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.

Suppression of heterotopic ossification in fibrodysplasia ossificans progressiva using AAV gene delivery

“…Thus, our findings provide the first in vivo evidence that AAV-based gene therapy is a promising option for the prevention of HO in FOP. The feasibility and obstacles of AAV-based gene therapy for FOP were further discussed in a recent review article 58 .…”

Navigating the Complex Landscape of Fibrodysplasia Ossificans Progressiva: From Current Paradigms to Therapeutic Frontiers

“…Experimental approaches for FOP, including allele-selective nucleic acid-based RNA knockdown strategies, BMP receptor kinase inhibitors, gene therapy, stem cell therapies, and immuno-therapies, hold promise for both managing symptoms and modifying the course of FOP [23,24,84]. Overall, the pharmacological landscape for FOP is evolving, with the goal of achieving a balance between symptom management and disease modification.…”

“…In the evolving landscape of FOP research, many experimental and prospective approaches are advancing toward translational medicine, numerous approaches transcending the limitations of traditional pharmacotherapies are emerging, each with its own set of promises and challenges. These can be grouped into four main categories: genetic approaches, enzymatic and transcriptional target modulators, stem cell therapies, and immunotherapies [23,24,84]. In addition, there have been some continuous works going on to repurpose drugs for FOP [85].…”

“…These therapeutic strategies primarily focus on the genetic root of the condition, typically mutations in the ACVR1 gene. Approaches such as gene editing, gene addition, gene silencing, and gene replacement are currently being explored [Table 1] [84]. Each approach offers a unique set of advantages and challenges; however, collectively, they aim to rectify or modulate the expression of the mutated gene, thereby alleviating the clinical outcome.…”

“…Drawing parallels from the therapeutic success in monogenic disorders, e.g., lipoprotein lipase deficiency, inherited retinal dystrophy, and spinal muscular atrophy, it is conceivable that extant gene therapies could be efficacious for FOP, as it is also caused by a monogenic gain-of-function mutation in the ACVR1 gene [23,84,94,95]. In general, gene addition aims to introduce genes encoding missing proteins or encoding corrective proteins if a genetic mutation produces defective proteins.…”