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Quarterly Trends Report

Q3 2021: another landmark year for gene editing

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  • Healthcare
  • North America

This year represents another landmark year for gene editing, with CRISPR gene editing treatment being inserted directly into the body — also known as in-vivo — becoming a reality. Third Bridge Forum spoke to several experts in Q3 2021 to gain their insights on recent developments and the competitive landscape.

As a professor at the UC Davis School of Medicine highlighted, Intellia Therapeutics released data supporting the treatment of transthyretin amyloidosis (ATTR), a disorder in which protein is deposited in organs and tissue, with the first single-dose, systemically delivered CRISPR/Cas9 therapy. “The very early clinical data… suggested that the 95% reduction in the ATTR protein that they saw in non-human primates, they’re also seeing in humans, so that’s really exciting,” they said. The US Food and Drug Administration (FDA) recently granted orphan drug designation to the treatment, NTLA-2001. As the first CRISPR therapy to edit a disease-causing gene inside the human body, the FDA said NLTA-2001 “has the potential to be the first single-dose treatment for ATTR amyloidosis”, halting and reversing its devastating complications.1https://ir.intelliatx.com/news-releases/news-release-details/intellia-therapeutics-receives-us-fda-orphan-drug-designation

Meanwhile, Editas’ EDIT-101, an experimental treatment delivered via an adeno-associated virus (AAV) vector for leber congenital amaurosis, a rare eye disorder, continues to make progress. Initial data from the BRILLIANCE trial demonstrated a positive safety profile for up to 15 months while early observations show “clinical evidence that gene editing has occurred, demonstrated by visual improvements”.2https://ir.editasmedicine.com/news-releases/news-release-details/editas-medicine-announces-positive-initial-clinical-data-ongoing

“Both of those were landmark cases of in-vivo use and a milestone in the field,” the UC Davis professor told us, adding that “they highlight the different kinds of directions that are happening in the field now in terms of delivery methods”. Intellia and Editas are “definitely leading the way” on in-vivo therapies, but, as we heard, it’s still early days. Companies are searching for cases where they know they can make a significant impact given today’s parameters. “If you were to ask, ‘which one of the two kinds of platform approaches is going to be able to treat the majority of the 7,000 or so single-gene disorders in the future?’ I think that’s still a very open question.”

Importantly, Intellia’s data also offer proof of concept for its lipid nanoparticles (LNP) platform, used to deliver the Cas9 protein. This was a major breakthrough, as lipid nanoparticles have “clear advantages” — but some limitations nonetheless — over AAV vectors, which have hitherto been the preferred delivery method. Notably, LNPs don’t have the same size restrictions, enabling the insertion of larger particles. Another advantage, but potentially a restriction, is that LNPs primarily target the liver — although the industry is beginning to make progress in targeting other tissues. They must also be kept cold and some require freezing, posing logistical concerns. “If we look at the groups that are using AAV vectors like Editas, again, there are advantages and there are challenges,” the US Davis professor said.

AAV vectors face “some very significant production challenges”, we heard, with some estimations that the industry is close to exceeding capacity. While LNP-based technology may offer a solution to their size restrictions, delivery outside of the liver must be better understood. Another consideration is the need to test for pre-existing antibodies, as someone cannot be treated with the same AAV vector. “A second injection would, at best, be cleared by the host immune system and, at worst, cause some severe adverse immune response,” the expert explained. “That’s the specific concern that I have for the Intellia therapy, but more broadly the use of lipid nanoparticles.” 

While viral vectors remain the most efficient delivery method for transferring genes and gene editors into cells, there is “great hope” that the industry will eventually be able to move away from them, with a former executive at Precision NanoSystems Inc particularly bullish on the prospect of LNPs eventually rendering viral vectors obsolete. But given the complexities of gene therapy, for now, no single approach is likely to reign supreme. “It’s still too early to decide if we’re going to have to go with lipid nanoparticles in the future or we can use adeno-associated viruses because now we have these smaller nucleases and things like that, it’s going to change that landscape,” the UC Davis professor said. As we heard, all of the major gene editing companies have strategic collaborations with LNP companies to design faster and more targeted LNPs with broader applications.

The Interview also highlighted research identifying new CRISPR variants that enable base editors, which allow the introduction of point mutations in DNA, to fit into a therapeutic vector for the first time. “I don’t know what their relationship is with Beam at the moment but let’s say we would very much look forward to seeing a real acceleration of seeing base editing head towards clinical trials now, because these types of new CRISPR systems make that possible,” the expert said. Similarly, smaller variants of the Cas13b family of RNA-targeted CRISPR systems were identified, allowing gene editing or base editors and prime editors to be packaged for RNA.

Looking into toxicity issues, we heard in another Interview with a co-director at Children’s Healthcare of Atlanta Inc that adverse events from gene therapies are a “major concern”, with unique problems for each vector. “The main toxicity with just about all the different vectors, all different AAVs, has been liver toxicity or hepatotoxicity,” the specialist said. Besides the immune response from existing antibodies, the payload or the genome of the AAV can induce inflammation. “And when you have gene-modified liver cells, the immune system begins to kill those cells, which is the cause of liver toxicity.” As was noted during the Interview, one question being considered is whether the FDA should set an upper limit on the size of the gene therapy doses to mitigate some of these risks. The specialist pointed out that that is what phase 1 trials are for, with the caveat that the risk of toxicity increases at the 10^14 (vector genomes per kilogram) dosage. 

Taking a closer look at developments in how DNA payloads are delivered to cells, particularly non-viral methods that reduce the risk of adverse immune responses, a principal scientist at CRISPR Therapeutics AG said MaxCyte is currently the “go-to [player for] electroporation”. This method is gaining momentum, using an electrical pulse to create temporary pores in cells and allowing substances that deliver therapies, such as nucleic acids, to pass through. Engineering cells to include or exclude specific markers without the need for a viral vector, with techniques that enable them to be “knocked out” and “knocked in”, is widely viewed as the future of cell and gene therapy. While electroporation is capable of knock-out edits with high efficiency, knock-ins have some way to go before the market can fully move away from viral vectors, garnering interest in transfection technology.

As we refine our understanding of gene therapy delivery methods, knowing which ones are best suited to which treatments will become increasingly apparent. As we heard from the UC Davis professor, “it’s still a very wide open field” and we are only seeing the tip of the iceberg in terms of treatments available and how they are delivered, revolutionising medicine and transforming lives.

Related Transcripts

The information used in compiling this document has been obtained by Third Bridge from experts participating in Forum Interviews. Third Bridge does not warrant the accuracy of the information and has not independently verified it. It should not be regarded as a trade recommendation or form the basis of any investment decision.

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