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Today, Akribion Therapeutics, a German biotech company announced its €8 million ($8.2 million) seed round. Akribion Therapeutics is working on G-dase E, a programmable nuclease designed to selectively deplete specific cell populations based on intracellular RNA markers. Unlike traditional CRISPR technology, which edits genes, Akribion’s approach aims to destroy cells outright.
Akribion Therapeutics’ work is part of a broader push to harness RNA-guided nucleases for therapeutic use. While CRISPR-Cas9 has dominated the gene-editing space, newer approaches – including Cas13 for RNA editing and emerging nucleases like G-dase E – are exploring cell depletion instead of modification.
Could RNA-guided cell depletion be the next frontier of oncology? And how does Akribion Therapeutics’ approach compare to existing technologies?
Akribion Therapeutics’ G-dase E technology, what’s it about?
“The G-dase E technology uses a CRISPR-like nuclease that recognizes cellular RNA biomarkers with high specificity via a programmable guide RNA. Once the RNA biomarker is bound by G-dase E’s gRNA, it becomes activated and turns into a collateral mode of action that shreds all types of nuclear acids in the affected cell into small pieces with a preference for double-stranded DNA. This leads to cell killing and final cell depletion of the cells expressing the targeted RNA Biomarker,” explained the co-founder and co-chief executive officer (CEO) of Akribion Therapeutics, Lukas Linnig,
Unlike traditional CRISPR systems, which typically introduce double-stranded breaks in DNA to edit genes, G-dase E operates through a distinct mechanism. This method allows for the selective depletion of cells expressing particular RNA biomarkers, offering potential applications in therapeutic areas such as precision oncology.
In contrast, RNA interference (RNAi) techniques, such as those utilizing small interfering RNA (siRNA), function by degrading specific messenger RNA (mRNA) molecules to reduce the expression of target proteins. While effective in gene silencing, RNAi does not lead to cell death but rather modulates protein levels.
Similarly, targeted protein degradation strategies, like those employing PROTACs (proteolysis targeting chimeras), aim to eliminate specific proteins by marking them for degradation via the ubiquitin-proteasome system. This approach focuses on degrading pathogenic proteins but does not necessarily result in the death of the cell.
“In contrast to the classical editing CRISPR Cas nucleases, G-dase E is the first to demonstrate a substantial cytotoxic effect in targeted cells, caused by the degradation of the genome. Contrary to Cas9-based editing events, G-dase E does not edit or mutate genomic sequences or leave edits in the genome so it is more comparable to a programmable payload. This makes G-dase E a relevant tool for the specific depletion of cells in cell populations that can be differentiated by RNA-biomarkers,” added Micheal Krohn, Akribion Therapeutic’s co-founder and co-CEO.
How does Akribion Therapeutics fit into the human papillomavirus (HPV) cancer treatment landscape?
Akribion Therapeutics has chosen to focus its initial efforts on HPV-induced oropharyngeal head and neck cancers (OPSCC).
This decision leverages the characteristics of these cancers, which express viral RNA biomarkers distinct from human cellular RNA. By targeting these specific viral RNA sequences, Akribion Therapeutics’ G-dase E technology aims to selectively deplete cancerous cells while sparing healthy tissue.
“Akribion’s goal is to develop G-dase E technology into a platform technology. That is why we turned our attention to the virus-related cancer indication, which usually expresses individual, non-human genes, offering a diverse set of distinguishable RNA-biomarkers,” said Krohn.
HPV-driven OPSCC is currently treated with a combination of surgery, chemotherapy, and radiation. While effective, these methods come with severe side effects. In recent years, newer therapeutic strategies have emerged:
- Antibody-drug conjugates (ADCs): ADCs, such as Seagen’s Tisotumab vedotin, work by targeting surface proteins on tumor cells and delivering a cytotoxic payload. These therapies are already making an impact in HPV-related cancers like cervical cancer, but their reliance on cell surface antigens may limit their application in OPSCC.
- CAR-T cell therapy: Engineered chimeric antigen receptor (CAR) T cells have shown promise in hematologic cancers, but their application in solid tumors like OPSCC remains limited. One challenge is that CAR-T relies on identifying extracellular protein targets, whereas HPV-driven cancers primarily express unique intracellular RNA markers – something G-dase E directly targets.
- Checkpoint inhibitors (e.g., PD-1/PD-L1 blockers): Immunotherapy drugs like pembrolizumab (Keytruda) and nivolumab (Opdivo) have become standard treatments for advanced HPV-related cancers. These work by removing inhibitory signals on T cells, allowing the immune system to attack tumors. However, not all patients respond, and immune-related side effects remain a concern.
- Therapeutic HPV vaccines: Unlike prophylactic vaccines, therapeutic HPV vaccines are being developed to treat existing infections and associated cancers. Companies such as Inovio Pharmaceuticals and Transgene are working on vaccine-based approaches to induce HPV-targeted immune responses.
In contrast to other approaches, Akribion Therapeutics’ G-dase E technology does not function by directly targeting tumor-associated antigens to activate the immune system, like CAR-T therapy, nor does it rely on ADCs that bind to membrane proteins on cancer cells.
“G-dase E specifically targets intracellular RNA Biomarkers, leading to genome degradation, with the potential to induce an immunogenic cell death response with anti-cancer efficacy in vivo. However, in principle, any type of cellular RNA can serve as a target for G-dase E including classical mRNAs from fusion genes up to regulatory RNAs like non-coding RNAs,” said Linnig.
What does the future hold?
While it is focusing on OPSCC for now, according to the press release, Akribion Therapeutics’ technology holds potential for other indications such as autoimmune diseases, fibrosis or infectious disease in addition to other oncology targets. However the company will remain focused in the early stages.
“It would not make sense for us to pursue too many indications at this early stage. We will be investing in bioinformatic target identification, identification of unique features of our G-dase E technology that can represent technological unique selling points, as opposed to investing lab capacities in applications that we term ‘outside the core field’. We are also open to partnership deals,” said Krohn.
The co-CEO said the company should have encouraging clinical data and have initiated partnerships for further applications in oncology in five years time. “We hope to have validated that G-dase E is applicable as a platform technology shown from in vivo proof of concepts for indications outside oncology by then.”
However, like most companies operating in gene therapy, Akribion Therapeutics is highly dependent on the efficacy of the targeted delivery of the therapy. “Fortunately, multiple companies currently develop and innovate these delivery systems. There have been encouraging breakthroughs in the field for CRISPR Cas applications which have led to cell specific editing rates of higher than 75%,” noted Linnig.The field of RNA-guided nuclease technologies is advancing rapidly, pushed by the success of CRISPR-Cas9. The field is also diversifying at a fast pace with companies using novel CRISPR proteins as well as more refined mechanisms. Akribion Therapeutics is proof that the field is one of the most dynamic biotech areas at the moment, with plenty to look forward to despite the challenges.
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