Realizing the Promise of CRISPR the Therapeutics: In vivo and Cell therapy Applications
Eliana Clark, PhD, Intellia Therapeutics
Although CRISPR has given biotechnology more opportunities to treat disease, it should be viewed as a tool rather than a panacea, according to an expert. Additionally, the genomic medicine sector still faces regulatory challenges.
Dr. Eliana Clark, Chief Technical Officer at Cambridge, Mass.-based biotech Intellia Therapeutics, spoke about gene editing at the TIDES USA oligonucleotide and peptides conference, informing delegates the technology has enriched the ability to treat disease.
“We started with small molecule drugs [and] then we developed biologics. We also developed RNAs. We have DNA through gene therapy and now genome editing,” Clark said.
“When you think about all the previous agents that we used to treat diseases, they either treated diseases by inhibition, by modulating, or by augmenting a function, adding a functional protein that is not present in the patients. The beauty of CRISPR technology is that it allows us to do all these things.”
Knockout cure
Clark used NTLA-2001, a candidate treatment for transthyretin amyloidosis (ATTR), as an example of how CRISPR can treat disease.
“Patients that have TTR amyloidosis have a disease that is progressive and fatal. It is caused by the accumulation of misfolded TTR protein in multiple organs in the body especially in the nerves and the heart,” she said.
The TTR protein is made in the liver and secreted to the serum from where it is transported to multiple organs where, when misfolded, it aggregates.
“So the goal of [the] NTLA-2001 candidate is to knock out that TTR gene in the liver with one dose. We can achieve deep reductions in the circulating levels of TTR in the body,” Clark said.
The drug comprises an mRNA sequence for the Cas9 nuclease enzyme and an RNA sequence that guides it to the site of cleavage. The Cas9 mRNA is translated into the Cas9 protein, which binds the guide RNA to form a complex.
The complex is translocated to the nucleus where the other portion of the guide RNA binds the DNA at the site of the edit – which is a double strand break. And that double strand break deactivates the TTR gene.
According to Clark, using CRISPR in this way enables the therapy to address the root cause of the disease and thereby all the symptoms.
“We can use it to address both forms of the disease cardiomyopathy and polyneuropathy. So again, with this single dose, we can halt the progression of the disease, and we have the potential to reverse the course of the disease with this technology,” she said.
Toolbox
However, it is important to keep in mind that CRISPR is just one of several tools – an extremely powerful one – in the genomic medicines space.
Developers working in the space need to keep their options open rather than being wedded to one particular technology, according to Clark.
“We are applying many editing tools that are novel and also many delivery tools to be able to tackle genomic diseases,” she said.
“So for in vivo application, we use CRISPR as a medicine. So in this particular case, we are going to fix a gene. In contrast, when used ex vivo, CRISPR creates the therapy by allowing us to engineer the cells and rewire them to treat the disease,” Clark continued.
“No single solution will address all the needs for genomic medicines. So what we have done at Intellia is create a very powerful toolbox that we continue to augment with other technologies.”
Clark cited CRISPR, alongside other DNA editing, writing and delivery technologies, as a core element in the company’s toolbox, adding that “the goal is to have unlimited opportunities to treat disease.”
Regulatory questions
Whether applying in vivo or ex vivo, developers using CRISPR to treat disease still need to be able to demonstrate the safety and efficacy. This is a major challenge for the sector, according to Clark.
“This technology is very new. It has incredible potential, but it’s unknown to many of the regulatory agencies. So the requirements are very large to be able to demonstrate both the safety and the efficacy of the products,” she said.
“I think it will take a few years and a few companies like Intellia to make regulators more comfortable with the power of our technology.”
