The story of a pioneer of CRISPR gene editing

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<p type = "text" content = "The gene editing promises to revolutionize healthcare, but there's only a handful of stocks available to invest in technology Intellia Therapeutics, Inc. (NASDAQ: NTLA) . "Data-reactid =" 11 "> Gene editing holds the promise of revolutionizing health care. But there is only a handful of stocks available to invest in technology. One of the leaders is Intellia Therapeutics, Inc. (NASDAQ: NTLA) .

* As of July 16, 2018. Data sources: Yahoo! Finance, YCharts.

How did Intellia Therapeutics become one of the pioneers of the most successful gene editing? Here is the story behind biotechnology and its stock.

Image Source: Getty Images.

Intellia Therapeutics is a biotech that focuses on the development of therapies using the CRISPR-Cas9 gene editing. The company's leading drug candidates are targeting remedies for genetic diseases such as transthyretin amyloidosis (ATTR) and sickle cell disease. Intellia also has several other programs in preclinical development.

CRISPR-Cas9 is considered by many to be the best approach for gene editing developed to date. CRISPR is an abbreviation for Short Palindromic Repeats, Clustered Regularly Interspaced. This refers to sections of DNA that can be read in the same way both forward and backward and separated by segments of "spacer DNA" that do not contain instructions for the construction of proteins. Cas9 is the abbreviation for CRISPR badociated with Protein 9.

Scientists discovered several years ago that certain types of bacteria used CRISPR-Cas9 to slice DNA from attacking viruses. Over time, researchers discovered how CRISPR-Cas9 works, and they learned how to guide CRISPR-Cas9 to a targeted DNA sequence to modify genes.

Other methods of gene editing already existed, including zinc-finger nuclease technology and transcriptional activator-type nuclease (TALEN). However, CRISPR-Cas9 was significantly less expensive and much easier to use than these earlier approaches.

Intellia Therapeutics was founded in May 2014. The name of the company is based on the Greek word entelia, which means "a situation of excellence, without fail, and having all the elements, qualities or characteristics required. "

=" text "content =" The biotech was formed by venture capital firm Atlas Venture and Caribou Biosciences. Since 1945, Alnylam Pharmaceuticals and Exelixis partner of Atlas Venture, became the first company of Intellia Therapeutics. CEO. "Data-reactid =" 45 "> Biotech was created by venture capital firm Atlas Venture and Caribou Biosciences, and Atlas Venture has a long history of investing in science and technology companies. life in the start-up phase, some of which became big winners such as Alnylam Pharmaceuticals and Exelixis .Nessan Bermingham, partner of Atlas Venture, became the first CEO of Intellia Therapeutics

Caribou Biosciences is a private biotechnology company focused on the use of CRISPR-Cas9 The company was co-founded by Jennifer Doudna, one of the pioneering CRISPR-Cas9 researchers. One of Intellia's first actions was to license Caribou's genetic publishing technology and award it research and development contracts.

= "text" content = "In November 2014, Intellia has Atlas V enture and Novartis provided the bulk of this funding, with the two companies each holding at least 8% of Intellia, Caribou Biosciences holding nearly 13% of the biotech. data-reactid = "47"> In November 2014, Intellia conducted a series A roundtable that raised $ 15 million in cash. Atlas Venture and Novartis contributed the largest amounts to this financing. Both companies each hold at least 8% of Intellia, Caribou Biosciences holding nearly 13% of biotech.

Novartis did not just buy a stake in Intellia. In January 2015, the large pharmaceutical group and small biotech announced a five-year research and development collaboration focused on the use of CRISPR-Cas9 in the development of T-cell (T-CARD) and cell therapies. chimeric hematopoietic strains (HSC). 19659013] <p clbad = "canvas-atom canvas-text Mb (1.0em) Mb (0) – sm Mt (0.8em) – sm" type = "text" content = "The expertise of Intellia in gene editing has attracted attention In April 2016, Regeneron Pharmaceuticals signed a six-year contract with Intellia to develop CRISPR-Cas9 therapies and received $ 75 million in advance under this agreement has acquired exclusive rights for products targeting up to 10 indications based on Intellia's CRISPR-Cas9 research. "data-reactid =" 53 "> The Intellia gene editing expertise caught the attention of another big company the following year. In April 2016, Regeneron Pharmaceuticals signed a six-year contract with Intellia to develop CRISPR-Cas9 therapies. Intellia received $ 75 million from the start as part of the deal. In exchange, Regeneron has obtained exclusive rights for products targeting up to 10 indications, based on Intellia's CRISPR-Cas9 research.

The initial public offering of Intellia

<p clbad = "web-atom canvas-text Mb (1.0em) Mo (0) – sm Mt (0.8em) – sm" type = "text" content = "In February 2016, Editas Medicine became the first CRISPR-based biotechnology company to launch an Initial Public Offering (IPO), and Intellia Therapeutics did not wait too long to Join the Fray data-reactid = "55"> In February 2016, Editas Medicine became the first CRISPR-focused biotech to conduct an Initial Public Offering (IPO). did not wait too long to join the fray

Biotech announced the price of its IPO on May 5, 2016. Intellia planned to sell 6 million shares at a price of $ 18 per share. of the stock offer also got an option to purchase 900,000 additional shares at the price of. IPO

Intellia announced on May 11, 2016 that the IPO had been concluded with 6.9 million shares sold. The net proceeds from biotechnology after all commissions, underwriting discounts and expenses amounted to approximately $ 112.9 million

Inventory History of Intellia Therapeutics

Possessing Great Potential for the CRISPR-Cas9 gene edition, you could expect. That was – but only briefly.

NTLA Data by YCharts

The price of Intellia's action has exploded in the days following its IPO. However, the stock quickly fell well below its IPO price. There were at least two reasons behind the decline of Intellia.

One was simple: Intellia climbed to a market cap of nearly $ 1 billion with no earnings and prospects of having years of products approved at best. To use the words of former Federal Reserve Chairman Alan Greenspan, there was probably some "irrational exuberance" among investors compared to the action of Intellia Therapeutics

< p clbad = "canvas-atom canvas-text Mb (1.0em) Mb (0) –sm Mt (0.8em) – sm" type = "text" content = "Another major factor was considerable uncertainty about the rights of Intellectual property of Intellia.As mentioned previously, Intellia has licensed its CRISPR-Cas9 technology from Caribou Biosciences.belong to a group of patents originally filed by the University of California Berkley (UCB ), the University of Vienna, and Dr. Emmanuelle Charpentier, who was one of the first CRISPR-Cas9 researchers and co-founder of another biotech gene editor, CRISPR Therapeutics . "Data-reactid =" 76 "> Another major factor was the uncertainty e considerable on intellectual property rights of Intellia. As previously mentioned, Intellia has obtained a license for its CRISPR-Cas9 technology from Caribou Biosciences. The patents concerned belong to a group of patents originally filed by the University of California Berkley (UCB), the University of Vienna and Dr. Emmanuelle Charpentier, who was one of the First CRISPR-Cas9 researchers and co-founder of another However, other parties also sub-licensed the intellectual property of UCB, University of Viena and Charpentier. These parties included CRISPR Therapeutics and ERS Genomics, which had been formed to provide access to Charpentier's intellectual property.

To further complicate matters, the Broad Institute, Harvard University and the Mbadachusetts Institute of Technology (MIT) obtained patents for use of CRISPR-Cas9 in eukaryotic cells – cells with a nuclease, including including all human and animal cells. The party of UCB and the parties aligned with the Broad Institute were embroiled in patent litigation that concerned investors who owned or were considering buying any CRISPR-based biotech stocks, including Intellia.

In December 2016, Intellia Therapeutics, Caribou Biosciences, CRISPR Therapeutics, and ERS Genomics announced "a Global Consent Agreement and Invention Management Agreement" that allowed all organizations to share the intellectual property held by UCB, the University of Vienna and Charpentier. This agreement has simplified some aspects of patent uncertainty.

But the situation deteriorated for Intellia and its allies in February 2017. The USPTO ruled that Broad Institute patents for the use of CRISPR-Cas9 in eukaryotic cells Have not interfered with patents on the UCB side. Although the UBC team appealed the decision in federal court, the decision definitely harmed the actions of Intellia and other biotechs aligned with UCB.

Finally, the attention of investors returned to the potential of CRISPR-Cas9. All CRISPR-focused biotech stocks performed well in the second half of 2017. However, Intellia's momentum ceased when the company announced a new share offering on November 1, 2017, diluting investors.

In 2018, the stock of Intellia is well behaved. The company has reported progress on several fronts, including the success of genetic modification in mice that contributes to liver problems badociated with some alpha-1 antitrypsin deficient patients and the initiation of final tests in non-human primates targeting l & # 39; ATTR.

CRISPR-Cas9 controversy

<p clbad = "canvas-atom canvas-text Mb (1.0em) Mb (0) – sm Mt (0.8em) – sm" type = "text" content = "Any questions have also been raised about the safety and effectiveness of CRISPR-Cas9 For example, in May 2017, Nature Methods published a study that showed that CRISPR-Cas9 could result in many unintentional genetic mutations.This was quite disturbing because one of the advantages of editing the CRISPR-Cas9 gene is its accuracy. "data-reactid =" 84 "> Questions were also raised about the safety and effectiveness of CRISPR-Cas9. For example, in May 2017, Nature Methods published a study that found that CRISPR-Cas9 could result in many unintended genetic mutations. This was quite disturbing since one of the benefits of editing the CRISPR-Cas9 gene is its accuracy.

Finally, this particular problem has been solved. In March 2018, the authors of the study published a retraction and an error correction. Their initial findings were erroneous: CRISPR-Cas9 did not cause hundreds of out-of-target mutations

Meanwhile, however, another potential problem with CRISPR-Cas9 surfaced. In January 2018, the researchers published an article on a web site focused on pre-printed scientific research that was not peer reviewed. This article suggests that human immune responses may interfere with CRISPR-Cas9.

Scientists have discovered that many humans have immune responses to the types of bacteria in which CRISPR-Cas9 self-defense mechanisms have been found. Although they did not demonstrate that the immune responses would certainly cause problems with the CRISPR-Cas9 function in humans, their research has raised concerns about this possibility

This news down inventory at Intellia, CRISPR Therapeutics and Editas Medicine. The decline was short-lived, however. Each stock bounced back quickly as investors learned that there could be workarounds to the problem of the immune response – if that actually happened to be a problem.

<p clbad = "web-atom canvas-text Mb (1.0em) Mb (0) – sm Mt (0.8em) – sm" type = "text" content = "This was not the end Alerts for CRISPR-Cas9 In June 2018, two separate articles published in Nature Medicine pointed out the possibility that the use of CRISPR-Cas9 could cause cancer.The editing method of gene works more efficiently in cells with mutations in the p53 gene However, p53 mutations are linked to an increased risk of several types of cancer data-reactid = "89"> This was not the end of the alerts for CRISPR-Cas9 In June 2018, two separate papers published in Nature Medicine emphasized the possibility that the use of CRISPR-Cas9 could cause cancer. [edit] The gene editing method works more efficiently in cells with mutations in the p53 gene.However, p53 mutations are linked to increased risk of several types of cancer.

These are not all bad news. At this point, the higher cancer risk seems to be only a problem when CRISPR-Cas9 is used to "knock out" or delete a DNA sequence and replace it with a corrected sequence. The principal candidate of Intellia targeting ATTR uses only the type of gene knockout edition. However, some preclinical biotechnology programs suppress and replace DNA sequences. There could be challenges for Intellia on the road related to increased cancer risk.

<p clbad = "canvas-atom canvas-text Mb (1.0em) Mb (0) – sm Mt (0.8em) – sm" type = "text" content = "More recently, another scientific article published in Nature Biotechnology on July 16, 2018, again raised concerns that CRISPR-Cas9 may cause unexpected genetic mutations, that unintentional DNA sequence modifications could occur far from the site. More recently, another scientific article published in Nature Biotechnology on July 16, 2018, raised again concerns about the possibility that CRISPR-Cas9 causes mutations. unexpected genetic Early results suggest that involuntary DNA sequence changes could occur far from the target site

What are the Next Steps for Intellia Therapeutics

Intellia Therapeutics and Regeneron Hope to Submit a Case to the Food and Drug Administration (FDA) By the end of 2019, begin Phase 1 clinical trials of the CRISPR-Cas9 gene editing therapy targeting AATR. The move to clinical trials in humans is an important step for Intellia.

The company however has other programs that it hopes to advance. Here is a summary of the pipeline candidates of Intellia: