Gene Therapy for Fibrodysplasia Ossificans Progressiva: Feasibility and Obstacles

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare and devastating genetic disease, in which soft connective tissue is converted into heterotopic bone through an endochondral ossification process. Patients succumb early as they gradually become trapped in a second skeleton of heterotopic bone. Although the underlying genetic defect is long known, the inherent complexity of the disease has hindered the discovery of effective preventions and treatments. New developments in the gene therapy field have motivated its consideration as an attractive therapeutic option for FOP. However, the immune system's role in FOP activation and the as-yet unknown primary causative cell, are crucial issues which must be taken into account in the therapy design. While gene therapy offers a potential therapeutic solution, more knowledge about FOP is needed to enable its optimal and safe application.

Keywords: ALK2 mutation; RNA; fibrodysplasia ossificans progressiva; gene therapy; heterotopic ossification.

Figure 1.

A flare-up with swelling of the back of a young girl diagnosed with FOP. Image is reproduced with the written consent of the patient and her parents. FOP, fibrodysplasia ossificans progressiva.

Figure 2.

Overview of FOP mutations in the exons of the different domains of the ACVR1 gene. Figure 2 was created with biorender.com. EC, extracellular; GS, glycine-serine rich; KD, kinase domain; TM, transmembrane; UTR, untranslated region.

Figure 3.

Two ways to express therapeutic genes in target cells and/or tissues. (1) Ex vivo gene therapy: genetic modification is executed on isolated patient cells using a viral vector, and after cell expansion in the culture, treated cells are introduced to patients via infusion. (2) In vivo gene therapy: AAV vector carrying a therapeutic gene is directly introduced to patient via systemic or local administration. AAV, adeno-associated virus.