus has been on the area of adeno-associated virus (AAV). Smith said Arbor is building its initial strategy around his specific CNS disease, but plans to partner to further expand its delivery capabilities in the CNS.
Beyond the liver and central nervous system, there are still many promising targets for in vivo gene therapy. According to Smith, Arbor has been very thoughtful about partnerships because there is a lot of interest in editing.
“It’s a very exciting field with a lot of potential, but we’re at the beginning of the marathon. We have a long way to go and a lot of new technologies need to be discovered,” said Smith. says Mr. “We have no approved products yet. We are in a hurry to do what we can, but we are not in a rush to make a million partnerships. It’s about ensuring that we bring something that makes what we do together better.”
Sowing the seeds of gene medicine
Sitting at a table in his room at the Handlery Union Square Hotel, Smith grabs a piece of paper and draws a circle to represent the world of genetic medicine.
“With the traditional knockdown approach, you can get some ailments,” he said, drawing smaller concentric circles. “And if you take a base-editing approach, you might get some other ailments. It depends on whether
Smith is particularly excited about Arbor’s advances in the remaining areas: reverse transcriptase for precise editing, precise excision, and large-scale gene insertion.
“Reverse transcriptase editing allows us to draw the right size circles,” says Smith. “And there are many diseases. [DNA] It’s an extension that basically couldn’t be hit with biologics and small molecules, and they’re right [precise excisions] Because you can go inside and cut. The remainder of this hoop is a large insertion, which can drop an exon or an entire gene into an endogenous locus. “
Of those five segments, Smith said Arbor focuses on all but base editing.
According to Smith, researchers are just beginning to understand the power of in vivo gene therapy drugs.
“We will begin to move beyond Mendelian disease, which is an easily achievable problem, into these broader disease states,” said Smith. “Think of an infectious disease or a big disease like Alzheimer’s that has a fundamentally solvable problem. [In vivo genetic medicine] It is one of the technologies that will change the future of medicine. I don’t think many of us even imagine what it does. Because we can fundamentally change the underlying cause of the disease rather than the approach we took to try to modulate the disease in some way. Now it’s just going to fix it!”