ABSTRACT
INTRODUCTION: Antisense nucleic acid analogues can interact with pre-mRNA motifs and influence exon or splice site selection and thereby alter gene expression. Design of antisense molecules to target specific motifs can result in either exon exclusion or exon inclusion during splicing. Novel drugs exploiting the antisense concept are targeting rare, life-limiting diseases; however, the potential exists to treat a wide range of conditions by antisense-mediated splice intervention. Areas covered: In this review, the authors discuss the clinical translation of novel molecular therapeutics to address the fatal neuromuscular disorders Duchenne muscular dystrophy and spinal muscular atrophy. The review also highlights difficulties posed by issues pertaining to restricted participant numbers, variable phenotype and disease progression, and the identification and validation of study endpoints. Expert opinion: Translation of novel therapeutics for Duchenne muscular dystrophy and spinal muscular atrophy has been greatly advanced by multidisciplinary research, academic-industry partnerships and in particular, the engagement and support of the patient community. Sponsors, supporters and regulators are cooperating to deliver new drugs and identify and define meaningful outcome measures. Non-conventional and adaptive trial design could be particularly suited to clinical evaluation of novel therapeutics and strategies to treat serious, rare diseases that may be problematic to study using more conventional clinical trial structures.
Subject(s)
Exons/genetics , Genetic Therapy/trends , Muscular Dystrophy, Duchenne/drug therapy , Oligonucleotides, Antisense/therapeutic use , RNA Splicing/genetics , Translational Research, Biomedical/methods , Animals , Biological Therapy/methods , Biological Therapy/trends , Dystrophin/genetics , Exons/drug effects , Gene Expression , Gene Expression Regulation , Genetic Therapy/methods , Humans , Muscular Atrophy, Spinal/drug therapy , Muscular Atrophy, Spinal/genetics , Muscular Dystrophy, Duchenne/genetics , Oligonucleotides, Antisense/genetics , Oligonucleotides, Antisense/pharmacology , RNA Splicing/drug effects , Translational Research, Biomedical/trendsABSTRACT
The Leucine-rich repeat kinase 2 (LRRK2) gene has been identified as a disease susceptibility gene for Parkinson's disease (PD), with G2019 (6055G>A) being the most frequent mutation. This mutation was present in 42% (38/91) of Tunisian families and 2% (1/39) of US families we have studied. A founding haplotype was identified in our data and it is shared by families from Tunisia, US, European and Middle Eastern countries. The most recent common founder of the mutation was dated to 2600 (95% CI: 1950-3850) years ago although additional studies are warranted to ensure an accurate age estimate for this mutation.
Subject(s)
Founder Effect , Haplotypes , Parkinson Disease/genetics , Protein Serine-Threonine Kinases/genetics , Adult , Aged , Europe , Female , Genotype , Humans , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 , Male , Middle Aged , Middle East , Mutation , Polymorphism, Single Nucleotide , Tunisia , United StatesABSTRACT
En las dos primeras partes de este texto nos cntraremos esencialmente sobre los aportes de Piaget y de Vygotsky a la pedagogia. Comparando la teoria de estos dos especialistas de la psicologia del desarrollo, tendremos la ocasion de ir mas alla de la tradicional antinomia Vygotsky-Piaget.
Subject(s)
Psychology, Educational , Education , Teaching , Psychology, Educational , Education , TeachingABSTRACT
Efficiency of regeneration of mechanically injured skeletal muscle is more pronounced in SJL/J mice, as compared to other laboratory strains in which regenerative properties of skeletal muscle are uniformly poor. Previously, we postulated that a small number of genes might differ between SJL/J and other mouse strains, and would be responsible for this variation in the efficiency of skeletal muscle regeneration. The results of initial experiments demonstrated that SJL/J mice have a unique form of the myogenic gene, Myo-D1, which partly influences efficiency of skeletal muscle repair, and that other genes were also involved. To identify other candidate genes, differences were sought within the myogenic paired box/homeobox-containing gene Pax7 between SJL/J and other laboratory mouse strains. Southern blotting indicated that SJL/J, Quackenbush and DDO mice share a Pax7/TaqI RFLP which differs from all other laboratory strains tested. This RFLP is most likely due to sequence differences within the homeobox of a Pax7-like gene. In vivo studies revealed that Quackenbush and DDO mice also share the same regenerative properties of mechanically damaged skeletal muscle as SJL/J mice. Since Quackenbush and DDO mice lack the SJL/J type of Myo-D1, and DDO belong to a different mouse sub-species, these studies suggest that structural alterations in the homeobox of a Pax7-like gene may be implicated in the effectiveness of renewal of damaged skeletal muscle of the limb in the mature animal.
