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From the bench to the meeting room | The Scientist Magazine®

When Anamoreno received her PhD in biotechnology from the University of California, San Diego, she wanted to design gene therapy for difficult-to-treat diseases. However, targeting the genome seemed like a daunting solution to diseases with more subtle changes in gene expression, such as chronic pain.

Ana Moreno founded Navega Therapeutics based on a PhD study that uses inactivated Cas9 to reduce the expression of pain-related genes.

Instead, she used an approach called CRISPR-dead Cas9 (dCas9). It takes advantage of the ability of CRISPR to home in to the target gene. When the CRISPR mechanism reaches there, dCas9 does not cut. Instead, work on molecules that increase or decrease gene expression. In a pain mouse model, this strategy reduced the expression of genes encoding sodium channels that are known to be overactive in chronic pain.1 After CRISPR treatment, the animal’s pain seems to have been reduced.

Now she was born out of her PhD study and founded a company called Navega Therapeutics to develop this pain-relieving strategy into an addictive opioid alternative.

Why use CRISPR to control gene regulation?

When thinking beyond common and rare diseases, we need to take advantage of genomic regulation. Genome editing cannot target multiple genes, causing translocations and other problems. Some diseases require multiple gene targeting and multiple targeting. This is where we consider this approach to be very exciting.

Why is dCas9 useful for this?

Traditionally, CRISPR uses nucleases that perform double-strand breaks. However, dCas9 has no DNA-cleaving activity due to the mutation of these nucleases. However, it still holds a guide RNA, this GPS of where it binds in the genome. Design the guide to navigate to the destination in the genome, then add an activation or repression domain to activate or repress the gene of interest.

Specifically, looking at pain, we can see that the gene encoding NaV1.7 is a very plastic gene and its expression is constantly increasing. The advantage of gene regulation by dCas9 is that it can not only downregulate the gene, but also prevent future upregulation.

How did you decide to use this strategy for pain?

We have all heard about opioid epidemics. We know that the development of chronic pain treatments has not progressed. Opioids are known to work well, making them difficult to tackle and difficult to overcome.

When I came across NaV 1.7, it was one of these random Sunday night reading papers. People with gene mutations (loss-of-function mutations) may not feel pain, but people with gain-of-function mutations cause more pain than normal people. Especially since I was using dCas9, I thought it was really exciting. What can this technology be used for? It makes a lot of sense to edit because of the pain.

What should you consider when working in pain-like conditions that affect normal functioning?

When we are chasing pain, we don’t want to mutate that gene permanently. We want a solution that suppresses it but is not permanent. We start with hereditary erythromelalgia, a rare disease in which patients live with this gain-of-function NaV1.7 mutation. Treatment with dCas9 will be their cure. Next, we can consider other neuropathic pain conditions that may benefit from gene therapy with the same medication.

When I first tackled the pain, I was excited and surprised that it worked. That is, things always work in vitro, but then. There are many problems in vivo. It not only prevents pain, but also restores it. That’s what we want in the clinic.

What made you start the company?

The motivation was to really be passionate about results and thoughts. I don’t want to stay in the mouse model, graduate and move on to anything else. I want to bring this to the clinic. I get a lot of emails from patients suffering from pain, which is very motivating. Someone really needs this. Science can also be lucky. You have the right lab, the right technology, the right application, and the driving force behind it. Immediately after getting my PhD, we started a company called Navega Therapeutics and are now in Janssen’s incubator space, JLABS.

What do you do every day?

Moreno started running his own company from a graduate student, but he still found himself on the bench from time to time to experiment with mice.

Startups are like academia. We wear a lot of hats and do a lot of things. It’s like a graduate school. When a device breaks, we have to come up with a way to fix it.

It’s been bench work all the time when I started.That was the first photo of the bench My bench.. It’s hard to find someone who specializes in these various components, so I’m still doing a lot of mouse work. But now that scientists and researchers are on the bench, my days are more managed and feel like PI. In graduate school, I used to study, publish, and read dissertations, but now I have everything else. I write grants, manage my lab, talk to investors, write patents, think about regulation.

My old PhD friend sometimes asks me if I’m tired of working on the same thing, but it’s not the same thing. Unlike other aspects of business, such as intellectual property, patents, and lawyers, it’s novel.

How did you learn the skills to lead the company?

I founded the company in 2018 when I was still a PhD. I searched for resources on campus. There are several incubators. Due to the challenges of female founders, some focused on female founders. In the end, I took a business class for about a year and got a “mini MBA”.

Much of it was trial and error. Looking at my first pitch deck and what I have now, it’s very different. I think the biggest thing I’ve learned is that, as a scientist, everyone wants what we produce or do. But then we need to think about other aspects: who is the audience in our market, who needs our treatment, what is our price, what about reimbursement? , Who makes this? All these things you don’t have to think about when you’re in graduate school.

I’m learning from a great advisor in the process. I met wonderful people who are really generous in their time. They help us grow the company and believe what we are doing. It’s good to know that such a person is there.

What’s coming next year?

We are currently in the preclinical stage and are excited about our work to demonstrate the concept. Currently, we are conducting IND-compatible research to bring this to the clinic and expand it to other targets. The next step is to expand your team and operations, and then hire people to think about the quality control, quality assurance, and other components needed to introduce the drug to the clinic.

This interview has been edited and summarized for clarity.

reference

  1. AM Moreno et al. , “Long-term analgesia by targeted in situ suppression of NaV 1.7 in mice” Sci Transl Med, 13: eaay9056, 2021.

From the bench to the meeting room | The Scientist Magazine®

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