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Gene therapy rescues disease phenotype in a spinal muscular atrophy with respiratory distress type 1 (SMARD1) mouse model.

Nizzardo M, Simone C, Rizzo F, Salani S, Dametti S, Rinchetti P, Del Bo R, Foust K, Kaspar BK, Bresolin N, Comi GP, Corti S - Sci Adv (2015)

Bottom Line: It is caused by mutations in the IGHMBP2 gene (11q13) and presently has no cure.AAV9-IGHMBP2 administration restored protein levels and rescued motor function, neuromuscular physiology, and life span (450% increase), ameliorating pathological features in the central nervous system, muscles, and heart.To test this strategy in a human model, we transferred wild-type IGHMBP2 into human SMARD1-induced pluripotent stem cell-derived motor neurons; these cells exhibited increased survival and axonal length in long-term culture.

View Article: PubMed Central - PubMed

Affiliation: Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, and Neurology Unit, IRCCS Foundation Ca' Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy.

ABSTRACT
Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an autosomal recessive motor neuron disease affecting children. It is caused by mutations in the IGHMBP2 gene (11q13) and presently has no cure. Recently, adeno-associated virus serotype 9 (AAV9)-mediated gene therapy has been shown to rescue the phenotype of animal models of another lower motor neuron disorder, spinal muscular atrophy 5q, and a clinical trial with this strategy is ongoing. We report rescue of the disease phenotype in a SMARD1 mouse model after therapeutic delivery via systemic injection of an AAV9 construct encoding the wild-type IGHMBP2 to replace the defective gene. AAV9-IGHMBP2 administration restored protein levels and rescued motor function, neuromuscular physiology, and life span (450% increase), ameliorating pathological features in the central nervous system, muscles, and heart. To test this strategy in a human model, we transferred wild-type IGHMBP2 into human SMARD1-induced pluripotent stem cell-derived motor neurons; these cells exhibited increased survival and axonal length in long-term culture. Our data support the translational potential of AAV-mediated gene therapies for SMARD1, opening the door for AAV9-mediated therapy in human clinical trials.

No MeSH data available.


Related in: MedlinePlus

AAV9-IGHMBP2 increases motor neuron and axon number.(A) Representative motor neuron pools in the lumbar segment of the spinal cords of AAV9-IGHMBP2-nmd, AAV9--nmd, and WT mice at 4 weeks of age. (B) Quantification of motor neurons in the lumbar spinal cords of treated mice and WT mice (mean ± SD) at 4 weeks of age (n = 6 per group per time point). (C) Quantification of myelinated axons in the L4 anterior roots in WT, AAV9-IGHMBP2-nmd, and AAV9- nmd mice (mean ± SD) at 4 weeks of age (n = 6 per group per time point). Motor neuron and myelinated axon counts significantly increased in the AAV9-IGHMBP2 treatment group compared to the AAV9- group (*P < 0.0001). (D) Representative images of the L4 anterior roots of AAV9-IGHMBP2-nmd, AAV9--nmd, and WT mice at 4 weeks of age. Scale bar, 50 μm (A and D).
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Figure 2: AAV9-IGHMBP2 increases motor neuron and axon number.(A) Representative motor neuron pools in the lumbar segment of the spinal cords of AAV9-IGHMBP2-nmd, AAV9--nmd, and WT mice at 4 weeks of age. (B) Quantification of motor neurons in the lumbar spinal cords of treated mice and WT mice (mean ± SD) at 4 weeks of age (n = 6 per group per time point). (C) Quantification of myelinated axons in the L4 anterior roots in WT, AAV9-IGHMBP2-nmd, and AAV9- nmd mice (mean ± SD) at 4 weeks of age (n = 6 per group per time point). Motor neuron and myelinated axon counts significantly increased in the AAV9-IGHMBP2 treatment group compared to the AAV9- group (*P < 0.0001). (D) Representative images of the L4 anterior roots of AAV9-IGHMBP2-nmd, AAV9--nmd, and WT mice at 4 weeks of age. Scale bar, 50 μm (A and D).

Mentions: To evaluate the impact of gene therapy on neuropathological SMARD1 hallmarks, we analyzed spinal cord motor neurons and ventral spinal nerve roots in 4-week-old mice. We detected a severe loss of motor neurons in AAV9--nmd mice compared to wild-type mice (Fig. 2). In contrast, in association with the increase in IGHMBP2 expression, we detected consistent preservation of the number of motor neurons in AAV9-IGHMBP2-nmd mice (Fig. 2A). In all analyzed sections, the number of motor neurons in AAV9-IGHMBP2-nmd mice was significantly higher than that in AAV9--nmd littermates (P < 0.01; Fig. 2B).


Gene therapy rescues disease phenotype in a spinal muscular atrophy with respiratory distress type 1 (SMARD1) mouse model.

Nizzardo M, Simone C, Rizzo F, Salani S, Dametti S, Rinchetti P, Del Bo R, Foust K, Kaspar BK, Bresolin N, Comi GP, Corti S - Sci Adv (2015)

AAV9-IGHMBP2 increases motor neuron and axon number.(A) Representative motor neuron pools in the lumbar segment of the spinal cords of AAV9-IGHMBP2-nmd, AAV9--nmd, and WT mice at 4 weeks of age. (B) Quantification of motor neurons in the lumbar spinal cords of treated mice and WT mice (mean ± SD) at 4 weeks of age (n = 6 per group per time point). (C) Quantification of myelinated axons in the L4 anterior roots in WT, AAV9-IGHMBP2-nmd, and AAV9- nmd mice (mean ± SD) at 4 weeks of age (n = 6 per group per time point). Motor neuron and myelinated axon counts significantly increased in the AAV9-IGHMBP2 treatment group compared to the AAV9- group (*P < 0.0001). (D) Representative images of the L4 anterior roots of AAV9-IGHMBP2-nmd, AAV9--nmd, and WT mice at 4 weeks of age. Scale bar, 50 μm (A and D).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4643829&req=5

Figure 2: AAV9-IGHMBP2 increases motor neuron and axon number.(A) Representative motor neuron pools in the lumbar segment of the spinal cords of AAV9-IGHMBP2-nmd, AAV9--nmd, and WT mice at 4 weeks of age. (B) Quantification of motor neurons in the lumbar spinal cords of treated mice and WT mice (mean ± SD) at 4 weeks of age (n = 6 per group per time point). (C) Quantification of myelinated axons in the L4 anterior roots in WT, AAV9-IGHMBP2-nmd, and AAV9- nmd mice (mean ± SD) at 4 weeks of age (n = 6 per group per time point). Motor neuron and myelinated axon counts significantly increased in the AAV9-IGHMBP2 treatment group compared to the AAV9- group (*P < 0.0001). (D) Representative images of the L4 anterior roots of AAV9-IGHMBP2-nmd, AAV9--nmd, and WT mice at 4 weeks of age. Scale bar, 50 μm (A and D).
Mentions: To evaluate the impact of gene therapy on neuropathological SMARD1 hallmarks, we analyzed spinal cord motor neurons and ventral spinal nerve roots in 4-week-old mice. We detected a severe loss of motor neurons in AAV9--nmd mice compared to wild-type mice (Fig. 2). In contrast, in association with the increase in IGHMBP2 expression, we detected consistent preservation of the number of motor neurons in AAV9-IGHMBP2-nmd mice (Fig. 2A). In all analyzed sections, the number of motor neurons in AAV9-IGHMBP2-nmd mice was significantly higher than that in AAV9--nmd littermates (P < 0.01; Fig. 2B).

Bottom Line: It is caused by mutations in the IGHMBP2 gene (11q13) and presently has no cure.AAV9-IGHMBP2 administration restored protein levels and rescued motor function, neuromuscular physiology, and life span (450% increase), ameliorating pathological features in the central nervous system, muscles, and heart.To test this strategy in a human model, we transferred wild-type IGHMBP2 into human SMARD1-induced pluripotent stem cell-derived motor neurons; these cells exhibited increased survival and axonal length in long-term culture.

View Article: PubMed Central - PubMed

Affiliation: Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, and Neurology Unit, IRCCS Foundation Ca' Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy.

ABSTRACT
Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an autosomal recessive motor neuron disease affecting children. It is caused by mutations in the IGHMBP2 gene (11q13) and presently has no cure. Recently, adeno-associated virus serotype 9 (AAV9)-mediated gene therapy has been shown to rescue the phenotype of animal models of another lower motor neuron disorder, spinal muscular atrophy 5q, and a clinical trial with this strategy is ongoing. We report rescue of the disease phenotype in a SMARD1 mouse model after therapeutic delivery via systemic injection of an AAV9 construct encoding the wild-type IGHMBP2 to replace the defective gene. AAV9-IGHMBP2 administration restored protein levels and rescued motor function, neuromuscular physiology, and life span (450% increase), ameliorating pathological features in the central nervous system, muscles, and heart. To test this strategy in a human model, we transferred wild-type IGHMBP2 into human SMARD1-induced pluripotent stem cell-derived motor neurons; these cells exhibited increased survival and axonal length in long-term culture. Our data support the translational potential of AAV-mediated gene therapies for SMARD1, opening the door for AAV9-mediated therapy in human clinical trials.

No MeSH data available.


Related in: MedlinePlus