A $100-million startup emerging from stealth is developing not one but two answers to the challenge that has long dogged the gene therapy field: How can genetic medicines best be delivered to patients safely and effectively?

Nvelop Therapeutics aims to answer that question with $100 million in seed funding, raised two years ago, and a pair of validated in vivo delivery approaches developed by gene editing pioneers David R. Liu, PhD, and J. Keith Joung, MD, PhD.

Jeff Walsh, Nvelop Therapeutics CEO

“Fundamentally both David’s lab and Keith’s lab were trying to solve the same problem,” Jeff Walsh, Nvelop’s CEO, told GEN Edge. “They’re both prolific in the field of gene editing independently, but they also realize that there are limitations today to the ability to take the amazing cargoes that we have in the field and deliver them in vivo in a specific enough way to cell types of interest.”

“Both have understood this challenge and the opportunity that if we can solve the problems of in vivo delivery, it’s going to open up an opportunity for cell and gene therapy—and specifically for gene editing cargoes—that today is just not plausible. And we’ll be able to get to some cell types and certainly to some populations of patients that today can’t be addressed by current technologies.”

One of Nvelop’s approaches, originating from Liu’s lab, centers on engineered DNA-free virus-like particles (eVLPs)—assemblies of viral proteins that can infect cells but lack viral genetic material. This platform was detailed in papers published over the past two years.

In a paper published in Cell in 2022, Liu and colleagues described the development and application of their eVLP platform, designed to package and deliver both in vitro and in vivo therapeutic ribonucleoproteins (RNPs), including base editors and Cas9 nuclease, thereby offering key advantages of both viral and nonviral delivery strategies. Using fourth-generation (v4) eVLPs that packaged an average of 16-fold more base editor (BE) RNPs compared with initial designs based on previously reported VLPs, Liu and colleagues showed how their eVLPs efficiently delivered base editors or Cas9 RNPs to multiple organs with minimal off-target effects.

In follow-up research published in Nature Biotechnology, Liu and colleagues showed that their prime editor (PE) eVLPs successfully delivered prime editors to cells in the eyes of two mouse models of genetic blindness, efficiently enough to restore protein expression and rescue partial visual function. The optimized PE eVLPs enhanced the safety of prime editing by reducing off-target editing and thus negating the possibility of oncogenic transgene integration.

“The PE-eVLP system reported here offers unique advantages of nonviral, single-particle delivery of PEs in their most transient form as RNPs, presenting safety and target specificity advantages over DNA or mRNA delivery methods,” Liu and colleagues concluded in the study.

Melissa Bonner, PhD, Nvelop’s CSO, told GEN Edge that Nvelop has worked to further develop the eVLP technology. She spent almost a decade at bluebird before joining the new venture.

Scaling up

Melissa Bonner, PhD, Nvelop Therapeutics CSO

“Our team really did a tremendous job in focusing on how to enable scalable manufacturing for that platform technology,” Bonner said. “Just seeing the progress the team has made has been really humbling, and we are on track to manufacture material at a scale that is going to allow us to determine whether or not there’s clinical applicability to a product like this.”

Liu is a professor and director of the Merkin Institute of Transformative Technologies in Healthcare at the Broad Institute, and a Howard Hughes Medical Institute investigator. Joung is on leave from his position as professor of pathology at Harvard Medical School to serve as lead translator for Arena BioWorks, a privately funded independent research institute launched in January. Last year, Joung departed Massachusetts General Hospital, where he was the Robert B. Colvin, MD, Endowed Chair in Pathology.

Nvelop has also been working to develop a platform originating from Joung’s lab that is also designed to produce VLPs. A patent application (US2023/0227793) from Joung’s lab published July 20, 2023, shows enhanced VLPs, which include one or more virally-derived glycoproteins outside the membrane, with a cargo molecule positioned inside. The enhanced VLP does not comprise a protein from any human endogenous or exogenous viral group-specific antigen (gag) or polymerase (pol).

“The technology coming from Keith’s lab was a little less mature when it was tech transferred into Nvelop,” Bonner recalled. “We did the first in vivo validation studies for that platform and were delighted to see the in vivo editing efficiencies that we were able to achieve even with our first study, not knowing what we were going to expect. We’ve made tremendous strides in improving the purity and potency material from that platform as well over the last seven months, and we continue to work on optimization there.”

Another patent application filed by Joung’s lab and published in recent years reveals work on two types of VLPs, both consisting of a membrane comprising a phospholipid bilayer. One application (US2022/0259617) published August 18, 2022, details human-derived VLPs, which include one or more human endogenous retrovirus (HERV)-derived envelope proteins outside the membrane, one or more HERV-derived GAG proteins in the human-derived VLP core, and a cargo molecule inside the membrane.

“These human envelope proteins enable us to make a fully human particle, which we believe could be really impactful, especially when you start thinking about the potential of things like redosing down the line,” Bonner said. “Because we have this human envelope protein library coming from Keith’s lab as well, we have the potential to pseudotype or encode in the membrane of these particles these human fusogens, which could enable immune tolerance and potential for redosability as a fully human particle human particle.”

Potentially Interchangeable

The components of the Liu lab and Joung lab platforms are potentially interchangeable, Nvelop believes, though how and when it plans to deploy each of these platforms remains under discussion.

“We are really focused on understanding the modularity of the platform separately, and how those components can and will be interchanged across the platforms to continually refine and optimize these particles moving forward,” Bonner added. “The fact that we have two in vivo validated platforms that have a high degree of modularity, I think really puts us in a great position, because we have what I think is tremendous optionality looking forward.”

Liu and Joung are among researchers focused on developing new delivery technologies for genetic medicines.

In January, the lab of Nobel laureate and CRISPR pioneer Jennifer Doudna, PhD, of the University of California, Berkeley,  published a study in Nature Biotechnology showing how its enveloped delivery vehicles (EDVs) carried Cas9 and gRNA proteins for precise genome editing in living organisms—a programmable delivery modality that the co-authors said held the potential for widespread therapeutic utility. Three years earlier, Doudna’s lab detailed the development of a strategy using engineered lentiviral particles to introduce Cas9 RNPs and a CAR transgene into primary human T cells without electroporation.

A different delivery approach is being pursued by another CRISPR pioneer. Last year, Feng Zhang, PhD, of the Broad Institute of MIT and Harvard, founded Aera Therapeutics to develop genetic medicines based on the protein nanoparticle (PNP) delivery platform developed by his lab. Aera was launched with $193 million in combined Series A and B financings.

The in vivo platforms being developed by Nvelop are designed to improve upon existing leading delivery technologies.

Lentiviral vectors offer the ability to infect both dividing and slow or non-dividing cells, efficient gene transfer, low immunogenicity, and the potential for long-term stable gene expression through permanent integration of transgenes into the host cell genome. However, the transgene may induce oncogenesis in infected cells due to the potential for insertional mutagenesis (the creation of mutations in DNA by the addition of one or more base pairs).

Adeno-associated virus (AAV) vectors have shown safety and efficiency in mediating gene transfer to the central nervous system, enabling treatment of neurodegenerative diseases, notably spinal muscular atrophy (SMA). A 2023 study concluded that Novartis’ AAV9-based gene therapy Zolgensma “is one of the best treatments for SMA type 1 available to date,” despite challenges such as high cost, limited access, and hepatotoxicity. More broadly, AAVs’ drawbacks include limited target specificity, immunogenicity, cytotoxicity, and have potential for insertional mutagenesis.

Lipid nanoparticles (LNPs) can be highly targeted and show no biotoxicity. But while stable at room temperatures and some specialized manufacturing and freezing processes, LNPs can show instability under in vivo conditions due to their short half-life, and also offer low drug load efficiency. Recently, Verve Therapeutics announced it had paused its lead clinical trial (for familial hypercholesterolemia) following a solitary, transient adverse event, pointing to the LNP formulation as the likely reason.

Addressing four limitations

Nvelop says the two platforms it is developing are designed to address limitations of these delivery technologies through improved:

  • Delivery efficiency—Creating therapies that target diseases across multiple tissues in which a high degree of activity is required for clinical benefit.
  • Tissue specificity—Applying targeted in vivo delivery to cells and tissues that have been historically difficult to reach.
  • Cargo diversity—Allowing delivery of a wide range of cargo types and sizes, including transiently expressed proteins such as base and prime editor RNPs.
  • Safety advantages—Optimizing RNP cargoes for delivery within intricately engineered particles with the potential to be fully humanized, thus expanding the number of diseases treatable with genetic medicines.

A key focus of Nvelop has been grasping how best to tackle delivery challenges, Walsh said: “It’s a real important question. Something we’ve been spending a fair amount of time of late is thinking about not only our own products where we would need our own cargo, but also enabling others through partnerships where they are struggling with delivery technology.”

“There are multiple ways that we can gain access to various nuclease cargoes. One is the ones we already have in-house, two is where we continue to look at different nuclease technology that is out there,” Walsh added. “There are a lot of libraries out there, and we continue to evaluate them. So, we may bring some of those in-house for our own purposes. But we also may be able to land and develop partnerships with those that need a delivery technology.”

The partnerships could yield therapy candidates for both partners, or simply for the partner, with Nvelop simply providing a means of delivery, Walsh added.

“We do have internal nuclease technology. We’re also looking at various methods of how we can get more cargo technologies into our particles, whether or not that’s a partnership down the line. We’re happy to enable others, in addition to building up our own pipeline.”

Signed, sealed, delivered?

Nvelop says its in vivo platforms will enable it to target a wider range of therapeutic areas than other gene editing therapy developers. However, the company won’t say which therapeutic areas it plans to focus on first, and says it’s too soon to say when its first gene edited therapy could reach the clinic.

“We’ve certainly gone through an internal process of identifying our initial likely target tissues. And some of that work is ongoing. But I think it’s a little premature to start talking about which ones we will be focused on initially,” Walsh said.

Liu and Joung are longtime friends and collaborators, having co-founded several biotech companies before, including Editas Medicine, Beam Therapeutics, and Pairwise. They are scientific co-founders of Nvelop and will serve as consultants to the company.

The company has attracted as investors a syndicate of top-tier venture capital firms that include Newpath Partners, Atlas Venture, FPrime Capital, and 5AM Ventures, with participation from GV (Google Ventures) and ARCH Venture Partners.

“We’re well capitalized. We’re in a great financial position right now,” Walsh said. Nvelop isn’t divulging how long its cash runway is expected to last, or when it might raise its next round of capital.

Nvelop has, however, disclosed its executive team—Walsh, Bonner, and Lisa McGrath, the company’s chief people officer—and board of directors. In addition to Walsh, the board includes former Spark Therapeutics CEO Jeff Marrazzo and investors that include Jess Alston, PhD, partner, F-Prime Capital; Kevin Bitterman, PhD, partner, Atlas Venture; Thomas Cahill, MD, PhD, founder and managing partner, Newpath Partners; and Deborah Palestrant, PhD, partner, 5AM Ventures.

Walsh and Bonner previously worked together at bluebird bio. Walsh was the company’s CFO and strategy officer, while Bonner had been bluebird’s head of research, leading a team that secured FDA approvals for the company’s three marketed autologous hematopoietic stem cell-based gene therapies—the beta-thalassemia treatment Zynteglo™ (betibeglogene autotemcel, “beti-cel”), the cerebral adrenoleukodystrophy (CALD) treatment Skysona™ (elivaldogene autotemcel, “eli-cel”), and Lyfgenia™ (lovotibeglogene autotemcel, “lovo-cel”).

Walsh joined Nvelop about a year ago after spending a year as a venture partner at Third Rock Ventures.

Looking at technologies

“After leaving Bluebird, I spent a fair amount of time looking at the next generation of technologies to advance the field of cell and gene therapy. I naturally went to looking at the different technologies that were out there for delivery, because that is what’s standing in our way of realizing the potential of these genetic cargoes, genetic medicines,” Walsh recalled.

When one of Nvelop’s investors reached out to Walsh, he said, “I was re-energized and ready to take a new operating role. The timing worked out great where I was really interested in this field, this technology, I felt like we were on a steep part of the innovation curve here now on the delivery side of genetic medicine and they were looking for a CEO. I said, ‘I’m your guy.’ So, I took the plunge, and I’m thrilled to be here!”

Bonner joined Nvelop seven months ago: “I said, ‘Oh, this could be really fun.’ It turned out to be really fun. I think we’re going to build a really great place to work and a strong culture with exciting science.”

Nvelop’s workforce stood at 62 people at the start of April. “We’ll grow a little bit beyond that, but not too much,” Walsh said.

“Obviously, that’s dictated a lot by the prosecution of the science, and where we ultimately take it. But right now, we’ll grow a little bit this year, and then the science will dictate how far we grow beyond that.”

“We believe we’re one of the few companies that has technologies, plural, that many don’t with this modularity, that could address all four of the major challenges to the field, and that alone is different,” Walsh said. “So, we couldn’t be more excited about the position we’re in to address a lot of the challenges that the field has faced.”

Previous articleNovel Treatment Options for Pancreatic Tumors Unlocked
Next articleViral RNA-Based Diagnostics: Nanopore System May Outperform PCR