Spinal Muscular Atrophy (SMA) Biomarkers Study in the Immediate Postnatal Period of Development

Study Description

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Brief Summary:

Spinal muscular atrophy (SMA) is the leading genetic cause of death of infants. Strong preclinical evidence suggests that effective therapy must be delivered as early as possible to prevent progression of the disease. The primary study objective will be to identify prognostic and surrogate biomarkers of disease progression that will facilitate the execution of therapeutic SMA clinical trials in infants.

Condition or disease
Spinal Muscular Atrophy (SMA)

Detailed Description:

October 2013 Enrollment Update: The healthy control enrollment has been filled and is now closed. The study is still enrolling eligible infants with SMA.

Aim 1. To establish the validity of putative physiological SMA biomarkers in the immediate postnatal period. A longitudinal, natural history examination of physiological markers of muscle innervation will be performed in healthy and SMA infants. The first week of life is the ideal first time point, with visits occurring at scheduled visits up to the age two. Compound motor action potential (CMAP) amplitude and electrical impedance myography (EIM) will be examined and will be correlated with motor function. Each of these is associated with muscle innervation and provides information on the number and function of lower motor neurons in the spinal cord, the cellular target of SMA therapeutic interventions. This trial will establish the natural history of these putative SMA biomarkers as the disease evolves in affected infants. Moreover, our approach will allow for measurements in pre-symptomatic and early symptomatic subjects and determine their predictive value.

Aim 2. To establish the validity of putative molecular SMA biomarkers in the immediate postnatal period.SMN2 copy number is a valid, predictive molecular SMA biomarker; however, it is fixed, and therefore not useful as a biomarker of clinical progression or response to therapy. SMN mRNA and protein expression is variable in different cell types and, in mice, naturally decreases with age postnatally. In this study, SMN expression levels will be measured longitudinally in SMA patients and controls. Additional putative molecular SMA markers that have been identified to correlate with motor function will be determined in an effort to distinguish between predictive markers that change prior to development of weakness and those that change as a consequence of weakness.

Study Design

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Study Type :	Observational
Actual Enrollment :	53 participants
Observational Model:	Cohort
Time Perspective:	Prospective
Official Title:	Spinal Muscular Atrophy (SMA) Biomarkers in the Immediate Postnatal Period of Development
Study Start Date :	November 2012
Actual Primary Completion Date :	September 2015
Actual Study Completion Date :	September 2015

Groups and Cohorts

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Group/Cohort
Infants with Spinal Muscular Atrophy; Infants diagnosed Spinal Muscular Atrophy
Healthy controls; Healthy control infants

Outcome Measures

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Primary Outcome Measures :

1. SMA Molecular Biomarker: SMN mRNA Levels [ Time Frame: Up to 24 months ]

   SMN mRNA determination:

   Quantitative RT-PCR: Absolute quantification of full length SMN transcripts will be performed essentially as described (Tiziano, Pinto et al. 2010). Briefly, SMN1 and SMN2 transcripts will be measured in a multiplex reaction and SMN-del7 will be quantified separately. Quantification of GAPDH transcripts will serve to control for RNA quantity and reverse transcriptase efficiency. No template and no reverse transcriptase controls will be included to track potential DNA contamination.

   Multiplex digital PCR: Droplet digital PCR (ddPCR) results in an absolute measure of target molecules. It does not rely on measurements in the log phase of PCR but instead measures the absolute count of positive gene copies. ddPCR will be used to determine SMN levels to further increase reliability and reduce variance in the SMN mRNA level determination.

2. SMA Biomarker: SMN protein levels (SMN protein in PBMCs) [ Time Frame: Up to 24 months ]

   SMN protein in PBMCs SMN cell-based immunoassay: Cell immunoassays will be performed(Kolb, Gubitz et al. 2006). This assay is performed using a single monoclonal antibody for SMN and does not involve the disruption of cells. The sensitivity and reliability of this assay will be compared to the commercially available ELISA assay.

   SMN ELISA: From the same PBMC sample, a commercially available SMN ELISA will also be performed according to the manufacturer's instructions (Enzo Life Sciences, Farmingdale, NY). It is possible that insufficient blood volumes will be collected at any given visit. The analysis will be prioritized as follows from the CPT tube: 1) SMN protein level using cell-based immunoassay, 2) SMN protein level using SMN ELISA. These samples will be coded, and the parent/guardian may request at any time that the child's samples be destroyed at this processing laboratory.

3. SMA Biomarker: Panel of plasma molecules (SMAF SMA Signature Panel) [ Time Frame: Up to 24 months ]
   SMAF SMA Signature Panel The B for SMA pilot study identified over 100 protein analytes that significantly correlated with motor function (as measured by Modified Hammersmith Functional Motor Scale) in SMA patients compared to controls (http://neuinfo.org/bforsma). The SMAF is currently contracted with Myriad Rules-Based Medicine (RBM) to develop a test for a subset of these proteins. The significance of these proteins is uncertain. For example, the proteins that most correlated with motor function in the B for SMA study was cartilage intermediate layer protein 2 and cartilage oligomeric matrix protein. This test analysis will be administered by the company Myriad RBM. These samples will be coded, and the parent/guardian may request at any time that the child's samples be destroyed at Myriad RMB.

Secondary Outcome Measures :

1. SMA Physiological Biomarker: Electrical Impedance Myography (EIM) [ Time Frame: Up to 24 months ]
   Convergence Medical Devices, Inc. has developed a handheld device specifically for performing EIM measurements on patients of all ages including infants. Data obtained with this handheld EIM device has shown marked alterations in the data between healthy and sick patients including those neurogenic and myopathic diseases. The device has not been used in infants to date. However, it has undergone independent safety testing by Intertek and has been used in more than 200 individuals, including 92 pediatric subjects ages 3-12, without any adverse events (AEs). EIM non-invasively measures the impedance of skeletal muscle. We anticipate that EIM will thus likely be able to assist in quantifying the severity of the disease affecting various muscle groups as well as in measuring changes in the disease over time. EIM measurements will be conducted on a core set of four muscles: biceps, the wrist extensor compartment, quadriceps, and tibialis anterior.
2. SMA Physiological Biomarker: Compound Motor Action Potential Testing [ Time Frame: Up to 24 months ]

   Maximumulnar CMAP amplitude and area will be obtained by recording from the abductor digitiminimi muscle following ulnar nerve stimulation at the wrist. All electrophysiologic testing will be performed by certified electromyographers experienced in the assessment of pediatric patients. Maximum values for both negative peak (NP) amplitude and NP area will be obtained. No medications will be used.

   This test is done routinely in this population. Pediatric electrodes and each site's standard electromyograph devices will be utilized. The test, while not considered to be painful, may cause some discomfort similar to a static electric shock. Infants may whimper or cry due to the surprise of the shock. If the first test does not provide adequate results, the evaluator may do a quick second or third stimulus to confirm the maximal response. Each shock lasts approximately 0.1 millisecond. The testing duration is expected to be approximately 30 seconds.

3. Motor Function Scale: Test for Infant Motor Performance Screening Items (TIMPSI) [ Time Frame: Up to 24 months ]
   Test for Infant Motor Performance Screening Items (TIMPSI): The TIMPSI is a reliable and validated, comprehensive assessment of the postural and selective control of movement needed by infants less than 5 months of age for functional activity in the early months of life (Morton, MacLaren et al. 2006; Campbell, Swanlund et al. 2008; Finkel, Hynan et al. 2008). This assessment includes up to 29 different items that assess the child's motor abilities. The test will be performed by a trained pediatric physical therapist. The detailed instructions on administration of the test are provided in the manual of operations. Reliability and validity of the TIMPSI for infants with SMA Type 1 has recently been established.
4. Motor Function Scales: Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND): [ Time Frame: Up to 24 months ]
   Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP IN-TEND): The CHOP INTEND was designed to evaluate the motor skills of patients with SMA-1.(Glanzman, Mazzone et al. 2010) The CHOP INTEND is a reliable measure of motor skills in patients with SMA-I and neuromuscular disorders presenting in infancy. However, further vali-dation is needed. The detailed instructions on administration of the test are provided in the ma-nual of operations.
5. Motor Function Scale: Alberta Infant Motor Scale (AIMS): [ Time Frame: Up to 24 months ]
   Alberta Infant Motor Scale (AIMS): The AIMS incorporates the neuromaturational concept and the dynamical systems theory and is used to measure gross motor maturation of infants from birth through the age of independent walking (Piper, Pinnell et al. 1992, Piper, Darrah et al 1994). In the AIMS, the impact of neurological components on motor development is reflected by a sequence of motor skills, which are used as the basis of assessment. (Piper, Darrah et al. 1994). The scale follows the principles of dynamical systems because motor skills are tested by observing infants as they move into and out of 4 positions: prone, supine, sitting, and standing. The detailed instructions on administration of the test are provided in the manual of operations.

Biospecimen Retention:   Samples With DNA

Absolute quantification of full length SMN transcripts will be performed. The SMN1 and SMN2 transcripts will be measured in a multiplex reaction and SMN-del7 will be quantified separately. Droplet digital PCR will be used to determine SMN levels to further increase reliability and reduce variance in the SMN mRNA level determination. SMN protein in PBMCs SMN cell-based immunoassays will be performed. This assay is performed using a single monoclonal antibody for SMN and does not involve the disruption of cells. From the same PBMC sample, a commercially available SMN ELISA will also be performed according to the manufacturer's instructions. The B for SMA pilot study identified over 100 protein analytes that significantly correlated with motor function in SMA patients compared to controls.

Eligibility Criteria

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Ages Eligible for Study:	up to 6 Months (Child)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	Yes
Sampling Method:	Non-Probability Sample

Study Population

Fifty four (54) volunteers will be enrolled at 15 NeuroNEXT Network centers. Any volunteer who signs an informed consent form and has blood collected for the study is considered enrolled.

Recruitment will be coordinated nationally through the Families of SMA Patient Network and NeuroNEXT who will help with the following:

• Identifying infants diagnosed genetically with SMA because of a clinical suspicion prior to 6 months of age.
• Publicize the project to raise awareness in medical and non-medical communities.

Any normal infant may enroll in this study.

Criteria

Inclusion Criteria:

All infants will be between 0-6 months of age at the time of enrollment. Parents or guardians of the enrolled infants must sign an informed consent form prior to any study procedure being performed.

The infants with SMA must have already had a positive DNA test outside of the study to qualify for enrollment. An infant with SMA can have any number of SMN2 gene copies. Knowledge of the number of SMN2 gene copies prior to enrollment is not required.

Healthy control infants who meet the following criteria will be enrolled:

• Birth between 36 and 42 weeks inclusive of gestation
• Siblings of children with SMA must have had prior SMA genetic testing completed con-firming the infant is a healthy control
• Principal investigator feels the family/infant is able and willing to comply with study procedures
• Parent or guardian able to give informed consent

SMA infants who meet the following criteria will be enrolled:

• Birth between 36 and 42 weeks inclusive of gestation
• Positive SMN1 gene mutation/deletion
• Principal investigator feels the family/infant is able and willing to comply with study procedures
• Parent or guardian able to give informed consent

Exclusion Criteria:

• Use of any putative therapy intended to increase the amount of SMN protein in cells
• Enrollment in an SMA therapeutic trial at the time of enrollment in the SMA biomarker study
• Have a systemic illness requiring ongoing treatment, such as pneumonia
• Clinically significant abnormal findings (as determined by the investigator) on the physical examination or medical history (including history of tracheostomy tubes and ventilator-dependency)
• Dependency upon non-invasive ventilatory support (ie: BiPAP) for more than 12 hours/day

Contacts and Locations

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Locations

United States, California
University of California - Davis
Davis, California, United States, 95616
University of California - Los Angeles
Los Angeles, California, United States, 90095
United States, Colorado
Children's Hospital Colorado
Aurora, Colorado, United States, 80045
United States, District of Columbia
Children's National Medical Center
Washington, District of Columbia, United States, 20010
United States, Illinois
Ann & Robert H. Lurie Children's Hospital of Chicago
Chicago, Illinois, United States, 60611
United States, Massachusetts
Boston Children's Hospital
Boston, Massachusetts, United States, 02115
United States, Missouri
Children's Mercy Hospital
Kansas City, Missouri, United States, 64108
Washington University in St. Louis School of Medicine
Saint Louis, Missouri, United States, 63110
United States, New York
Columbia University Medical Center
New York, New York, United States, 10032
State University of New York Upstate Medical Center
Syracuse, New York, United States, 13210
United States, Ohio
Nationwide Children's Hospital
Columbus, Ohio, United States, 43205
United States, Oregon
Doernbecher Children's Hospital
Portland, Oregon, United States, 97239
United States, Tennessee
Vanderbilt University
Nashville, Tennessee, United States, 37212
United States, Texas
Children's Medical Center of Dallas
Dallas, Texas, United States, 75235
United States, Utah
University of Utah Health Sciences Center
Salt Lake City, Utah, United States, 84132

Sponsors and Collaborators

Ohio State University

National Institute of Neurological Disorders and Stroke (NINDS)

Families of Spinal Muscular Atrophy

Massachusetts General Hospital

University of Iowa

Investigators

Principal Investigator:	Stephen J Kolb, MD PhD	Ohio State University

More Information

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications:

Campbell SK, Swanlund A, Smith E, Liao PJ, Zawacki L. Validity of the TIMPSI for estimating concurrent performance on the test of infant motor performance. Pediatr Phys Ther. 2008 Spring;20(1):3-10. doi: 10.1097/PEP.0b013e31815f66a6.

Dominguez E, Marais T, Chatauret N, Benkhelifa-Ziyyat S, Duque S, Ravassard P, Carcenac R, Astord S, Pereira de Moura A, Voit T, Barkats M. Intravenous scAAV9 delivery of a codon-optimized SMN1 sequence rescues SMA mice. Hum Mol Genet. 2011 Feb 15;20(4):681-93. doi: 10.1093/hmg/ddq514. Epub 2010 Nov 30.

Finkel RS, Hynan LS, Glanzman AM, Owens H, Nelson L, Cone SR, Campbell SK, Iannaccone ST; AmSMART Group. The test of infant motor performance: reliability in spinal muscular atrophy type I. Pediatr Phys Ther. 2008 Fall;20(3):242-6. doi: 10.1097/PEP.0b013e318181ae96.

Foust KD, Wang X, McGovern VL, Braun L, Bevan AK, Haidet AM, Le TT, Morales PR, Rich MM, Burghes AH, Kaspar BK. Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. Nat Biotechnol. 2010 Mar;28(3):271-4. doi: 10.1038/nbt.1610. Epub 2010 Feb 28.

Hua Y, Sahashi K, Hung G, Rigo F, Passini MA, Bennett CF, Krainer AR. Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model. Genes Dev. 2010 Aug 1;24(15):1634-44. doi: 10.1101/gad.1941310. Epub 2010 Jul 12.

Kolb SJ, Gubitz AK, Olszewski RF Jr, Ottinger E, Sumner CJ, Fischbeck KH, Dreyfuss G. A novel cell immunoassay to measure survival of motor neurons protein in blood cells. BMC Neurol. 2006 Feb 1;6:6.

Kolb SJ, Kissel JT. Spinal muscular atrophy: a timely review. Arch Neurol. 2011 Aug;68(8):979-84. doi: 10.1001/archneurol.2011.74. Epub 2011 Apr 11.

Le TT, McGovern VL, Alwine IE, Wang X, Massoni-Laporte A, Rich MM, Burghes AH. Temporal requirement for high SMN expression in SMA mice. Hum Mol Genet. 2011 Sep 15;20(18):3578-91. doi: 10.1093/hmg/ddr275. Epub 2011 Jun 13.

Lutz CM, Kariya S, Patruni S, Osborne MA, Liu D, Henderson CE, Li DK, Pellizzoni L, Rojas J, Valenzuela DM, Murphy AJ, Winberg ML, Monani UR. Postsymptomatic restoration of SMN rescues the disease phenotype in a mouse model of severe spinal muscular atrophy. J Clin Invest. 2011 Aug;121(8):3029-41. doi: 10.1172/JCI57291. Epub 2011 Jul 25.

Morton JP, MacLaren DP, Cable NT, Bongers T, Griffiths RD, Campbell IT, Evans L, Kayani A, McArdle A, Drust B. Time course and differential responses of the major heat shock protein families in human skeletal muscle following acute nondamaging treadmill exercise. J Appl Physiol (1985). 2006 Jul;101(1):176-82. Epub 2006 Mar 24.

Narver HL, Kong L, Burnett BG, Choe DW, Bosch-Marcé M, Taye AA, Eckhaus MA, Sumner CJ. Sustained improvement of spinal muscular atrophy mice treated with trichostatin A plus nutrition. Ann Neurol. 2008 Oct;64(4):465-70. doi: 10.1002/ana.21449.

Passini MA, Bu J, Richards AM, Kinnecom C, Sardi SP, Stanek LM, Hua Y, Rigo F, Matson J, Hung G, Kaye EM, Shihabuddin LS, Krainer AR, Bennett CF, Cheng SH. Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy. Sci Transl Med. 2011 Mar 2;3(72):72ra18. doi: 10.1126/scitranslmed.3001777.

Piper MC, Pinnell LE, Darrah J, Maguire T, Byrne PJ. Construction and validation of the Alberta Infant Motor Scale (AIMS). Can J Public Health. 1992 Jul-Aug;83 Suppl 2:S46-50.

Porensky PN, Mitrpant C, McGovern VL, Bevan AK, Foust KD, Kaspar BK, Wilton SD, Burghes AH. A single administration of morpholino antisense oligomer rescues spinal muscular atrophy in mouse. Hum Mol Genet. 2012 Apr 1;21(7):1625-38. doi: 10.1093/hmg/ddr600. Epub 2011 Dec 20.

Rutkove SB, Shefner JM, Gregas M, Butler H, Caracciolo J, Lin C, Fogerson PM, Mongiovi P, Darras BT. Characterizing spinal muscular atrophy with electrical impedance myography. Muscle Nerve. 2010 Dec;42(6):915-21. doi: 10.1002/mus.21784.

Tiziano FD, Pinto AM, Fiori S, Lomastro R, Messina S, Bruno C, Pini A, Pane M, D'Amico A, Ghezzo A, Bertini E, Mercuri E, Neri G, Brahe C. SMN transcript levels in leukocytes of SMA patients determined by absolute real-time PCR. Eur J Hum Genet. 2010 Jan;18(1):52-8. doi: 10.1038/ejhg.2009.116.

Valori CF, Ning K, Wyles M, Mead RJ, Grierson AJ, Shaw PJ, Azzouz M. Systemic delivery of scAAV9 expressing SMN prolongs survival in a model of spinal muscular atrophy. Sci Transl Med. 2010 Jun 9;2(35):35ra42. doi: 10.1126/scitranslmed.3000830.

Responsible Party:	Stephen J. Kolb, Prinicipal Investigator of NeuroNEXT, Ohio State University
ClinicalTrials.gov Identifier:	NCT01736553 History of Changes
Other Study ID Numbers:	NN101; U01NS079163 ( U.S. NIH Grant/Contract )
First Posted:	November 29, 2012
Last Update Posted:	October 14, 2015
Last Verified:	October 2015

Keywords provided by Stephen J. Kolb, Ohio State University:

Spinal Muscular Atrophy (SMA) Biomarkers; Healthy controls; Infants

Additional relevant MeSH terms:

Atrophy; Muscular Atrophy; Muscular Atrophy, Spinal; Pathological Conditions, Anatomical; Neuromuscular Manifestations; Neurologic Manifestations; Nervous System Diseases	Signs and Symptoms; Spinal Cord Diseases; Central Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; Neuromuscular Diseases