Turning science into business: Amplifying mRNA by targeting regRNAs

RNA strand

DDW’s Diana Spencer speaks to Josh Mandel-Brehm, CEO of Massachusetts-based biotech CAMP4, to understand the role regulatory RNAs play in gene expression and how the founders overcame the challenge of launching a business based on brand new science.

DS: CAMP4 leverages research from co-founder Richard Young on how regulatory RNA (regRNA) molecules control the expression of genes. What is regRNA and why hasn’t it been exploited as a therapeutic target before? What are the challenges of drug discovery in this area?

JMB: Regulatory RNAs (or regRNAS) are molecules that directly control the expression of nearby protein-coding genes. Recently, research published by Dr Richard (Rick) Young (Whitehead Institute) describes the key mechanism of how these regRNAs regulate gene expression. CAMP4 is exploiting these regulatory interactions to specifically control the expression of genes tied to disease.

So, regRNAs haven’t been exploited previously because scientists have only recently understood their role in regulating gene expression. Our approach and platform are based on brand new, groundbreaking science, and we’re fortunate to have a close collaboration with Rick Young.

There are, of course, many challenges inherent in pioneering a new space — that includes starting from scratch when describing our novel targets and platform approach to potential investors and partners. We are also tackling the process of mapping out all the areas where our platform may be applied – there is vast potential in the ability to finely tune gene expression, and we want to leave no stone unturned.

DS: How easy was it to transfer theoretical research into a viable business? What advice do you have for other start-ups hoping to launch in a similar field?

JMB: Since the early days of CAMP4, we have always followed the science. When the science pointed to new directions, we haven’t been afraid to pivot. Since the company’s founding, we have built an exhaustive database of regRNA maps and built an efficient platform to harness the power of regRNAs as therapeutic targets. This has created an exceptionally strong scientific foundation upon which to build our pipeline.

In terms of advice for other startups, I’ll share a few lessons that I’ve taken from being in this role, which is a first-time CEO role for me. First, I’d say that you’re going to make mistakes; so just give yourself forgiveness when that happens and keep moving forward. Second, trust in your people. Third, be deliberate about your culture. Culture is a set of virtues and articulated actions, and it matters how you model, lead and reinforce them. It’s only when things get tough that you find out what you and your team are made of – and that’s when culture comes into play.

DS: You raised $100 million in a Series B financing round in 2022. How have you navigated a difficult investment climate?

JMB: There’s no doubt that it’s been a tough environment to raise funds, and the market has only worsened in 2023. We’re fortunate to have investors who share our vision – many of whom have been involved from the early days and have continued to support CAMP4 through multiple rounds. Being able to raise $100 million, over 70% from new investors, in such a difficult climate speaks to investors’ conviction in the potential of our platform. 

DS: You describe your therapeutics as RNA Amplifiers. How do they work? What are the advantages compared to other gene modulating approaches?

JMB: Our therapeutics are designed to amplify mRNA by targeting regRNAs — intervening in innate regulatory mechanisms hard-wired into the nucleus of every cell. regRNAs act locally on transcription factors (TFs), disrupting the activity of negative-acting TFs, effectively taking the brakes off the transcriptional system in a controlled way and increasing mRNA production from a healthy copy of the target gene. Our proprietary RAP Platform identifies the most impactful regRNA for a given gene and programmes anti-sense oligonucleotides (ASOs) to engage the regRNA and amplify mRNA production. For many diseases, only small increases in expression are needed to make the difference between sickness and health.

As for gene-modulating approaches, I want to point out that our therapeutic candidates do not in any way modulate the gene itself. Increasing gene expression via protein replacement or gene therapy has been shown to have limitations and drawbacks. At CAMP4, by leveraging the cell’s transcriptional machinery, we’re essentially tapping into a natural process at the cellular level and asking slightly more of it. Another advantage is the ability to finely tune to the amount we dial up (or down) the expression of the gene of interest. CAMP4 is the only company modulating gene expression at the transcriptional level to increase mRNA production and thereby increase healthy protein production.

DS: You say on your website that your approach is applicable to any disease where increasing protein expression is beneficial. Can you give some examples? What diseases are you currently targeting?

JMB: Hundreds of genetic diseases involve a missing or deficient protein and/or enzyme. Our approach is aimed at genetic diseases where amplifying healthy protein can offer therapeutic benefits. Our lead programme is in Urea Cycle Disorders (UCDs), an example of a metabolic disorder that benefits from increased expression of a healthy enzyme. UCDs are a group of rare, inherited genetic diseases in which ammonia builds up to dangerous levels in the blood, due to a defective enzyme. This impacts the body’s ability to metabolise ammonia, resulting in toxic levels of ammonia that cause damage to the brain and other side effects. In UCD, we take a gene augmentation approach by elevating production of a rate-limiting enzyme, CPS1, which catalyses the first step of the urea cycle. This boost in healthy CPS1 enzyme results in greater flux (conversion of ammonia to urea) throughout the rest of the cycle, regardless of which downstream step harbors the specific genetic deficiency causing the disease.

Our pipeline also includes programmes in other metabolic and rare disorders, ALS, genetic epilepsies and neurodegenerative diseases. Our amplification pipeline has the potential to address hundreds of genetic diseases.

DS: Is there potential for this approach beyond diseases of the liver and central nervous system? What are the challenges to expanding its use?

JMB: Yes, we believe that there’s immense potential for this approach beyond metabolic and CNS diseases. We’ve chosen to work with ASOs because they are a de-risked modality whose delivery, safety and efficacy have been established in the liver and CNS. One of the great things about ASOs are that they create the most optimal binding possible between the drug and the target. That said, the state of the field of ASOs delivery is currently most well-trod from a clinical and regulatory perspective in the liver and CNS; we have developed regRNA maps for many tissues beyond these two areas, and we are keeping a close eye on exciting new technology that will allow us to deliver oligos to new tissues such as the heart, eye, smooth muscle, kidney and lung. Given the realities of being a small organisation, we recognise that we can’t take on everything, and we’re staying attuned to new advances as we consider expanding our pipeline to these areas.  

DS: What does CAMP4 have planned for 2024? What’s in the pipeline?

JMB: We’re looking forward to a lot of exciting developments in 2024. First, we anticipate entering the clinic with our UCD programme. We’ve designed it to act as a pan-UCD therapy that may address the vast majority of UCD subtypes and potentially become a backbone therapy upon which genetic subtype-specific treatments, such as therapeutic candidates for ornithine transcarbamylase (OTC)-deficient patients, could be overlaid. 

Additionally, we’re continuing to expand and advance our CNS pipeline and plan to form partnerships with biopharma companies on mRNA-amplification programs originating from our platform.

DS: Richard Young recently published a paper revealing that many transcription factors can bind RNA. What is the therapeutic potential of this discovery?

JMB: Rick Young’s publication shows that RNA binding TFs fine-tunes gene expression. It had been known for decades that TFs, which orchestrate a cell’s gene expression programs, bind to DNA and proteins. The seminal discovery that is the subject of Rick Young’s recent Molecular Cell paper reveals that many TFs also bind to RNA through a previously unrecognised domain. 

The Molecular Cell paper describes the underlying biological mechanism our ASOs are modulating. We can envision it this way: at a given genomic site, some TFs are engaged in activating the gene, while others are engaged in suppressing it. Interactions between the transcription factors and RNAs determine the balance between gene activation and gene suppression and, ultimately, the level of gene expression. By using an ASO that interferes with a specific regRNA-transcription factor interaction, we can shift that balance to dial up (or down) the expression of any gene of interest.

DDW Volume 25 – Issue 2, Spring 2024

Josh Mandel-BrehmBiography:

Josh Mandel-Brehm is the President & Chief Executive Officer of CAMP4 Therapeutics and was previously an entrepreneur partner with Polaris Partners. He also co-founded VICO Therapeutics and is starting a next-generation diagnostics company. He previously held key business development and operations leadership roles at leading biotech companies, including at Biogen and Genzyme.

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