0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Neurological Review |

Stem Cell Model of Spinal Muscular Atrophy FREE

Allison D. Ebert, PhD; Clive N. Svendsen, PhD
[+] Author Affiliations

Author Affiliations: Stem Cell and Regenerative Medicine Center (Drs Ebert and Svendsen), and Departments of Anatomy (Dr Svendsen) and Neurology (Drs Ebert and Svendsen), University of Wisconsin–Madison. Dr Svendsen is now with the Cedars-Sinai Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California.


Section Editor: David E. Pleasure, MD

More Author Information
Arch Neurol. 2010;67(6):665-669. doi:10.1001/archneurol.2010.89.
Text Size: A A A
Published online

Human embryonic stem cells provide a useful source of material for studying basic human development and various disease states. However, ethical issues concerning their procurement limit their acceptance and possible clinical applicability. Recent advances in stem cell technology have provided an alternative source of pluripotent stem cells that does not require the use of an embryo. This review addresses the generation of induced pluripotent stem cells from skin fibroblasts taken from various patient populations, with a specific focus on the pediatric disorder spinal muscular atrophy. These patient-derived cells may help researchers devise more appropriate therapies through a greater understanding of the molecular mechanisms that underlie neuron dysfunction and death in a variety of diseases. Furthermore, they provide an ideal platform for small-molecule screening and subsequent drug development.

Figures in this Article

Since their isolation in 1998,1 human embryonic stem cells (hESCs) have garnered much attention for a wide range of experimental and therapeutic applications. These cells are pluripotent because after injection into immunodeficient mice they form teratomas consisting of cell types from all 3 primitive germ layers (endoderm, mesoderm, and ectoderm), including muscle, heart, liver, and the central nervous system. For neurodegenerative diseases, hESCs can be further lineage restricted to generate very specific neural subtypes, including dopaminergic neurons, motor neurons, oligodendrocytes, and astrocytes, which display many of the neurochemical and electrical attributes of mature neurons (eg, neurotransmitters, transporters, and evoked action potentials).2 Because of these attributes, hESCs offer a tremendous advantage to model diseases. However, ethical concerns surround their use because the embryo is destroyed in the process of their procurement.

The groundbreaking discovery that mouse and human fibroblasts have the capacity to be reverted to an ESC fate through reprogramming has significantly advanced the field of stem cell and neurodegenerative disease research. Although performed independently and with some variation, these cells were all modified using DNA technology to overexpress important pluripotent stem cell genes in human neonatal or adult fibroblasts. These exogenously expressed genes reprogrammed the DNA of the fibroblast cells to make them display ESC-like morphologic features, exponential growth properties, and gene expression profiles. Similar to hESCs, the newly reprogrammed cells, termed induced pluripotent stem cells (iPSCs), can form teratomas and can be lineage restricted to the various cell types in the body.3 Because these cells are derived from adult skin, 2 important implications arise. First, a fertilized embryo is not needed for the production of iPSCs, thus reducing some of the ethical concerns with their generation and use. Second, iPSCs can be derived from any patient population,47 which allows for analysis and modeling of the disease in the cell types particularly affected. This technique also provides the generation of a human model system for diseases with no known genetic component or for which few appropriate experimental models are available.

Spinal muscular atrophy (SMA) is an autosomal recessive disease that causes specific loss of alpha motor neurons in the spinal cord and is one of the leading genetic causes of infant mortality. Spinal muscular atrophy is caused by a mutation in the survival motor neuron gene (SMN; GenBank U18423) that leads to loss of SMN1 protein8 and concomitant loss of motor neurons. Spinal muscular atrophy can be divided into 4 categories based on disease severity, with type I being the most severe and type IV being the least severe (Table). The SMN gene is located on chromosome 5, and approximately 95% of all patients with SMA are missing this gene. Humans are unique in that they have 2 versions of SMN: SMN1 and SMN2.9SMN1 produces a full-length protein found in the cytoplasm and the nucleus and is part of a large complex involved in a variety of RNA processes.1012 In contrast, a single C to T nucleotide transition in SMN2 causes exon 7 to be excluded, generating low levels (approximately 10%-15%) of full-length SMN protein and high levels of an essentially nonfunctional, truncated SMN2 protein (SMNΔ7).13,14 Because SMN2 can produce a small amount of full-length SMN protein, one study15 has shown that disease severity is mitigated by how much full-length protein is produced. Therefore, many of the current experimental approaches use small-molecule induction or RNA manipulation to increase SMN2 protein production to compensate for the loss of SMN1 protein.16

Table Graphic Jump LocationTable. Spinal Muscular Atrophy Categories

Several experimental models using single and multiple cellular organisms have been used to study the molecular processes involved in SMA. Mice have become the most often used vertebrate model for mammalian genetic research because of the ability to manipulate the genome. Using homologous recombination technology and mating crosses, Schrank and colleagues17 found that embryos that lack SMN die before uterine implantation, which underscores the importance of SMN during development in all cell types, not just motor neurons. Other mice have been developed that harbor the entire human SMN2 locus or the SMNΔ7 mutation on the mouse SMN knockout background to better represent the human condition.1820 Despite providing invaluable protein and disease information, these animal models may not adequately represent the human condition because the physiologic and anatomical features of mice are radically different from those of humans, especially regarding the central nervous system.

Possibly some of the most useful cells studied in culture have been fibroblasts taken from patients with SMA. Fibroblasts are relatively easy to obtain from skin biopsy samples, are easy to grow and maintain in the culture dish, and have the added benefit of naturally lacking SMN1. One important weakness is that fibroblasts do not make motor neurons, astrocytes, or muscle. Owing to the selective loss of motor neurons and the importance of astrocytes and muscle on motor neuron health,21,22 having a source of human cells that harbor the genetic mutation and that are capable of making these specific tissues would be highly beneficial. Patient-derived iPSCs can fulfill this need.

We generated iPSCs from commercially available fibroblast samples obtained from a 3-year-old boy with type I SMA and his unaffected (WT) mother.7 To do this, we used lentiviral vectors to stably express reprogramming genes in the fibroblast samples. After a few weeks in culture, iPSCs formed, which are visually and functionally distinct from fibroblast cells, and expressed a range of pluripotency markers found in hESCs. We further showed that these cells were indeed pluripotent because, unlike the fibroblasts, they could generate teratomas. The iPS-SMA cells retained a lack of SMN1 expression compared with the iPS-WT cells.7 Finally, given the appropriate culture conditions, the iPS-SMA and iPS-WT cells produced neural cells that expressed some of the molecular markers typical of motor neurons (Figure 1). Together, these characteristics represent a full conversion from the fibroblast state to a pluripotent stem cell.

Place holder to copy figure label and caption
Figure 1.

Induced pluripotent stem cells (iPSCs) can be lineage restricted to form motor neurons. Motor neurons were differentiated from iPSCs produced from an unaffected fibroblast sample and were stained for the neurofilament protein SMI-32 (red) (original magnification ×100). Cell nuclei appear in blue.

Graphic Jump Location

Although SMN is present in all cell types, it is curious that such an essential and ubiquitously expressed cellular protein should cause such specific degeneration of motor neurons. In this regard, we analyzed motor neuron production in the iPS-SMA and iPS-WT cells. Early in the differentiation protocol, the affected and nonaffected iPSCs could form motor neurons of approximately the same number and size, which we used as an indication of neuron health. However, after a few more weeks of motor neuron development, we observed a selective reduction in the number and size of motor neurons derived from the iPS-SMA cells compared with nondiseased iPS-WT–derived motor neurons.7 Additional data are needed to determine the mechanism that induces the motor neuron changes, but the present data suggest that an intrinsic property of the SMA-derived motor neuron was leading to damaged (or dying) neurons rather than to a lack of motor neuron development (Figure 2). The SMN1 protein has been shown to have antioxidant properties, and it is possible that the metabolism and energy requirements in the SMA motor neurons generate more reactive oxygen species compared with other cell types. Oxidative stress can be initiated by a variety of processes, including mitochondrial dysfunction, that may lead to motor neuron dysfunction through activation of programmed cell death pathways. Answering these mechanistic questions hopefully will provide insight into the best method of therapeutic intervention.

Place holder to copy figure label and caption
Figure 2.

Fibroblast cells can be converted to induced pluripotent stem cells (iPSCs) to model spinal muscular atrophy (SMA). Fibroblast cells were infected with viruses to express reprogramming genes. The iPSCs were cultured as flat colonies and then were lifted to form free-floating aggregate spheres in a nutrient medium. Next, using a series of chemical induction signals, iPSCs were instructed to form motor neurons, which the iPS-SMA and iPS-WT (from his unaffected mother) cells were able to do. Only after additional time in culture did we observe a specific deficit in the iPS-SMA–derived motor neurons. We speculate that this effect could be due to increased reactive oxygen species production or damaged mitochondria in the iPS-SMA cells.

Graphic Jump Location

Despite the fact that gene therapy for SMA (eg, using RNA technology or oligonucleotides to modify SMN2 splicing)16 is only recently becoming more widely used in research, experimental and clinical applications for gene therapy have been developed for other neurodegenerative diseases.23 Using viral vectors to replace SMN1 was shown to decrease motor neuron death and increase life span in SMA mice.24,25 Although this technique holds great clinical promise, the future of gene therapy may one day combine iPSC technology and cellular replacement with gene modification. In this regard, Hanna et al26 reported an elegant study in which sickle cell anemia was corrected in a mouse by generating iPSCs from this mouse, using gene-specific targeting to repair the hemoglobin allele, generating hematopoietic progenitor cells, and transplanting the repaired blood cells back into the same mouse. It is intriguing to consider the possibility of generating iPSCs from a patient with SMA, genetically elevating SMN1 expression, deriving motor neurons and astrocytes that now express SMN1, and then transplanting these cells back to repopulate and repair the patient's spinal cord. Although there are major challenges associated with this approach, one study27 reported that the growth of axons from transplanted motor neurons can reinnervate the muscle and have functional effects.

A more near-term use of iPS-SMA cells may be in the area of small-molecule drug discovery. The SMN protein is found in aggregate nuclear structures called gems, and the number of gems present is inversely correlated with disease severity15,28; therefore, therapeutic agents that increase protein output would be clinically valuable. Various compounds have been tested on fibroblast cells from patients with SMA and have been shown to increase SMN protein levels through stabilization or prevention of exon 7 skipping,2932 and one such compound, valproic acid, is currently being used in clinical trials for SMA.33 Using 2 previously tested compounds (valproic acid and tobramycin), we found that the number of gems significantly increased in the iPS-SMA cells after treatment with each compound compared with untreated iPS-SMA cells,7 suggesting that SMN protein production, stabilization, or both were enhanced. These results confirm that patient-derived iPSCs have similar molecular responses to drug treatment as do the routinely used fibroblast cells. We went on to identify gems in motor neurons, so the next step is to derive high-throughput screening assays assessing gem number specifically in motor neurons derived from patients with SMA. Further drug discovery investigation is crucial and, by using iPSCs, novel compounds can be tested in a human system on particularly vulnerable cell types, thereby increasing efficacy and the discovery of highly clinically relevant compounds.

In conclusion, SMA is a devastating and oftentimes fatal disease without an effective treatment. Much effort has been focused on determining the role of SMN in cellular function, on identifying the molecular processes involved in neuronal death, and on developing effective therapies. The ability to generate patient-specific iPSCs has opened new avenues of study for cell therapy and disease modeling. Spinal muscular atrophy may serve as a “proof of concept” that a specific neurologic abnormality can be mirrored in the culture dish. Armed with this model system, the hope is that new discoveries will be made that allow cell replacement and new drugs to be found to treat this disease.

Correspondence: Allison D. Ebert, PhD, Wisconsin Institutes for Medical Research, 1111 Highland Ave, Room 5033, Madison, WI 53705 (aebert@wisc.edu).

Accepted for Publication: April 14, 2009.

Author Contributions: Drs Ebert and Svendsen had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drafting of the manuscript: Ebert and Svendsen. Critical revision of the manuscript for important intellectual content: Ebert and Svendsen.

Financial Disclosure: None reported.

Funding/Support: This work was supported by the ALS Association (Dr Svendsen) and the National Institutes of Health (Dr Svendsen).

Thomson  JAItskovitz-Eldor  JShapiro  SS  et al.  Embryonic stem cell lines derived from human blastocysts [published correction appears in Science. 1998;282(5395):1827]. Science 1998;282 (5391) 1145- 1147
PubMed Link to Article
Murry  CEKeller  G Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell 2008;132 (4) 661- 680
PubMed Link to Article
Müller  LUDaley  GQWilliams  DA Upping the ante: recent advances in direct reprogramming. Mol Ther 2009;17 (6) 947- 953
PubMed Link to Article
Dimos  JTRodolfa  KTNiakan  KK  et al.  Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 2008;321 (5893) 1218- 1221
PubMed Link to Article
Park  IHArora  NHuo  H  et al.  Disease-specific induced pluripotent stem cells. Cell 2008;134 (5) 877- 886
PubMed Link to Article
Soldner  FHockemeyer  DBeard  C  et al.  Parkinson's disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell 2009;136 (5) 964- 977
PubMed Link to Article
Ebert  ADYu  JYRose  FF  Jr  et al.  Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 2009;457 (7227) 277- 280
PubMed Link to Article
Lefebvre  SBürglen  LReboullet  S  et al.  Identification and characterization of a spinal muscular atrophy-determining gene. Cell 1995;80 (1) 155- 165
PubMed Link to Article
Rochette  CFGilbert  NSimard  LR SMN gene duplication and the emergence of the SMN2 gene occurred in distinct hominids: SMN2 is unique to Homo sapiens. Hum Genet 2001;108 (3) 255- 266
PubMed Link to Article
Pellizzoni  LYong  JDreyfuss  G Essential role for the SMN complex in the specificity of snRNP assembly. Science 2002;298 (5599) 1775- 1779
PubMed Link to Article
Fischer  ULiu  QDreyfuss  G The SMN-SIP1 complex has an essential role in spliceosomal snRNP biogenesis. Cell 1997;90 (6) 1023- 1029
PubMed Link to Article
Liu  QFischer  UWang  FDreyfuss  G The spinal muscular atrophy disease gene product, SMN, and its associated protein SIP1 are in a complex with spliceosomal snRNP proteins. Cell 1997;90 (6) 1013- 1021
PubMed Link to Article
Monani  URLorson  CLParsons  DW  et al.  A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2. Hum Mol Genet 1999;8 (7) 1177- 1183
PubMed Link to Article
Lorson  CLHahnen  EAndrophy  EJWirth  B A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci U S A 1999;96 (11) 6307- 6311
PubMed Link to Article
Lefebvre  SBurlet  PLiu  Q  et al.  Correlation between severity and SMN protein level in spinal muscular atrophy. Nat Genet 1997;16 (3) 265- 269
PubMed Link to Article
Baughan  TShababi  MCoady  THDickson  AMTullis  GELorson  CL Stimulating full-length SMN2 expression by delivering bifunctional RNAs via a viral vector. Mol Ther 2006;14 (1) 54- 62
PubMed Link to Article
Schrank  BGötz  RGunnersen  JM  et al.  Inactivation of the survival motor neuron gene, a candidate gene for human spinal muscular atrophy, leads to massive cell death in early mouse embryos. Proc Natl Acad Sci U S A 1997;94 (18) 9920- 9925
PubMed Link to Article
Hsieh-Li  HMChang  JGJong  YJ  et al.  A mouse model for spinal muscular atrophy. Nat Genet 2000;24 (1) 66- 70
PubMed
Monani  URSendtner  MCoovert  DD  et al.  The human centromeric survival motor neuron gene (SMN2) rescues embryonic lethality in Smn(−/−) mice and results in a mouse with spinal muscular atrophy [published correction appears in Hum Mol Genet. 2007;16(21):2648]. Hum Mol Genet 2000;9 (3) 333- 339
PubMed Link to Article
Le  TTPham  LTButchbach  ME  et al.  SMN Delta 7, the major product of the centromeric survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and associates with full-length SMN. Hum Mol Genet 2005;14 (6) 845- 857
PubMed Link to Article
Guettier-Sigrist  SCoupin  GBraun  SWarter  JMPoindron  P Muscle could be the therapeutic target in SMA treatment. J Neurosci Res 1998;53 (6) 663- 669
PubMed Link to Article
Van Damme  PBogaert  EDewil  M  et al.  Astrocytes regulate GluR2 expression in motor neurons and their vulnerability to excitotoxicity. Proc Natl Acad Sci U S A 2007;104 (37) 14825- 14830
PubMed Link to Article
Björklund  AKirik  DRosenblad  CGeorgievska  BLundberg  CMandel  RJ Towards a neuroprotective gene therapy for Parkinson's disease: use of adenovirus, AAV and lentivirus vectors for gene transfer of GDNF to the nigrostriatal system in the rat Parkinson model. Brain Res 2000;886 (1-2) 82- 98
PubMed Link to Article
Azzouz  MLe  TRalph  GS  et al.  Lentivector-mediated SMN replacement in a mouse model of spinal muscular atrophy. J Clin Invest 2004;114 (12) 1726- 1731
PubMed Link to Article
Foust  KDWang  X McGovern  VL  et al.  Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. Nat Biotechnol 2010;28 (3) 271- 274
PubMed Link to Article
Hanna  JWernig  MMarkoulaki  S  et al.  Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 2007;318 (5858) 1920- 1923
PubMed Link to Article
Deshpande  DMKim  YSMartinez  T  et al.  Recovery from paralysis in adult rats using embryonic stem cells. Ann Neurol 2006;60 (1) 32- 44
PubMed Link to Article
Coovert  DDLe  TT McAndrew  PE  et al.  The survival motor neuron protein in spinal muscular atrophy. Hum Mol Genet 1997;6 (8) 1205- 1214
PubMed Link to Article
Brichta  LHofmann  YHahnen  E  et al.  Valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscular atrophy. Hum Mol Genet 2003;12 (19) 2481- 2489
PubMed Link to Article
Mattis  VBRai  RWang  JHChang  CWCoady  TLorson  CL Novel aminoglycosides increase SMN levels in spinal muscular atrophy fibroblasts. Hum Genet 2006;120 (4) 589- 601
PubMed Link to Article
Sumner  CJHuynh  TNMarkowitz  JA  et al.  Valproic acid increases SMN levels in spinal muscular atrophy patient cells. Ann Neurol 2003;54 (5) 647- 654
PubMed Link to Article
Wolstencroft  ECMattis  VBajer  AAYoung  PJLorson  CL A non-sequence-specific requirement for SMN protein activity: the role of aminoglycosides in inducing elevated SMN protein levels. Hum Mol Genet 2005;14 (9) 1199- 1210
PubMed Link to Article
Tsai  LKYang  CCHwu  WLLi  H Valproic acid treatment in six patients with spinal muscular atrophy. Eur J Neurol 2007;14 (12) e8- e9
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Induced pluripotent stem cells (iPSCs) can be lineage restricted to form motor neurons. Motor neurons were differentiated from iPSCs produced from an unaffected fibroblast sample and were stained for the neurofilament protein SMI-32 (red) (original magnification ×100). Cell nuclei appear in blue.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Fibroblast cells can be converted to induced pluripotent stem cells (iPSCs) to model spinal muscular atrophy (SMA). Fibroblast cells were infected with viruses to express reprogramming genes. The iPSCs were cultured as flat colonies and then were lifted to form free-floating aggregate spheres in a nutrient medium. Next, using a series of chemical induction signals, iPSCs were instructed to form motor neurons, which the iPS-SMA and iPS-WT (from his unaffected mother) cells were able to do. Only after additional time in culture did we observe a specific deficit in the iPS-SMA–derived motor neurons. We speculate that this effect could be due to increased reactive oxygen species production or damaged mitochondria in the iPS-SMA cells.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable. Spinal Muscular Atrophy Categories

References

Thomson  JAItskovitz-Eldor  JShapiro  SS  et al.  Embryonic stem cell lines derived from human blastocysts [published correction appears in Science. 1998;282(5395):1827]. Science 1998;282 (5391) 1145- 1147
PubMed Link to Article
Murry  CEKeller  G Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell 2008;132 (4) 661- 680
PubMed Link to Article
Müller  LUDaley  GQWilliams  DA Upping the ante: recent advances in direct reprogramming. Mol Ther 2009;17 (6) 947- 953
PubMed Link to Article
Dimos  JTRodolfa  KTNiakan  KK  et al.  Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 2008;321 (5893) 1218- 1221
PubMed Link to Article
Park  IHArora  NHuo  H  et al.  Disease-specific induced pluripotent stem cells. Cell 2008;134 (5) 877- 886
PubMed Link to Article
Soldner  FHockemeyer  DBeard  C  et al.  Parkinson's disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell 2009;136 (5) 964- 977
PubMed Link to Article
Ebert  ADYu  JYRose  FF  Jr  et al.  Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 2009;457 (7227) 277- 280
PubMed Link to Article
Lefebvre  SBürglen  LReboullet  S  et al.  Identification and characterization of a spinal muscular atrophy-determining gene. Cell 1995;80 (1) 155- 165
PubMed Link to Article
Rochette  CFGilbert  NSimard  LR SMN gene duplication and the emergence of the SMN2 gene occurred in distinct hominids: SMN2 is unique to Homo sapiens. Hum Genet 2001;108 (3) 255- 266
PubMed Link to Article
Pellizzoni  LYong  JDreyfuss  G Essential role for the SMN complex in the specificity of snRNP assembly. Science 2002;298 (5599) 1775- 1779
PubMed Link to Article
Fischer  ULiu  QDreyfuss  G The SMN-SIP1 complex has an essential role in spliceosomal snRNP biogenesis. Cell 1997;90 (6) 1023- 1029
PubMed Link to Article
Liu  QFischer  UWang  FDreyfuss  G The spinal muscular atrophy disease gene product, SMN, and its associated protein SIP1 are in a complex with spliceosomal snRNP proteins. Cell 1997;90 (6) 1013- 1021
PubMed Link to Article
Monani  URLorson  CLParsons  DW  et al.  A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2. Hum Mol Genet 1999;8 (7) 1177- 1183
PubMed Link to Article
Lorson  CLHahnen  EAndrophy  EJWirth  B A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci U S A 1999;96 (11) 6307- 6311
PubMed Link to Article
Lefebvre  SBurlet  PLiu  Q  et al.  Correlation between severity and SMN protein level in spinal muscular atrophy. Nat Genet 1997;16 (3) 265- 269
PubMed Link to Article
Baughan  TShababi  MCoady  THDickson  AMTullis  GELorson  CL Stimulating full-length SMN2 expression by delivering bifunctional RNAs via a viral vector. Mol Ther 2006;14 (1) 54- 62
PubMed Link to Article
Schrank  BGötz  RGunnersen  JM  et al.  Inactivation of the survival motor neuron gene, a candidate gene for human spinal muscular atrophy, leads to massive cell death in early mouse embryos. Proc Natl Acad Sci U S A 1997;94 (18) 9920- 9925
PubMed Link to Article
Hsieh-Li  HMChang  JGJong  YJ  et al.  A mouse model for spinal muscular atrophy. Nat Genet 2000;24 (1) 66- 70
PubMed
Monani  URSendtner  MCoovert  DD  et al.  The human centromeric survival motor neuron gene (SMN2) rescues embryonic lethality in Smn(−/−) mice and results in a mouse with spinal muscular atrophy [published correction appears in Hum Mol Genet. 2007;16(21):2648]. Hum Mol Genet 2000;9 (3) 333- 339
PubMed Link to Article
Le  TTPham  LTButchbach  ME  et al.  SMN Delta 7, the major product of the centromeric survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and associates with full-length SMN. Hum Mol Genet 2005;14 (6) 845- 857
PubMed Link to Article
Guettier-Sigrist  SCoupin  GBraun  SWarter  JMPoindron  P Muscle could be the therapeutic target in SMA treatment. J Neurosci Res 1998;53 (6) 663- 669
PubMed Link to Article
Van Damme  PBogaert  EDewil  M  et al.  Astrocytes regulate GluR2 expression in motor neurons and their vulnerability to excitotoxicity. Proc Natl Acad Sci U S A 2007;104 (37) 14825- 14830
PubMed Link to Article
Björklund  AKirik  DRosenblad  CGeorgievska  BLundberg  CMandel  RJ Towards a neuroprotective gene therapy for Parkinson's disease: use of adenovirus, AAV and lentivirus vectors for gene transfer of GDNF to the nigrostriatal system in the rat Parkinson model. Brain Res 2000;886 (1-2) 82- 98
PubMed Link to Article
Azzouz  MLe  TRalph  GS  et al.  Lentivector-mediated SMN replacement in a mouse model of spinal muscular atrophy. J Clin Invest 2004;114 (12) 1726- 1731
PubMed Link to Article
Foust  KDWang  X McGovern  VL  et al.  Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. Nat Biotechnol 2010;28 (3) 271- 274
PubMed Link to Article
Hanna  JWernig  MMarkoulaki  S  et al.  Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 2007;318 (5858) 1920- 1923
PubMed Link to Article
Deshpande  DMKim  YSMartinez  T  et al.  Recovery from paralysis in adult rats using embryonic stem cells. Ann Neurol 2006;60 (1) 32- 44
PubMed Link to Article
Coovert  DDLe  TT McAndrew  PE  et al.  The survival motor neuron protein in spinal muscular atrophy. Hum Mol Genet 1997;6 (8) 1205- 1214
PubMed Link to Article
Brichta  LHofmann  YHahnen  E  et al.  Valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscular atrophy. Hum Mol Genet 2003;12 (19) 2481- 2489
PubMed Link to Article
Mattis  VBRai  RWang  JHChang  CWCoady  TLorson  CL Novel aminoglycosides increase SMN levels in spinal muscular atrophy fibroblasts. Hum Genet 2006;120 (4) 589- 601
PubMed Link to Article
Sumner  CJHuynh  TNMarkowitz  JA  et al.  Valproic acid increases SMN levels in spinal muscular atrophy patient cells. Ann Neurol 2003;54 (5) 647- 654
PubMed Link to Article
Wolstencroft  ECMattis  VBajer  AAYoung  PJLorson  CL A non-sequence-specific requirement for SMN protein activity: the role of aminoglycosides in inducing elevated SMN protein levels. Hum Mol Genet 2005;14 (9) 1199- 1210
PubMed Link to Article
Tsai  LKYang  CCHwu  WLLi  H Valproic acid treatment in six patients with spinal muscular atrophy. Eur J Neurol 2007;14 (12) e8- e9
PubMed Link to Article

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.

Multimedia

Some tools below are only available to our subscribers or users with an online account.

1,296 Views
12 Citations
×

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
Jobs