DUBLIN – The twin phenomena of protein aggregation and deposition have been viewed almost exclusively through a pathology lens. The amyloid hypothesis in Alzheimer's disease – still not conclusively proven in clinical settings but by no means refuted either – is the most prominent example in human biology. But about 30 different proteins are implicated in a range of diseases that are characterized by the formation of extracellular, insoluble amyloid fibrils.

Indeed, the first-ever approval for a drug based on RNA interference (RNAi) technology is set to gain approval in the coming year in one of those conditions. Cambridge, Mass.-based Alnylam Pharmaceuticals Inc. completed regulatory filings for patisiran with the FDA and the EMA in December, on the back of solid phase III efficacy and safety data in hereditary transthyretin amyloidosis with polyneuropathy (hATTR). (See BioWorld, Sept. 21, 2017.)

The condition arises from mutations in the gene encoding transthyretin, a liver protein that forms tetramers to perform its usual function as a carrier of the hormone thyroxine and of retinol-binding protein. Mutated versions of the protein cannot form tetramers with the same efficiency, and the resulting monomers tend to aggregate and form deposits in various organs and tissues, including the peripheral nerves, heart and gastrointestinal system. Alnylam has shown that switching off most transthyretin production can not only slow disease progression but can actually improve the condition of patients.

Protein misfolding and deposition have also been implicated in type 2 diabetes, Parkinson's disease, Huntington's disease, Creutzfeldt-Jakob disease and a range of systemic amyloidoses. Although the individual proteins and associated disease processes differ, all of them share a common trigger. "The ability of normally soluble proteins to convert into amyloid fibrils is now recognized to be a generic phenomenon," noted Christopher Dobson, of Cambridge University, Cambridge, U.K., in a review that appeared in the June 1, 2017, issue of Cold Spring Harbor Perspectives in Biology.

Moreover, he added, it can happen to – or be induced in – many proteins that are not normally associated with disease.

Belgian startup Aelin Therapeutics SA is looking to harness that process by creating a novel platform for peptide-based drugs, based on an intimate understanding of the dynamics of protein folding and amyloid formation. The company, a spinout from the Flanders Institute of Biotechnology (Vlaams Instituut voor Biotechnologie; VIB) and the Catholic University of Leuven (Katholieke Universiteit Leuven; KU Leuven), is pursuing a distinctive strategy, which sets it apart from other players in that space. Instead of preventing protein misfolding and amyloid fibril formation, it aims to induce them in order to achieve a therapeutic benefit.

The Leuven-based firm is not focused on classical forms of amyloidosis, therefore. Its first-in-class "Pept-in" molecules, which selectively trigger amyloid cascades by binding aggregation-prone regions on their target proteins, have potential across broad swathes of human biology and beyond. The company's founders Frederic Rousseau and Joost Schymkowitz – who are co-leaders of the VIB Switch Laboratory at KU Leuven – have even demonstrated their ability to promote plant growth by de-repressing a negative regulator.

Despite the novelty of its technology, the company has landed what looks to be the second largest series A round in European biotechnology this year, from a deep-pocketed syndicate of investors. Participants in its €27 million (US$32.96 million)series A financing round include Life Sciences Partners, of Amsterdam; Brussels-based PMV; Novartis Venture Fund, of Basel, Switzerland; Boehringer Ingelheim Venture Fund, of Ingelheim, Germany; and Fund+, of Leuven.

"It's a combination of really groundbreaking technology, having a solid proof-of-concept data package and a very strong IP position," interim CEO Els Beirnaert told BioWorld. "We have now a number of investors around the table who are able to fund development to completion of phase I," added Beirnaert, who is also head of new ventures at VIB.

Its initial focus will be on antibacterial drugs. It will also establish a program in one other area, which has yet to be finalized. Oncology and autosomal dominant disease are both candidates.

"What you would be going after is those protein targets with a high turnover," Beirnaert said. In that context, the technology could be readily applied to antiviral drugs, too, given the massive scale of viral replication within infected cells. By initially targeting bacterial proteins, the company aims to side-step the obvious safety concerns that arise from triggering an amyloidogenic protein cascade in patients. Off-target cross-reactivity is unlikely to be an issue, Beirnaert said.

The whole process of protein targeting appears to be highly selective in any case. Rousseau's and Schymkowitz's group has already reported on its ability to target vascular endothelial growth factor receptor 2 (VEGFR2) using a peptide containing amyloidogenic fragments that it identified in the native VEGFR2 protein. Crucially, the peptide, termed vascin, was selectively toxic in cells that required VEGFR2 function, and it did not induce aggregation of known amyloidogenic proteins. It also reduced tumor growth in a VEGFR2-sensitive mouse model of melanoma. The data appeared in the Nov. 11, 2016, issue of Science, in a paper, titled "De novo design of a biologically active amyloid."

The group has also reported proof-of-concept data in a mouse model of sepsis, using aggregating peptides identified in a screen against methicillin-resistant Staphylococcus aureus. The precise molecular targets were not reported in that study, which appeared in the March 2016 issue of Molecular Microbiology, in a paper, titled "Protein aggregation as an antibiotic design strategy."

At this point, the work begins in earnest, in converting the company's understanding of the genomic signatures of protein aggregation into drug-like molecules – no small task when the molecules in question are peptides, which are notoriously unstable and difficult to get across cell membranes. The company aims to obtain phase I data from its lead program five years from now, Beirnaert said.