Treatment for a Rare Genetic Skeletal Dysplasia

Background

Mutation in the membrane-bound transcription factor peptidase site 1 (MBTPS1) gene leads to a rare genetic skeletal disorder called Spondyloepiphyseal dysplasia, Kondo-Fu type (SEDKF). Currently, there are only 11 patients identified with this defect. This small number of patients is likely due to the fact that SEDKF patients have clinical features that overlap with type II collagenopathy patients leading to the SEDKF patients being misdiagnosed. Clinical presentations of patients with mutations in the MBTPS1 gene include spondyloepiphyseal dysplasia with associated kyphosis, dysmorphic facial features, retarded growth with skeletal abnormalities, decreased bone mineral density, and elevated plasma levels of lysosomal enzymes ().

The MBTPS1 gene encodes Site‑1 Protease (S1P), a key serine protease in the Golgi required for intracellular transportation of large molecules such as collagen; targeting lysosomal enzymes to lysosomes; and lipid metabolism. MBTPS1 gene mutation causes S1P deficiency due to alternative splicing resulting in premature termination. S1P deficiency is associated with abnormal accumulation of collagen in endoplasmic reticulum (ER) and elevated blood lysosomal enzymes (). Lack of S1P also causes defective unfolded protein response and subsequent cell death owing to collagen accumulation in the ER of the patient chondrocytes. ER retention of collagen in chondrocytes results in chondrocyte apoptosis and bone matrix degradation (). While ER dysfunction is common in genetic skeletal disorders, to date, there is no treatment targeting ER stress responses in these disorders.

Technology Overview

A team of OMRF researchers have demonstrated that treatment of SEDKF patient fibroblasts with a chemical chaperone sodium phenlybutyrate (PBA) or an ER chaperone inducer BiP (immunoglobulin heavy-chain binding protein) inducer X (BIX) decreases the accumulation of collagen I in chondrocytes and enhances collagen secretion (). Treatment with antisense morpholino oligos (AMO) corrects the mutation in the MBTPS1 gene which also results in increased collagen I secretion in patient fibroblasts ().

Treatment with the proposed therapeutics enhances collagen secretion from ER by reducing ER stress and can be used for treating subjects with mutations in S1P-encoding gene, MBTPS1 ().

Further Details

Publication

Stage of Development

This technology is at the stage of preclinical validation.

Benefits

Currently, there is no standard treatment for SEDKF. Patients can be managed with symptomatic/supportive treatment. OMRF findings may lead to new therapies for SEDKF and other similar genetic skeletal diseases.

Applications

Genetic skeletal diseases constitute a large and diverse group. Although each individual disease is rare, collectively, they are common (1 per 4,000 children) and have very few therapeutic options. Cartilage related disorders, that account for the majority of skeletal dysplasia, are frequently associated with ER stress. Lifelong treatment with chemical chaperones and ER chaperone inducers could be a potential therapy for ER stress-induced skeletal dysplasias such as SEDKF.

Opportunity

Licensing and sponsored research.