Neuromuscular disorders are a large group of rare pathologies characterised by skeletal muscle atrophy and weakness, with the common involvement of respiratory and/or cardiac muscles. These diseases ...lead to life-long motor deficiencies and specific organ failures, and are, in their worst-case scenarios, life threatening. Amongst other causes, they can be genetically inherited through mutations in more than 500 different genes. In the last 20 years, specific pharmacological treatments have been approved for human usage. However, these "à-la-carte" therapies cover only a very small portion of the clinical needs and are often partially efficient in alleviating the symptoms of the disease, even less so in curing it. Recombinant adeno-associated virus vector-mediated gene transfer is a more general strategy that could be adapted for a large majority of these diseases and has proved very efficient in rescuing the symptoms in many neuropathological animal models. On this solid ground, several clinical trials are currently being conducted with the whole-body delivery of the therapeutic vectors. This review recapitulates the state-of-the-art tools for neuron and muscle-targeted gene therapy, and summarises the main findings of the spinal muscular atrophy (SMA), Duchenne muscular dystrophy (DMD) and X-linked myotubular myopathy (XLMTM) trials. Despite promising efficacy results, serious adverse events of various severities were observed in these trials. Possible leads for second-generation products are also discussed.
The R-spondin (Rspo) proteins constitute a novel class of ligands that induce Wnt signalling.
Rspo1 knockout XX mice were previously shown to be sex-reversed, but some remain sub-fertile. These last ...were unable to feed their pups for some unknown reason. Using these mice and transplanted mammary tissues from
Rspo1
−/− virgin mice in nude mice, we report that the lack of
Rspo1 expression results in the absence of duct side-branching development and subsequent alveolar formation, explaining the above mentioned phenotype. Our data demonstrate that local epithelial Rspo1 signalling is required for normal development of the mammary gland.
X-linked myotubular myopathy (XLMTM) results from MTM1 gene mutations and myotubularin deficiency. Most XLMTM patients develop severe muscle weakness leading to respiratory failure and death, ...typically within 2 years of age. Our objective was to evaluate the efficacy and safety of systemic gene therapy in the p.N155K canine model of XLMTM by performing a dose escalation study. A recombinant adeno-associated virus serotype 8 (rAAV8) vector expressing canine myotubularin (cMTM1) under the muscle-specific desmin promoter (rAAV8-cMTM1) was administered by simple peripheral venous infusion in XLMTM dogs at 10 weeks of age, when signs of the disease are already present. A comprehensive analysis of survival, limb strength, gait, respiratory function, neurological assessment, histology, vector biodistribution, transgene expression, and immune response was performed over a 9-month study period. Results indicate that systemic gene therapy was well tolerated, prolonged lifespan, and corrected the skeletal musculature throughout the body in a dose-dependent manner, defining an efficacious dose in this large-animal model of the disease. These results support the development of gene therapy clinical trials for XLMTM.
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Mack and colleagues conducted a gene therapy dose-finding study in a dog model of X-linked myotubular myopathy (XLMTM), a severe monogenic muscle disease. A single systemic treatment prolonged lifespan and corrected skeletal musculature throughout the body in a dose-dependent manner. These data support development of gene therapy clinical trials for XLMTM.
Abstract
N
6
-threonyl-carbamoylation of adenosine 37 of ANN-type tRNAs (t
6
A) is a universal modification essential for translational accuracy and efficiency. The t
6
A pathway uses two ...sequentially acting enzymes, YRDC and OSGEP, the latter being a subunit of the multiprotein KEOPS complex. We recently identified mutations in genes encoding four out of the five KEOPS subunits in children with Galloway-Mowat syndrome (GAMOS), a clinically heterogeneous autosomal recessive disease characterized by early-onset steroid-resistant nephrotic syndrome and microcephaly. Here we show that mutations in
YRDC
cause an extremely severe form of GAMOS whereas mutations in
GON7
, encoding the fifth KEOPS subunit, lead to a milder form of the disease. The crystal structure of the GON7/LAGE3/OSGEP subcomplex shows that the intrinsically disordered GON7 protein becomes partially structured upon binding to LAGE3. The structure and cellular characterization of GON7 suggest its involvement in the cellular stability and quaternary arrangement of the KEOPS complex.
N
-threonyl-carbamoylation of adenosine 37 of ANN-type tRNAs (t
A) is a universal modification essential for translational accuracy and efficiency. The t
A pathway uses two sequentially acting ...enzymes, YRDC and OSGEP, the latter being a subunit of the multiprotein KEOPS complex. We recently identified mutations in genes encoding four out of the five KEOPS subunits in children with Galloway-Mowat syndrome (GAMOS), a clinically heterogeneous autosomal recessive disease characterized by early-onset steroid-resistant nephrotic syndrome and microcephaly. Here we show that mutations in YRDC cause an extremely severe form of GAMOS whereas mutations in GON7, encoding the fifth KEOPS subunit, lead to a milder form of the disease. The crystal structure of the GON7/LAGE3/OSGEP subcomplex shows that the intrinsically disordered GON7 protein becomes partially structured upon binding to LAGE3. The structure and cellular characterization of GON7 suggest its involvement in the cellular stability and quaternary arrangement of the KEOPS complex.
RSPO1
is a newly discovered gene involved in sex differentiation. Two goat BAC clones encompassing the
RSPO1
gene (
gRSPO1
) were injected into mouse oocytes and several transgenic lines derived. ...Both clones induced
gRSPO1
over-expression in various tissues, including male and female gonads, with no obvious phenotype and normal sex-ratios. Introgression of the
gRSPO1
transgene into a mouse
RSPO1
knockout genotype resulted in the rescue of the fertility and the disappearance of the masculinized gonadic features of the females, demonstrating the functionality of the goat protein in a mouse context. On the contrary, over-expression of
gRSPO1
within a
mSRY
or a
gSRY
-XX genotypes did not interfere with the
SRY
-induced male phenotype.
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