Enabling topical drug delivery of biologics across skin

Grantee: Niclas Roxhed, Associate Professor, KTH Royal Institute of Technology

Amount: DKK 4,031,088

Grant category: Research Grants in open competition

Year: 2024

Geography: Sweden

Niclas Roxhed’s technology-focused project aims to investigate the potential of spiked microspheres as vehicles for large-molecular drug delivery into skin to treat diseases.

Modern biologic drugs have transformed the way we treat many diseases. However, these drug molecules are too large to pass biologic barriers and therefore need to be injected. For skin diseases, the outermost skin layer effectively prevents larger molecules from entering the skin.

To address this problem, Niclas Roxhed and his team have tailor-made ultra-sharp spiked microspheres that painlessly penetrate only the outermost skin layer and allow delivery of large molecules into skin. In this project, they will use these spiked microspheres in an atopic dermatitis model to topically deliver large-molecular nucleic acids and nanocarriers to inhibit inflammatory reactions. To verify effective delivery, Niclas Roxhed and his team will quantify inflammatory markers in skin using micro-sampling and proteomics profiling.

The results could form the basis for highly effective delivery of biopharmaceuticals as topical creams and potentially revolutionize treatment strategies in skin disease.

Structural dissection and dynamic insights into the molecular switch of mast cells and basophils: a blueprint for novel urticaria therapies

Grantee: Rosaria Gandini, Assistant Professor, Aarhus University

Amount: DKK 3,462,144

Grant category: Research Grants in open competition

Year: 2024

Geography: Denmark

Deciphering the cellular and molecular role of mitophagy in wound healing

Grantee: Jakob Wikstrom, Associate Professor, Karolinska Institutet

Amount: DKK 4,302,900

Grant category: Research Grants in open competition

Year: 2024

Geography: Sweden

Epigenetic regulation of sebaceous gland development and homeostasis

Grantee: Brian Capell, Assistant Professor, University of Pennsylvania

Amount: DKK 2,885,457

Grant category: Research Grants in open competition

Year: 2024

Geography: USA

Brian Capell’s project seeks to better understand how epigenetic changes (modifications that do not change the sequence of genomic DNA) regulate the development of sebaceous glands.

Dysfunction of sebaceous glands (SGs) has been linked to a variety of common skin disorders ranging from atopic dermatitis to acne, sebaceous hyperplasia, seborrheic dermatitis and sebaceous tumors.

Brian Capell and his team have recently discovered that through genetic modification of the epigenome, they could promote a dramatic increase in the number and size of SGs (Ko, et al. Developmental Cell. In press. 2024). This surprising result demonstrated the direct role that epigenetics and chromatin organization plays in controlling SG development and abundance. It also suggested that targeting the epigenome might offer new ways to treat disorders characterized by aberrant SG development and activity.

Diseases related to aberrant SG development or activity can have a deleterious effect on both human physical and mental health. Despite this, very little is known of the role of epigenetics in SG development and homeostasis. To address this, Brian Capell’s project aims to test the influence of epigenomic modifiers and modifications upon SG development and disease to further dissect their contribution to the pathogenesis of these very common conditions.

Collectively, this project will address outstanding questions regarding the role of the epigenome in SG development and homeostasis and in common diseases driven by SG dysfunction – diseases that are both understudied and in need of better therapies.

Single-cell ribosome profiling to monitor the translational landscape in skin wound healing

Grantee: Ataman Sendoel, Assistant Professor, University of Zurich

Amount: DKK 3,979,800

Grant category: Research Grants in open competition

Year: 2024

Geography: Switzerland

Protein stability and misfolding in keratin disorders

Grantee: Rasmus Hartmann-Petersen, Professor, University of Copenhagen

Amount: DKK 2,600,678

Grant category: Research Grants in open competition

Year: 2024

Geography: Denmark

Rasmus Hartmann-Petersen’s project aims to characterize all possible missense variants (changes in genes which introduce a different amino acid in the resulting protein) in human keratins and investigate the importance of these variants in associated diseases.

Keratins are intermediate filament proteins that form a cytoskeletal network within cells. They are expressed in a tissue-specific fashion and form heterodimers, which then further oligomerize into filaments. Variants in several keratin encoding genes are linked to a range of hereditary disorders, including several epidermal skin diseases. On the molecular level, some pathogenic keratin variants appear to cause aggregation of the keratins.

In Rasmus Hartmann-Petersen’s project it is hypothesized that most keratin-disorders are protein misfolding diseases, i.e. diseases where the underlying genetic variants cause misfolding of the encoding protein. Rasmus and his team aim to explore this hypothesis by using computational tools, including large language models (a specific form of AI). They will test the validity of the computational predictions through focused cellular studies on selected keratins and identify components regulating keratin turnover.

The results will highlight the underlying molecular mechanisms for keratin-linked human disorders and provide predictions on the severity of all possible (both known and yet unobserved) coding variants in human keratin genes. The results could be of diagnostic value, but may also highlight the cellular protein folding and protein quality control machinery as potential therapeutic targets.

Architecture of the Herpes simplex replication machinery and its inhibitors

Grantee: Eva Kummer, Associate Professor, Copenhagen University

Amount: DKK 4,902,307

Grant category: Research Grants in open competition

Year: 2024

Geography: Denmark

Eva Kummer’s project targets to improve our understanding of the replication machinery of the skin-infecting herpes simplex virus (HSV) in order to improve and expand treatment opportunities.

HSV is one of the most widespread viral infections. The virus persists lifelong in the nerve system of the host and causes recurrent infections with mild to severe symptoms.

Since decades, treatment of herpes infections has exclusively targeted the viral replicative DNA polymerase (an enzyme that copies the viral DNA) using nucleoside analogs. However, resistance to current nucleoside analogs is emerging necessitating the search for alternative targets.

A major caveat in developing anti-herpetic compounds is a lack of structural information of other components of the herpes simplex replication system, which are likely strong candidates for targeted drug development. Eva Kummer and her team will use cryo-electron microscopy to visualize the architecture and working principles of the protein complexes that drive herpes simplex replication. They will also aim to clarify how novel anti-herpetic drugs block the viral replication machinery and why naturally occurring resistance mutations inhibit their action.

Overall, the project will generate structural and functional insights of the HSV replication strategy and potentially improve and accelerate anti-viral drug design.

SKINSTRUCT – Human skin structural cells instruct T cell tissue adaptation

Grantee: Georg Stary, Associate Professor, Medical University of Vienna

Amount: DKK 3,996,806

Grant category: Research Grants in open competition

Year: 2024

Geography: Austria

Endothelial senescence in the pathogenesis of systemic sclerosis

Grantee: Eliza Pei-Suen Tsou, Assistant Professor, University of Michigan

Amount: DKK 3,990,092

Grant category: Research Grants in open competition

Year: 2024

Geography: USA

Understanding structural and functional differences between JAK family JH1 and JH2 domains

Grantee: Christopher Bunick, Associate Professor, Yale University

Amount: DKK 4,165,955

Grant category: Research Grants in open competition

Year: 2024

Geography: USA