PABPN1 gene therapy for oculopharyngeal muscular dystrophy.

Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant, late-onset muscle disorder characterized by ptosis, swallowing difficulties, proximal limb weakness and nuclear aggregates in skeletal muscles. OPMD is caused by a trinucleotide repeat expansion in the PABPN1 gene that results in an N-terminal expanded polyalanine tract in polyA-binding protein nuclear 1 (PABPN1). Here we show that the treatment of a mouse model of OPMD with an adeno-associated virus-based gene therapy combining complete knockdown of endogenous PABPN1 and its replacement by a wild-type PABPN1 substantially reduces the amount of insoluble aggregates, decreases muscle fibrosis, reverts muscle strength to the level of healthy muscles and normalizes the muscle transcriptome. The efficacy of the combined treatment is further confirmed in cells derived from OPMD patients. These results pave the way towards a gene replacement approach for OPMD treatment.

TSH-regulation and goitrogenesis in severe iodine deficiency.

Since goitre prevalence increases sharply during the first two decades of life, age-related changes in the adaptation of the thyroid to iodine deficiency may occur. In order to study this, we have measured serum levels of TSH, T4 and T3 in 247 subjects (age range 5 to 60 years) living in an endemic goitre area of North Algeria (group A) and in 64 control subjects living in the non-iodine deficient city of Algiers (group B). TRH tests were also performed in 88 subjects from the goitrous area and in 30 controls. Patients from group A had significantly higher serum TSH and T3 and lower serum T4 than those from group B. Analysis of group A by age groups revealed significantly higher TSH concentrations in the 2-9 years group and a moderate but significant decrease in the group from 50-59 years. No significant changes were demonstrated for T4 and T3. In the goitrous area, the response of TSH to TRH was exaggerated and prolonged. delta TSH20 was inversely correlated with age. The different age groups showed a significantly progressive and continuous decrease of delta TSH20, delta TSH60, delta TSH120 from age 10-19 to age 50-59 years. Our findings thus show a sharp increase of TSH during the first decades of life, which coincides with the phase of maximal growth of the thyroid gland. These results suggest that TSH plays a definite role in the genesis of endemic goitre. The subsequent progressive decrease of TSH secretion and reserve, with unchanged T4 and T3, imply a gradual development of autonomous activity in longstanding multinodular goitre.