ABSTRACT
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.
Subject(s)
Genetic Therapy/methods , Muscle Strength/genetics , Muscular Dystrophy, Oculopharyngeal/therapy , Myoblasts, Skeletal/metabolism , Poly(A)-Binding Protein I/genetics , Transcriptome/genetics , Animals , Disease Models, Animal , Gene Knockdown Techniques/methods , HEK293 Cells , Humans , In Vitro Techniques , Mice , Mice, Transgenic , Muscular Dystrophy, Oculopharyngeal/physiopathology , Trinucleotide Repeat ExpansionABSTRACT
AIM: The clinical usefulness of 2-deoxy-2-[F-18]fluoro-D-glucose-positron emission tomography (FDG-PET) in head and neck squamous cell carcinoma (HNSCC) is now well-documented. However, its sensitivity is greater than its specificity due to false-positive results in inflammatory or infectious lesions, which are frequent in this area, in particular after treatment by surgery and/or radiotherapy. O-2-fluoro-(18F)-ethyl-L-thyrosine (FET) has been reported not to be taken up by such lesions, and a preliminary study indicated that this may be clinically useful in HNSCC. We performed a prospective study to compare the diagnostic performances of FDG and FET PET/CT in the different settings of HNSCC. MATERIALS AND METHODS: Twenty-seven patients (20 men and seven women, aged 48-76, among 30 patients included) and 69 suspected cancer sites are now evaluable on basis of postsurgical histology and/or follow-up greater than 6 months; 15 patients were referred for initial staging and 12 during posttherapy follow-up, a recurrence being suspected in eight of them. FDG and FET PET/CT were performed on two different days, the patient fasting for 6 h, 1 h after injection of 5 MBq/kg of body mass of each radiopharmaceutical. Both PET/CT examinations were blind read more than 6 months after the end of inclusions in a random order for each tracer and with a time interval greater than 1 month between FDG and FET PET/CT blind readings. RESULTS: Overall diagnostic performances, derived from blind reading: FDG PET/CT on a per patient basis: sensitivity 100%, specificity 71%, accuracy 93%; FDG PET/CT on a per site basis: sensitivity 95%, specificity 63%, accuracy 83%; FET PET/CT on a per patient basis: sensitivity 70%, specificity 100%, accuracy 78%; FET PET/CT on a per site basis: sensitivity 64%, specificity 100%, accuracy 78%. At site level, sensitivity was significantly greater with FDG (p<0.02) and specificity with FET (p<0.01). The statistical level of significance was not reached at patient level. CONCLUSION: Although its good specificity was confirmed, FET did not appear to be suited as a first-line PET tracer in HNSCC imaging and cannot replace FDG for staging due to insufficient sensitivity. However, it was useful in a few selected cases to favor a wait and see attitude when a FDG+ FET- focus was discovered in patients referred for systematic FDG PET during follow-up. In contrast, second primary cancers should not be ruled out if FDG was clearly positive in the lungs or the digestive tract.
