7 research outputs found
The response of pigs inoculated with a thymidine kinase-negatrive (TK-) pseudorabies virus to challenge infection with virulent virus
High incidence of improvement after autolugus in relapse-remitting phase of multiple sclerosis
Autologous HSCT for severe progressive Multiple Sclerosis in a multicenter trial: impact on disease activity and quality of life
Hematopoietic stem cell transplantation
(HSCT) has been proposed for the treatment
of severe multiple sclerosis (MS). In
a phase 2 multicenter study we selected
19 non–primary progressive MS patients
showing high disease activity on the basis
of both brain magnetic resonance
imaging (MRI) and sustained clinical deterioration
despite conventional treatments.
After stem cell mobilization with cyclophosphamide
(CY) and filgrastim, patients
were conditioned with BCNU (1,3-
bis(2-chloroethyl)-1-nitrosourea), cytosine
arabinoside, etoposide, and melphalan
(BEAM) followed by antithymocyte globulin
(ATG). Unmanipulated peripheral blood stem
cells (PBSCs) were then infused. No maintenance
treatment was administered with a
median follow-up of 36 months (range, 12 to
72 months). All patients showed clinical
stabilization or improvement; 3 subsequently
deteriorated, 1 beyond the baseline.
No MRI active lesions were detected after
the HSCT except in 1 patient who showed a
new lesion at 4.5 years. Infections were
limitedandrestricted to 3monthsafterHSCT.
Health-related quality of life was assessed
through the 54-item MS quality of life
(MSQOL-54) questionnaire, showing a statistically
significant improvement in both composite
scores and in most of the individual
domains. HSCT is able to induce a prolonged
clinical stabilization in severe progressive
MS patients, resulting in both
sustained treatment-free periods and
quality of life improvemen
Autologus HSCT induce a sustained inhibition of new MRI lesions in severe refractory Multple Slerosis. Long term results of a prospective multicenter trial
Successful use of Out-of-Frame Exon 2 Skipping induces IRES-Driven expression of the N-Truncated dystrophin isoform: promising approach for treating other 5 ' Dystrophin Mutations
Most mutations that truncate the reading frame of the DMD gene result in loss of dystrophin expression and lead to the most common childhood muscle disease, the severe and progressive Duchenne muscular dystrophy. However, frame-truncating mutations within the first five exons of the DMD gene typically do not result in Duchenne muscular dystrophy, but instead result in milder dystrophinopathy syndromes as originally observed in patients with very mild clinical features despite nonsense mutations in exon 1. We have previously shown that amelioration of disease severity result from the expression of a highly functional N-truncated dystrophin beginning in exon 6 of the DMD. Here we demonstrate that this protein represents a novel dystrophin isoform resulting from usage of an internal ribosome entry site (IRES) within exon 5 that is glucocorticoid-inducible. In vitro studies with bicistronic reporter assays demonstrate translation at levels approximately 60% of the well-known viral IRES (eMCV), suggesting a relatively strong activity. Activity in humans was confirmed in patient muscle tissues using ribosome profiling and mass-spectrometric peptide sequencing. The resultant N-truncated dystrophin protein produced from this IRES, lacks the first calponin homology domain of the canonical actin binding domain 1. Nevertheless, it is highly functional, raising the possibility of the therapeutic use of this isoform. We use a novel out-of-frame exon-skipping approach to generate a truncated reading frame upstream of the IRES in both patient-derived cell lines and in a new DMD mouse model, leading to synthesis of a functional N-truncated isoform. In the mouse, this expression protects muscle from contraction-induced injury and corrects muscle force to the same level as control mice. Together these results support a novel therapeutic approach for patients with mutations within the 5' exons of DMD