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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 treatment improves neuromuscular function and survival in nmd mice.(A) Representative images of AAV9-IGHMBP2-nmd mice showing their capacity to extend their hindlimbs in comparison to AAV9--nmd mice. (B) Rotarod test data. The performance of AAV9-IGHMBP2-nmd mice was significantly improved versus AAV9--nmd mice, which were never able to complete the test (P < 0.0001). Error bars denote SEM. (C) The mean body weight of AAV9-IGHMBP2-nmd mice significantly increased relative to AAV9--nmd mice (P< 0.01). Error bars show SEM. (D) Kaplan-Meier survival curves of AAV9-IGHMBP2-nmd mice and AAV9--nmd mice (P < 0.0001). For all graphs: AAV9-IGHMBP2-nmd mice, n = 17; AAV9--nmd mice, n = 24.
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Figure 4: AAV9-IGHMBP2 treatment improves neuromuscular function and survival in nmd mice.(A) Representative images of AAV9-IGHMBP2-nmd mice showing their capacity to extend their hindlimbs in comparison to AAV9--nmd mice. (B) Rotarod test data. The performance of AAV9-IGHMBP2-nmd mice was significantly improved versus AAV9--nmd mice, which were never able to complete the test (P < 0.0001). Error bars denote SEM. (C) The mean body weight of AAV9-IGHMBP2-nmd mice significantly increased relative to AAV9--nmd mice (P< 0.01). Error bars show SEM. (D) Kaplan-Meier survival curves of AAV9-IGHMBP2-nmd mice and AAV9--nmd mice (P < 0.0001). For all graphs: AAV9-IGHMBP2-nmd mice, n = 17; AAV9--nmd mice, n = 24.

Mentions: We evaluated whether AAV9-IGHMBP2 treatment improved the disease phenotype and extended survival in nmd mice. Functional recovery was assessed in all animal groups through blind evaluation of their general appearance, weight, neuromuscular function, and survival after treatment (Fig. 4). The first clinical symptoms in nmd mice presented in the second postnatal week when mice rapidly developed muscle weakness in the hindlimbs, which were contracted, causing impaired locomotor activity. This limited limb extension made standing on all four limbs impossible. Suspended by the tail, homozygous affected mice were not able to clench their hindlimbs and could not grip a cage cover (Fig. 4A). As the disease progressed, this weakness worsened to include the forelimbs and trunk muscles, as previously reported (18–20).


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 treatment improves neuromuscular function and survival in nmd mice.(A) Representative images of AAV9-IGHMBP2-nmd mice showing their capacity to extend their hindlimbs in comparison to AAV9--nmd mice. (B) Rotarod test data. The performance of AAV9-IGHMBP2-nmd mice was significantly improved versus AAV9--nmd mice, which were never able to complete the test (P < 0.0001). Error bars denote SEM. (C) The mean body weight of AAV9-IGHMBP2-nmd mice significantly increased relative to AAV9--nmd mice (P< 0.01). Error bars show SEM. (D) Kaplan-Meier survival curves of AAV9-IGHMBP2-nmd mice and AAV9--nmd mice (P < 0.0001). For all graphs: AAV9-IGHMBP2-nmd mice, n = 17; AAV9--nmd mice, n = 24.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: AAV9-IGHMBP2 treatment improves neuromuscular function and survival in nmd mice.(A) Representative images of AAV9-IGHMBP2-nmd mice showing their capacity to extend their hindlimbs in comparison to AAV9--nmd mice. (B) Rotarod test data. The performance of AAV9-IGHMBP2-nmd mice was significantly improved versus AAV9--nmd mice, which were never able to complete the test (P < 0.0001). Error bars denote SEM. (C) The mean body weight of AAV9-IGHMBP2-nmd mice significantly increased relative to AAV9--nmd mice (P< 0.01). Error bars show SEM. (D) Kaplan-Meier survival curves of AAV9-IGHMBP2-nmd mice and AAV9--nmd mice (P < 0.0001). For all graphs: AAV9-IGHMBP2-nmd mice, n = 17; AAV9--nmd mice, n = 24.
Mentions: We evaluated whether AAV9-IGHMBP2 treatment improved the disease phenotype and extended survival in nmd mice. Functional recovery was assessed in all animal groups through blind evaluation of their general appearance, weight, neuromuscular function, and survival after treatment (Fig. 4). The first clinical symptoms in nmd mice presented in the second postnatal week when mice rapidly developed muscle weakness in the hindlimbs, which were contracted, causing impaired locomotor activity. This limited limb extension made standing on all four limbs impossible. Suspended by the tail, homozygous affected mice were not able to clench their hindlimbs and could not grip a cage cover (Fig. 4A). As the disease progressed, this weakness worsened to include the forelimbs and trunk muscles, as previously reported (18–20).

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