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• W3192953669 abstract "Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an autosomal recessive disorder that develops in infancy and arises from mutation of the immunoglobulin helicase μ-binding protein 2 (IGHMBP2) gene. Whereas IGHMBP2 is ubiquitously expressed, loss or reduction of function leads to alpha motor neuron loss and skeletal muscle atrophy. We previously developed a gene therapy strategy for SMARD1 using a single-stranded AAV9-IGHMBP2 vector and compared two different delivery methods in a validated SMARD1 mouse model. An important question in the field relates to the temporal requirements for this or any potential treatment. To examine the therapeutic window, we utilized our recently developed SMARD1 model, FVB/NJ-Ighmpb2nmd-2J, to deliver AAV9-IGHMBP2 at four different time points starting at post-natal day 2 (P2) through P8. At each time point, significant improvements were observed in survival, weight gain, and motor function. Similarly, treatment improved important hallmarks of disease, including motor unit pathology. Whereas improvements were more pronounced in the early-treatment groups, even the later-treatment groups displayed significant phenotypic improvements. This work suggests that an effective gene therapy strategy could provide benefits to pre-symptomatic and early-symptomatic individuals, thereby expanding the potential therapeutic window for SMARD1. Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an autosomal recessive disorder that develops in infancy and arises from mutation of the immunoglobulin helicase μ-binding protein 2 (IGHMBP2) gene. Whereas IGHMBP2 is ubiquitously expressed, loss or reduction of function leads to alpha motor neuron loss and skeletal muscle atrophy. We previously developed a gene therapy strategy for SMARD1 using a single-stranded AAV9-IGHMBP2 vector and compared two different delivery methods in a validated SMARD1 mouse model. An important question in the field relates to the temporal requirements for this or any potential treatment. To examine the therapeutic window, we utilized our recently developed SMARD1 model, FVB/NJ-Ighmpb2nmd-2J, to deliver AAV9-IGHMBP2 at four different time points starting at post-natal day 2 (P2) through P8. At each time point, significant improvements were observed in survival, weight gain, and motor function. Similarly, treatment improved important hallmarks of disease, including motor unit pathology. Whereas improvements were more pronounced in the early-treatment groups, even the later-treatment groups displayed significant phenotypic improvements. This work suggests that an effective gene therapy strategy could provide benefits to pre-symptomatic and early-symptomatic individuals, thereby expanding the potential therapeutic window for SMARD1. Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an infantile autosomal recessive neurodegenerative disease that is characterized by loss of alpha motor neurons and muscle atrophy.1Grohmann K. Schuelke M. Diers A. Hoffmann K. Lucke B. Adams C. Bertini E. Leonhardt-Horti H. Muntoni F. Ouvrier R. et al.Mutations in the gene encoding immunoglobulin mu-binding protein 2 cause spinal muscular atrophy with respiratory distress type 1.Nat. Genet. 2001; 29: 75-77Google Scholar,2Grohmann K. Varon R. Stolz P. Schuelke M. Janetzki C. Bertini E. Bushby K. Muntoni F. Ouvrier R. Van Maldergem L. et al.Infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1).Ann. Neurol. 2003; 54: 719-724Google Scholar In contrast to 5q-linked spinal muscular atrophy (SMA), the first clinical symptom in SMARD1 is respiratory distress that develops between 6 weeks and 13 months of age.1Grohmann K. Schuelke M. Diers A. Hoffmann K. Lucke B. Adams C. Bertini E. Leonhardt-Horti H. Muntoni F. Ouvrier R. et al.Mutations in the gene encoding immunoglobulin mu-binding protein 2 cause spinal muscular atrophy with respiratory distress type 1.Nat. Genet. 2001; 29: 75-77Google Scholar,3Grohmann K. Wienker T.F. Saar K. Rudnik-Schöneborn S. Stoltenburg-Didinger G. Rossi R. Novelli G. Nürnberg G. Pfeufer A. Wirth B. et al.Diaphragmatic spinal muscular atrophy with respiratory distress is heterogeneous, and one form Is linked to chromosome 11q13-q21.Am. J. Hum. Genet. 1999; 65: 1459-1462Google Scholar,4Pitt M. Houlden H. Jacobs J. Mok Q. Harding B. Reilly M. Surtees R. Severe infantile neuropathy with diaphragmatic weakness and its relationship to SMARD1.Brain. 2003; 126: 2682-2692Google Scholar Respiratory distress is a result of diaphragm muscle atrophy,1Grohmann K. Schuelke M. Diers A. Hoffmann K. Lucke B. Adams C. Bertini E. Leonhardt-Horti H. Muntoni F. Ouvrier R. et al.Mutations in the gene encoding immunoglobulin mu-binding protein 2 cause spinal muscular atrophy with respiratory distress type 1.Nat. Genet. 2001; 29: 75-77Google Scholar, 2Grohmann K. Varon R. Stolz P. Schuelke M. Janetzki C. Bertini E. Bushby K. Muntoni F. Ouvrier R. Van Maldergem L. et al.Infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1).Ann. Neurol. 2003; 54: 719-724Google Scholar, 3Grohmann K. Wienker T.F. Saar K. Rudnik-Schöneborn S. Stoltenburg-Didinger G. Rossi R. Novelli G. Nürnberg G. Pfeufer A. Wirth B. et al.Diaphragmatic spinal muscular atrophy with respiratory distress is heterogeneous, and one form Is linked to chromosome 11q13-q21.Am. J. Hum. Genet. 1999; 65: 1459-1462Google Scholar,5Pitt M.A. Kim W. Myung I.J. Flexibility versus generalizability in model selection.Psychon. Bull. Rev. 2003; 10: 29-44Google Scholar whereas in the related disease, SMA, intercostal muscle atrophy is typically the cause of respiratory failure. The respiratory complications in SMARD1 typically lead to complete paralysis of the diaphragm and artificial ventilation. Additional symptoms for SMARD1 include intrauterine growth delay, autonomic dysfunction, distal-to-proximal spread of muscle atrophy, and decreased diameter of myofibrils in skeletal muscles including the diaphragm.2Grohmann K. Varon R. Stolz P. Schuelke M. Janetzki C. Bertini E. Bushby K. Muntoni F. Ouvrier R. Van Maldergem L. et al.Infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1).Ann. Neurol. 2003; 54: 719-724Google Scholar,4Pitt M. Houlden H. Jacobs J. Mok Q. Harding B. Reilly M. Surtees R. Severe infantile neuropathy with diaphragmatic weakness and its relationship to SMARD1.Brain. 2003; 126: 2682-2692Google Scholar,6Kaindl A.M. Guenther U.P. Rudnik-Schoneborn S. Varon R. Zerres K. Schuelke M. Hubner C. von Au K. Spinal muscular atrophy with respiratory distress type 1 (SMARD1).J. Child. Neurol. 2008; 23: 199-204Google Scholar,7Rudnik-Schöneborn S. Stolz P. Varon R. Grohmann K. Schächtele M. Ketelsen U.P. Stavrou D. Kurz H. Hübner C. Zerres K. Long-term observations of patients with infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1).Neuropediatrics. 2004; 35: 174-182Google Scholar SMARD1 is caused by loss-of-function mutations in the housekeeping gene immunoglobulin μ-DNA binding protein 2 (IGHMBP2), located on chromosome 11q13.3.3Grohmann K. Wienker T.F. Saar K. Rudnik-Schöneborn S. Stoltenburg-Didinger G. Rossi R. Novelli G. Nürnberg G. Pfeufer A. Wirth B. et al.Diaphragmatic spinal muscular atrophy with respiratory distress is heterogeneous, and one form Is linked to chromosome 11q13-q21.Am. J. Hum. Genet. 1999; 65: 1459-1462Google Scholar,8Viollet L. Barois A. Rebeiz J.G. Rifai Z. Burlet P. Zarhrate M. Vial E. Dessainte M. Estournet B. Kleinknecht B. et al.Mapping of autosomal recessive chronic distal spinal muscular atrophy to chromosome 11q13.Ann. Neurol. 2002; 51: 585-592Google Scholar,9Fukita Y. Mizuta T.R. Shirozu M. Ozawa K. Shimizu A. Honjo T. The human S mu bp-2, a DNA-binding protein specific to the single-stranded guanine-rich sequence related to the immunoglobulin mu chain switch region.J. Biol. Chem. 1993; 268: 17463-17470Google Scholar The ubiquitously expressed IGHMBP2 gene is comprised of 15 exons encoding 993 amino acids corresponding to a ~110 kDa product. IGHMBP2 consists of an ATP-binding motif, a helicase-like motif, and two nucleic-acid-binding motifs. Patient mutations are predominately located in these functional motifs; however, the helicase domain is the region most frequently mutated.2Grohmann K. Varon R. Stolz P. Schuelke M. Janetzki C. Bertini E. Bushby K. Muntoni F. Ouvrier R. Van Maldergem L. et al.Infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1).Ann. Neurol. 2003; 54: 719-724Google Scholar,4Pitt M. Houlden H. Jacobs J. Mok Q. Harding B. Reilly M. Surtees R. Severe infantile neuropathy with diaphragmatic weakness and its relationship to SMARD1.Brain. 2003; 126: 2682-2692Google Scholar,8Viollet L. Barois A. Rebeiz J.G. Rifai Z. Burlet P. Zarhrate M. Vial E. Dessainte M. Estournet B. Kleinknecht B. et al.Mapping of autosomal recessive chronic distal spinal muscular atrophy to chromosome 11q13.Ann. Neurol. 2002; 51: 585-592Google Scholar, 9Fukita Y. Mizuta T.R. Shirozu M. Ozawa K. Shimizu A. Honjo T. The human S mu bp-2, a DNA-binding protein specific to the single-stranded guanine-rich sequence related to the immunoglobulin mu chain switch region.J. Biol. Chem. 1993; 268: 17463-17470Google Scholar, 10Maystadt I. Zarhrate M. Landrieu P. Boespflug-Tanguy O. Sukno S. Collignon P. Melki J. Verellen-Dumoulin C. Munnich A. Viollet L. Allelic heterogeneity of SMARD1 at the IGHMBP2 locus.Hum. Mutat. 2004; 23: 525-526Google Scholar, 11Lim S.C. Bowler M.W. Lai T.F. Song H. The Ighmbp2 helicase structure reveals the molecular basis for disease-causing mutations in DMSA1.Nucleic Acids Res. 2012; 40: 11009-11022Google Scholar Based on in vitro and in vivo studies, the IGHMBP2 protein functions in immunoglobulin-class switching,9Fukita Y. Mizuta T.R. Shirozu M. Ozawa K. Shimizu A. Honjo T. The human S mu bp-2, a DNA-binding protein specific to the single-stranded guanine-rich sequence related to the immunoglobulin mu chain switch region.J. Biol. Chem. 1993; 268: 17463-17470Google Scholar pre-mRNA maturation,12Molnar G.M. Crozat A. Kraeft S.K. Dou Q.P. Chen L.B. Pardee A.B. Association of the mammalian helicase MAH with the pre-mRNA splicing complex.Proc. Natl. Acad. Sci. USA. 1997; 94: 7831-7836Google Scholar transcription regulation by either DNA binding activity13Chen N.N. Kerr D. Chang C.F. Honjo T. Khalili K. Evidence for regulation of transcription and replication of the human neurotropic virus JCV genome by the human S(mu)bp-2 protein in glial cells.Gene. 1997; 185: 55-62Google Scholar,14Miao M. Chan S.L. Fletcher G.L. Hew C.L. The rat ortholog of the presumptive flounder antifreeze enhancer-binding protein is a helicase domain-containing protein.Eur. J. Biochem. 2000; 267: 7237-7246Google Scholar or interaction with TATA-binding protein,15Zhang Q. Wang Y.C. Montalvo E.A. Smubp-2 represses the Epstein-Barr virus lytic switch promoter.Virology. 1999; 255: 160-170Google Scholar and translation by direct interaction with tRNA and other components of translational machinery.16de Planell-Saguer M. Schroeder D.G. Rodicio M.C. Cox G.A. Mourelatos Z. Biochemical and genetic evidence for a role of IGHMBP2 in the translational machinery.Hum. Mol. Genet. 2009; 18: 2115-2126Google Scholar,17Guenther U.P. Handoko L. Laggerbauer B. Jablonka S. Chari A. Alzheimer M. Ohmer J. Plöttner O. Gehring N. Sickmann A. et al.IGHMBP2 is a ribosome-associated helicase inactive in the neuromuscular disorder distal SMA type 1 (DSMA1).Hum. Mol. Genet. 2009; 18: 1288-1300Google Scholar However, the precise disease-causing role of IGHMBP2 mutation that leads to selective motor neuron loss remains unclear. A spontaneous mutation in Ighmbp2 resulted in the initial identification and characterization of the neuromuscular degeneration (nmd2J) mouse model.18Cook S.A. Johnson K.R. Bronson R.T. Davisson M.T. Neuromuscular degeneration (nmd): a mutation on mouse chromosome 19 that causes motor neuron degeneration.Mamm. Genome. 1995; 6: 187-191Google Scholar,19Cox G.A. Mahaffey C.L. Frankel W.N. Identification of the mouse neuromuscular degeneration gene and mapping of a second site suppressor allele.Neuron. 1998; 21: 1327-1337Google Scholar The original nmd2J mouse is on the C57BLKS background and contains a mutation in Ighmbp2 intron 4, giving rise to a cryptic splice site, resulting in an aberrant splicing event in ~75%–80% of the transcripts. The altered splicing causes an addition of 23 nucleotides to the transcript that creates a premature translational termination codon.19Cox G.A. Mahaffey C.L. Frankel W.N. Identification of the mouse neuromuscular degeneration gene and mapping of a second site suppressor allele.Neuron. 1998; 21: 1327-1337Google Scholar At 3 weeks of age, nmd2J mice become symptomatic and rapidly develop hindlimb muscle weakness to the extent that mice were paralyzed by 5 weeks of age with survival to 14 weeks.20Grohmann K. Rossoll W. Kobsar I. Holtmann B. Jablonka S. Wessig C. Stoltenburg-Didinger G. Fischer U. Hübner C. Martini R. Sendtner M. Characterization of Ighmbp2 in motor neurons and implications for the pathomechanism in a mouse model of human spinal muscular atrophy with respiratory distress type 1 (SMARD1).Hum. Mol. Genet. 2004; 13: 2031-2042Google Scholar By postnatal day 10, nmd2J mice demonstrated over a 40% loss in motor neurons that progressed until death.20Grohmann K. Rossoll W. Kobsar I. Holtmann B. Jablonka S. Wessig C. Stoltenburg-Didinger G. Fischer U. Hübner C. Martini R. Sendtner M. Characterization of Ighmbp2 in motor neurons and implications for the pathomechanism in a mouse model of human spinal muscular atrophy with respiratory distress type 1 (SMARD1).Hum. Mol. Genet. 2004; 13: 2031-2042Google Scholar Our lab and another group have developed a single-stranded AAV9 (ssAAV9) vector containing human IGHMBP2 cDNA that demonstrated excellent efficacy in rescuing the nmd mice.21Shababi M. Feng Z. Villalon E. Sibigtroth C.M. Osman E.Y. Miller M.R. Williams-Simon P.A. Lombardi A. Sass T.H. Atkinson A.K. et al.Rescue of a Mouse Model of Spinal Muscular Atrophy With Respiratory Distress Type 1 by AAV9-IGHMBP2 Is Dose Dependent.Mol. Ther. 2016; 24: 855-866Google Scholar,22Nizzardo M. Simone C. Rizzo F. Salani S. Dametti S. Rinchetti P. Del Bo R. Foust K. Kaspar B.K. Bresolin N. et al.Gene therapy rescues disease phenotype in a spinal muscular atrophy with respiratory distress type 1 (SMARD1) mouse model.Sci. Adv. 2015; 1: e1500078Google Scholar We compared the efficacy of two delivery methods (intravenous [i.v.] and intracerebroventricular [i.c.v.]) in the nmd2J model using a single low dose, which demonstrated that i.v. injections are not as effective as i.c.v. injections in rescuing motor deficits.23Shababi M. Villalón E. Kaifer K.A. DeMarco V. Lorson C.L. A Direct Comparison of IV and ICV Delivery Methods for Gene Replacement Therapy in a Mouse Model of SMARD1.Mol. Ther. Methods Clin. Dev. 2018; 10: 348-360Google Scholar We recently developed a closely related strain of nmd mice on the FVB background called FVB/NJ-Ighmpb2nmd-2J or “FVB-nmd” from this point on, resulting in a model that was consistent, severe, and well-suited for therapeutic studies, with a median survival of ~18–20 days.24Shababi M. Smith C.E. Kacher M. Alrawi Z. Villalón E. Davis D. Bryda E.C. Lorson C.L. Development of a novel severe mouse model of spinal muscular atrophy with respiratory distress type 1: FVB-nmd.Biochem. Biophys. Res. Commun. 2019; 520: 341-346Google Scholar To date, AAV-mediated gene replacement has been shown to be the most effective means to rescue the SMARD1 mouse model. To advance the pre-clinical animal studies, we examined the therapeutic window to determine the relative efficacy of AAV9-IGHMBP2 at various stages of disease development by delivering vector at post-natal day 2 (P2), P4, P6, and P8. Our results suggest that the therapeutic window of IGHMBP2 gene replacement is not limited to early asymptomatic stages such as P1 or P2; rather, significant phenotypic benefit was observed in all treatment groups, including the cohort that received treatment at P8. This was surprising, since the vector is single-stranded, and maximal expression typically occurs more than 10 days after delivery. These results provide the first evidence of the effectiveness of SMARD1 gene therapy at later time points following disease onset. A single low dose of AAV9-IGHMBP2 at P2 via i.c.v. or i.v. injection at P2 significantly rescues the nmd phenotype.21Shababi M. Feng Z. Villalon E. Sibigtroth C.M. Osman E.Y. Miller M.R. Williams-Simon P.A. Lombardi A. Sass T.H. Atkinson A.K. et al.Rescue of a Mouse Model of Spinal Muscular Atrophy With Respiratory Distress Type 1 by AAV9-IGHMBP2 Is Dose Dependent.Mol. Ther. 2016; 24: 855-866Google Scholar,23Shababi M. Villalón E. Kaifer K.A. DeMarco V. Lorson C.L. A Direct Comparison of IV and ICV Delivery Methods for Gene Replacement Therapy in a Mouse Model of SMARD1.Mol. Ther. Methods Clin. Dev. 2018; 10: 348-360Google Scholar Here, we analyzed the phenotype of the severe FVB-nmd model following i.c.v. delivery of two different doses of AAV9-IGHMBP2 (Figure 1A) at 4 different time points starting at P2–P3 (asymptomatic) through P8–P9 (early symptomatic). A single low dose (1.25e11 vector genomes [vg]) was injected at P2, P4, P6, and P8, whereas the high dose (total of 2.5e11 vg) was applied on two consecutive days for each time point (P2,3; P4,5; P6,7; P8,9). Interestingly, all treated groups displayed significantly extended lifespans compared to untreated animals (Figures 1B and 1C; Figures S1A–S1D). Within the low-dose cohort, earlier P2 and P4 were similarly effective, while P6 and P8 significantly improved survival compared to the early injections. The same pattern was also observed in the cohorts that received the high-dose treatment, although the high dose reduced the number of early deaths in the P6 and P8 cohorts (Figure 1C). While one death occurred prior to P80 in the P2 and P4 low-dose treatment cohorts, all of the high-dose-treated animals in the P2 and P4 groups lived beyond 100 days (Figures 1B and 1C). Delivery of the vector at P6 and P8 time points still resulted in a significant extension in survival for treated FVB-nmd mice, albeit not as robust as the earlier treatment groups (p = 0.0002 for P6 and p = 0.001 for P8) (Figure 1B). The endpoint for these experiments was 132 days, and all remaining cohorts were euthanized. The weight of untreated FVB-nmd mice fluctuates between 3–4 g, whereas the nmd2J mice can weigh up to 10 g.21Shababi M. Feng Z. Villalon E. Sibigtroth C.M. Osman E.Y. Miller M.R. Williams-Simon P.A. Lombardi A. Sass T.H. Atkinson A.K. et al.Rescue of a Mouse Model of Spinal Muscular Atrophy With Respiratory Distress Type 1 by AAV9-IGHMBP2 Is Dose Dependent.Mol. Ther. 2016; 24: 855-866Google Scholar,24Shababi M. Smith C.E. Kacher M. Alrawi Z. Villalón E. Davis D. Bryda E.C. Lorson C.L. Development of a novel severe mouse model of spinal muscular atrophy with respiratory distress type 1: FVB-nmd.Biochem. Biophys. Res. Commun. 2019; 520: 341-346Google Scholar To investigate the effect of the low- and high-dose AAV9-IGHMBP2 on the weight of FVB-nmd mice treated at different time points, daily weight was recorded starting at P2 until P132, when the survival and weight analyses were terminated. Consistent with the extension of the lifespan, both low and high doses of the viral vector led to a considerable increase in the weight of every treated group compared to untreated (p < 0.001) (Figures 1D and 1E). All treated groups gained weight until 40–50 days of age and then reached a plateau. Weight gain for each group was directly correlated to the time point of therapy rather than the dose of the vector. Treatment at earlier time points led to higher weight gain than the later time points, indicating a significant difference between each treated group regardless of the dose (P2 versus P4, p < 0.001; P4 versus P6, p < 0.001; P6 versus P8, p < 0.05; P2,3 versus P4,5, p < 0.01; P4,5 versus P6,7, p < 0.001; P6,7 versus P8,9, p < 0.01) (Figures 1D and 1E). Additionally, there was no significance in the weight gain of any individual group treated with either low or high dose (Figures S2A–S2D) except for P4-treated mice, in which the increased dose led to higher weight gain during the age of 85–115 days (p < 0.05). Rotarod and grip strength were performed starting at P40 for 7 consecutive days following a training and acclimation period. Untreated FVB-nmd animals were not included in these studies focused upon motor function, since younger animals are not capable of performing these tasks and their lifespan is too short. Therefore, each treatment group was compared to the heterozygous unaffected littermates (HET: FVB-Ighmbp2nmd/+) and to each other in low- and high-dose-treated groups. Rotarod performance, as determined by the time an animal remained on the rotating cylinder, of early-treated animals (P2 and P4 treated) were indistinguishable from unaffected HET counterparts in both low- and high-dose groups (Figures 2A and 2B ; Figures S3A and S3B). The rotarod performance of P6- and P8-treated mice, though improved, was significantly less compared to the HET and early-treated littermates in the low- and high-dose groups (p < 0.001) (Figures 2A and 2B). High-dose delivery slightly improved the rotarod performance of the P6- and P8-treated compared to low dose, but it did not differ statistically (Figures S3C and S3D). In contrast to the rotarod performance, forelimb strength in all treated groups was significantly weaker than unaffected animals (p < 0.001) (Figures 2C and 2D). This reduced level of rescue in forelimb strength is consistent with the original nmd mice, demonstrating that the i.c.v. delivery of the vector is capable of repairing hindlimb activity more efficiently than forelimb,21Shababi M. Feng Z. Villalon E. Sibigtroth C.M. Osman E.Y. Miller M.R. Williams-Simon P.A. Lombardi A. Sass T.H. Atkinson A.K. et al.Rescue of a Mouse Model of Spinal Muscular Atrophy With Respiratory Distress Type 1 by AAV9-IGHMBP2 Is Dose Dependent.Mol. Ther. 2016; 24: 855-866Google Scholar,23Shababi M. Villalón E. Kaifer K.A. DeMarco V. Lorson C.L. A Direct Comparison of IV and ICV Delivery Methods for Gene Replacement Therapy in a Mouse Model of SMARD1.Mol. Ther. Methods Clin. Dev. 2018; 10: 348-360Google Scholar although the grip strength in each treated group improved significantly using the high dose of the viral vector when compared to low-dose group (Figures 2C and 2D). Single comparison of each time point treatment in low- and high-dose groups revealed that improvements in forelimb strength, resulting from high-dose administration, are more obvious in early-treated (P2 versus p2,3 and P4 versus P4,5, p < 0.001) (Figures S4A and S4B) but still significant in the P6-treated (P6,7 versus P6, p < 0.01) (Figure S4C) and P8-treated mice (P8,9 versus P8, p < 0.05) (Figure S4D). Nevertheless, the high dose could not sufficiently increase the grip strength to reach the level of the HET littermates in any treated group (p < 0.001) (Figures 2D; Figures S4A–S4D). Western blot analysis of early- and late-treated mice (P2, P8) showed no statistical difference among the various cohorts (Figure S5). FVB-nmd mice have a severe hindlimb phenotype characterized by contracture in the hindlimbs and an inability to splay their legs by P17.24Shababi M. Smith C.E. Kacher M. Alrawi Z. Villalón E. Davis D. Bryda E.C. Lorson C.L. Development of a novel severe mouse model of spinal muscular atrophy with respiratory distress type 1: FVB-nmd.Biochem. Biophys. Res. Commun. 2019; 520: 341-346Google Scholar In our previous study, we showed that FVB-nmd mice have significantly decreased gastrocnemius muscle fiber size compared to FVB mice.24Shababi M. Smith C.E. Kacher M. Alrawi Z. Villalón E. Davis D. Bryda E.C. Lorson C.L. Development of a novel severe mouse model of spinal muscular atrophy with respiratory distress type 1: FVB-nmd.Biochem. Biophys. Res. Commun. 2019; 520: 341-346Google Scholar Additionally, we have previously reported that P2-treated nmd2J/2J have a high level of rescue in their gastrocnemius muscle.21Shababi M. Feng Z. Villalon E. Sibigtroth C.M. Osman E.Y. Miller M.R. Williams-Simon P.A. Lombardi A. Sass T.H. Atkinson A.K. et al.Rescue of a Mouse Model of Spinal Muscular Atrophy With Respiratory Distress Type 1 by AAV9-IGHMBP2 Is Dose Dependent.Mol. Ther. 2016; 24: 855-866Google Scholar,23Shababi M. Villalón E. Kaifer K.A. DeMarco V. Lorson C.L. A Direct Comparison of IV and ICV Delivery Methods for Gene Replacement Therapy in a Mouse Model of SMARD1.Mol. Ther. Methods Clin. Dev. 2018; 10: 348-360Google Scholar To investigate whether the early (P2) and late (P8) time point treatment led to muscle fiber rescue in FVB-nmd, we compared laminin-immunostained cross-sectioned gastrocnemius muscles of high-dose-treated animals with those of the wild-type (WT) FVB at 42 days of age. The muscles of phenotypically unaffected age-matched HET mice were used as a control for untreated FVB-nmd harvested at 14 days of age, a late symptomatic stage. Consistent with our previous results, muscle fiber area and perimeter of the gastrocnemius muscle are significantly decreased in untreated FVB-nmd mice compared to HET (p < 0.0001) (Figures 3A–3C). A blinded quantitative assessment of muscles revealed that muscle fiber area and perimeter of the gastrocnemius in P2-treated mice were significantly larger than P8-treated mice (p < 0.0001) but still notably smaller than WT (p < 0.0001) (Figures 3A–3C). Diaphragm muscle fiber has been shown to be significantly smaller in SMARD1 patients. We wanted to determine if the FVB-nmd mice have reduced diaphragm muscle fiber area and evaluate the extent AAV-IGHMBP2 treatment rescues. A blinded quantitative assessment of muscles showed that diaphragm muscle area and perimeter are significantly reduced in P14 FVB-nmd mice compared to age-matched HET mice (p < 0.0001) (Figures 3D and 3E). AAV-IGHMBP2 treatment at both P2 and P8 improved the diaphragm muscle fiber; however, were both significantly smaller than WT (p < 0.0001) (Figures 3D and 3E). Additionally, P2-treated mice had a significantly larger diaphragm size than P8-treated mice (p < 0.0001) (Figures 3D and 3E). These results demonstrate that AAV-IGHMBP2 treatment at P2 and P8 significantly improves the skeletal muscle phenotype in SMARD1 model mice; however, consistent with the other parameters, earlier delivery provides an even greater degree of protection. NMJs from the gastrocnemius muscle exhibit severe denervation defects in FVB-nmd mice, but these can be partially rescued by delivery of AAV9-IGHBMP2 on P1.23Shababi M. Villalón E. Kaifer K.A. DeMarco V. Lorson C.L. A Direct Comparison of IV and ICV Delivery Methods for Gene Replacement Therapy in a Mouse Model of SMARD1.Mol. Ther. Methods Clin. Dev. 2018; 10: 348-360Google Scholar,24Shababi M. Smith C.E. Kacher M. Alrawi Z. Villalón E. Davis D. Bryda E.C. Lorson C.L. Development of a novel severe mouse model of spinal muscular atrophy with respiratory distress type 1: FVB-nmd.Biochem. Biophys. Res. Commun. 2019; 520: 341-346Google Scholar To examine how early and late delivery of AAV9-IGHMBP2 impacts the FVB-nmd NMJ phenotype, we conducted a blinded quantitative assessment of NMJ pathology from the gastrocnemius of P2- and P8-treated FVB-nmd mice and age-matched, untreated WT mice at P42. The untreated FVB-nmd and their age-matched HET counterparts harvested at P14 were compared to each other at a relatively early time point. As expected, NMJs from untreated FVB-nmd mice displayed severe pathology, with less than 40% fully innervated endplates and more than 50% fully denervated endplates compared to age-matched HET mice (p < 0.0001) (Figures 4A and 4B ). The P2-treated mice had similar level of innervation and denervation to age-matched WT counterparts, with almost 85% fully innervated endplates (p > 0.05) (Figures 4A and 4B). Interestingly, the P8-treated NMJs, albeit not as improved as P2-treated, were 65% fully innervated (P8-treated versus WT and P2-treated, p < 0.0001) and approximately 22% fully denervated endplates (P8-treated versus WT, p < 0.01; P8-treated versus P2-treated, p < 0.05) (Figures 4A and 4B). These results are consistent with the other phenotypic parameters and further demonstrate that early delivery is the most efficacious, but even the symptomatic cohort (P8) significantly benefits from this effective treatment. Based on our previous analysis, the number of motor neurons in the lumbar region of the original nmd2J mice was reduced nearly 65% at 8 weeks of age.21Shababi M. Feng Z. Villalon E. Sibigtroth C.M. Osman E.Y. Miller M.R. Williams-Simon P.A. Lombardi A. Sass T.H. Atkinson A.K. et al.Rescue of a Mouse Model of Spinal Muscular Atrophy With Respiratory Distress Type 1 by AAV9-IGHMBP2 Is Dose Dependent.Mol. Ther. 2016; 24: 855-866Google Scholar We investigated whether the delivery of AAV9-IGHMBP2 prevents motor neuron loss and pathology of motor neurons in the FVB-nmd model. Lumbar spinal cord sections representing L3–L5 regions from P14 cohorts, FVB-nmd and HET, and P42 cohorts, WT, P2 treated, and P8 treated, were analyzed through a blinded quantification of immunofluorescent images. As predicted, FVB-nmd contained a significantly reduced number of motor neurons, with an average of ~5 motor neurons per section, compared to ~6.6 or 8 motor neurons per section in the age-matched HET or WT mice (p < 0.001) (Figures 5A and 5B ). However, the area and perimeter of the FVB-nmd motor neurons were only slightly smaller than those in HET (p > 0.05), suggesting that even though motor neurons at P14 are reduced in numbers, the remaining motor neurons do not yet exhibit dramatic cellular pathology (Figures 5A–5D). Interestingly, the average motor neuron nu" @default.
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• W3192953669 title "Defining the optimal dose and therapeutic window in SMA with respiratory distress type I model mice, FVB/NJ-Ighmpb2" @default.
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