HCR.20.077 – Cell type specific delivery of in vivo gene therapy

Route: Health care research, sickness prevention and treatment

Cluster question: 081 How will our knowledge of genetics play a role in analysing, screening for, and treating diseases?

Rare bone diseases (RBDs) such as Osteogenesis Imperfecta (OI) and Fibrous Dysplasia (FD), are characterized by gene mutations resulting in derailed bone formation, leading to high fracture incidence, deformations, and severely reduced Quality of Life. Current treatments are only symptomatic. To address the cause of the problem the genetic defects have to be repaired to revert aberrant cells to functional osteoblasts, but this requires currently unavailable specific targeting of the dysregulated cells. In previous research, we have developed dual-targeted ‘stealth’ nanoliposomes encompassing a cell-specific surface target, an intracellularly targeted siRNA, a chemotherapeutic drug, and a ‘stealth’ coating to avoid unspecific trapping in other organs such as the liver. Our aim is to develop RBD-targeted nanoliposomes in which gene-modifying compounds will be incorporated, alone or in combination with appropriate bone formation-stimulating drugs. FD, characterized by local lesions of fibrotic bone, will serve as a model for local application of targeted therapy. We will identify FD-enriched surface markers using RNA-seq and proteomics on patient-derived FD material. In parallel, we will design CRISPR/Cas strategies such as prime editing to repair the FD-characteristic GNAS mutation. After assembly in nanoliposomes, delivery efficacy and functional repair will be evaluated first in in vitro FD and control cell cultures, and subsequently in an available mouse FD model to evaluate safety (including biodistribution) and treatment efficacy. OI, a systemic bone disorder with often single-allele mutations in the collagen type 1 genes, causes multiple fractures and skeletal dysplasia already at very young age. Using a similar strategy, we will evaluate both a pharmacological and a gene therapy strategy for the affected allele which are currently being tested in OI mouse models to enhance collagen production. The knowledge gained will subsequently be applied to other osteoblast-dependent rare bone diseases such as Fibrodysplasia Ossificans Progressiva (FOP) and X-linked osteoporosis.


gene therapy, nanotechnology, rare bone diseases, targeted delivery

Other organisations

Erasmus Medical Center (EMC), patientenvereniging Osteogenesis Imperfecta (VOI)


Organisation Amsterdam UMC
Name Dr. M.N. (Marco) Helder
E-mail m.helder@amsterdamumc.nl
Website www.vumc.nl