A Pilot Study of Biomarkers for Spinal Muscular Atrophy

Study Overview
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Brief Summary
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The goal of this pilot study is to identify a marker or panel of markers in the blood or urine from a wide range of Spinal Muscular Atrophy (SMA) patients that segregates with measures of clinical severity. From this identification of candidate biomarkers, it is hoped that further investigations, both longitudinal natural history and clinical efficacy studies, will verify a biomarker with the sensitivity and specificity that will allow its eventual use as a validated pharmacodynamic marker or surrogate endpoint. In addition, this effort may elucidate biological pathways that may be potential therapeutic targets.

Detailed Description
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Spinal Muscular Atrophy (SMA) is one of the two most common inherited children's neuromuscular disorders. There currently is no cure and no therapeutics approved to slow progression of the disease. SMA is characterized by a loss of alpha motor neurons in the spinal cord, severe atrophy of proximal muscles and progressive debility and disability due to respiratory, gastrointestinal and functional complications of the disease. Although SMA is a relatively common orphan disease, recruitment of patients for the number of candidate therapies is expected to become rate-limiting for the development of therapeutics. STUDY OBJECTIVES Primary: To identify candidate blood and urine biochemical markers that correlate with disease severity as determined by the Modified Hammersmith Functional Motor Scale across a range of type I, type II and type III children with Spinal Muscular Atrophy (SMA) (1). Secondary: To determine if there are biomarkers from types I-III SMA patients that correlate with SMA type, age at disease onset, 10-meter Timed Walk Test (ambulatory subjects only), pulmonary function, nutritional assessment, SMN protein level, SMN transcript level or SMN2 copy number. To determine if identified candidate biomarkers are associated with the disease state through comparison of SMA specimens with control volunteer specimens. To determine if there are potential biochemical pathways that may represent targets for therapeutic intervention in SMA.

Official Title
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A Pilot Study of Biomarkers for Spinal Muscular Atrophy

Conditions
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Spinal Muscular Atrophy

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 2 to 12 years, inclusive In good health (other than SMA) in the judgement of the clinical investigator ar the time of assessment Exclusion Criteria: Systemic or specific-organ illness Any known genetic condition other than SMA requiring pharmaceutical treatment Use of any putative SMN-enhancing medications or treatments in the past 14 days prior to enrollment Use of carnitine, creatine, oral albuterol or riluzole for 14 days prior to enrollment Use of any oral prescription medications for 14 days prior to enrollment (exceptions: anti-reflux medications, constipation or stoll softening medications, stool bulking agents, and inhaled bronchodilator medications) Any illness requiring treatment of antibiotics or anti-inflammatory medication within the past 14 days Any rash requiring treatment within the past 7 days Any severe asthma attack requiring treatment with oral or parenteral steroids within the past 7 days Any fever over 100 degrees Fahrenheit or 38 degree Celsius within the past 7 days Any immunization within the past 7 days Any injury sustained that resulted in a bone fracture or needed stitches within the past 7 days Any surgery within the past 7 days Any receipt of anesthesia within the past 7 days Any Emergency Room visit or hospitalization within the past 7 days Any stomach illness with vomiting within the past 7 days Any migraine headache within the past 7 days Participation in a clinical trial (except observational studies) within the past 7 days

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| SMA cohort<br>Subjects between the ages of 2-12 years diagnosed with SMA Type I, II, or III. | |
| Control cohort<br>Healthy children between the ages of 2-12 years. These children may be either genetically-related siblings of SMA children (genetically confirmed non-carriers of SMA),or unrelated children. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To identify candidate blood and urine biochemical markers that correlate with disease severity as determined by the Modified Hammersmith Functional Motor Scale across a range of type I, type II and type III children with Spinal Muscular Atrophy (SMA) |  | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine if there are biomarkers from types I-III SMA patients that correlate with SMA type, age at disease onset, 10-meter Timed Walk Test, pulmonary function, nutritional assessment, SMN protein level, SMN transcript level or SMN2 copy number. |  | 1 year | 
| To determine if identified candidate biomarkers are associated with the disease state through comparison of SMA specimens with control volunteer specimens. |  | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Spinal Muscular Atrophy, Blood Biomarkers, Urine Biomarkers, Type I Spinal Muscular Atrophy, Type II Spinal Muscular Atrophy, Type III Spinal Muscular Atrophy, Modified Hammersmith Functional Motor Scale, Disease severity, Biomarkers