Please select the eligibility criteria that correspond to the clinical trial below.
Title: In Vivo Study of Safety, Tolerability and Dosing Effect on SMN mRNA and Protein Levels of Valproic Acid in Patients With Spinal Muscular Atrophy
Brief Summary: This is an open label phase I/II clinical trial to assess safety, tolerability and potential effect on SMN mRNA and protein in vivo of a compound in which preliminary evidence supports a potential effect on SMN levels in vitro.


Options:
A: Inclusion Criteria:

* Patients must have a diagnosis of SMA, confirmed by genetic testing
* Only patients 2 years of age and older at enrollment will be eligible

Exclusion Criteria:

* Patients taking any medications with known hepatotoxicity, congenital metabolic disorders or on multiple anticonvulsant medications
* Patients taking medications which may interact with VPA
* Patients on ventilatory support for more than 16 hours per day
* Patients currently enrolled in other treatment trials
B: Key Inclusion Criteria:

* Genetic documentation of 5q SMA (homozygous gene deletion or mutation)
* Onset of clinical signs and symptoms consistent with SMA at ≥ 21 days and \<6 months (180 days) of age
* At study entry, receiving adequate nutrition and hydration (with or without gastrostomy), in the opinion of the Site Investigator
* Body weight \>5th percentile for age using Center of Disease Control and Prevention (CDC) guidelines
* Medical care meets and is expected to continue to meet guidelines set out in the Consensus Statement for Standard of Care in SMA (Wang et al. 2007), in the opinion of the Site Investigator
* Gestational age of 35 to 42 weeks and gestation body weight ≥2 kg
* Reside within approximately 9 hours ground-travel distance from a participating study center for the duration of the study. Residence \>2 hours ground-travel distance from a study center must obtain clearance from the Site Investigator and the study Medical Monitor
* Able to complete all study procedures, measurements and visits and parent or guardian/participant has adequately supportive psychosocial circumstances, in the opinion of the Site Investigator

Exclusion Criteria:

* Hypoxemia (O2 saturation awake \<96% or O2 saturation asleep \<96%, without ventilation support)
* Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the screening period
* History of brain or spinal cord disease that would interfere with the lumbar puncture (LP) procedures, CSF circulation, or safety assessments
* Presence of an implanted shunt for the drainage of cerebrospinal fluid (CSF) or an implanted central nervous system (CNS) catheter
* History of bacterial meningitis
* Clinically significant abnormalities in hematology or clinical chemistry parameters, as assessed by the Site Investigator, at screening that would render the participant unsuitable for inclusion
* Treatment with another investigational drug (e.g., albuterol, riluzole, carnitine, creatine, sodium phenylbutyrate, salbutamol, valproate, hydroxyurea etc), biological agent, or device within 90 days prior to enrollment or anytime during the study. Any history of gene therapy or cell transplantation
* The participants parent(s) or legal guardian(s) is unable to understand the nature, scope, and possible consequences of the study, or does not agree to comply with the protocol defined schedule of assessments
* Ongoing medical condition that according to the Site Investigator would interfere with the conduct and assessments of the study. Examples are medical disability other than SMA that would interfere with the assessment of safety or would compromise the ability of the participant to undergo study procedures

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.
C: Key Inclusion Criteria:

* Documented Survival Motor Neuron1 (SMN1) homozygous gene deletion
* Clinical signs attributable to Spinal Muscular Atrophy (SMA)
* Able to complete all study procedures, measurements and visits and parent/participant has adequately supportive psychosocial circumstances, in the opinion of the investigator
* Estimated life expectancy \> 2 years from Screening
* Meets age-appropriate institutional criteria for use of anesthesia/sedation, if use is planned for study procedure

Key Exclusion Criteria:

* Respiratory insufficiency defined by the need for invasive or non-invasive ventilation during a 24 hour period
* Presence of a gastric feeding tube
* Previous scoliosis surgery or scoliosis surgery planned during the duration of the study that would interfere with the lumbar puncture (LP) injection procedure
* Hospitalization for surgery or pulmonary event within the last 2 months or planned during the study
* Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy
* History of brain or spinal cord disease that would interfere with LP procedures or cerebrospinal fluid (CSF) circulation
* Presence of an implanted shunt for the draining of CSF or an implanted Central Nervous System (CNS) catheter
* History of bacterial meningitis
* Clinically significant abnormalities in hematology or clinical chemistry parameters
* Treatment with another investigational drug, biological agent, or device within 1-month of Screening or 5 half-lives of study agent whichever is longer. Any history of gene therapy or cell transplantation
* Ongoing medical condition that would interfere with the conduct and assessments of the study. Examples are medical disability (e.g. wasting or cachexia, severe anemia, etc.) that would interfere with the assessment of safety or would compromised the ability of the participant to undergo study procedures

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.
D: Inclusion Criteria:

* Six or nine months of age and younger (depending on cohort) on day of vector infusion with Type 1 SMA as defined by the following features:

  * Diagnosis of SMA based on gene mutation analysis with bi-allelic SMN1 mutations (deletion or point mutations) and 2 copies of SMN2.
  * Onset of disease at birth up to 6 months of age.
  * Hypotonia by clinical evaluation with delay in motor skills, poor head control, round shoulder posture and hypermobility of joints.

Exclusion Criteria:

* Active viral infection (includes HIV or serology positive for hepatitis B or C)
* Use of invasive ventilatory support (tracheotomy with positive pressure)\* or pulse oximetry \<95% saturation.
* Patients may be put on non-invasive ventilator support (BiPAP) for less than 16 hours a day at the discretion of their physician or research staff.
* Concomitant illness that in the opinion of the PI creates unnecessary risks for gene transfer
* Concomitant use of any of the following drugs: drugs for treatment of myopathy or neuropathy, agents used to treat diabetes mellitus, or ongoing immunosuppressive therapy or immunosuppressive therapy within 3 months of starting the trial (e.g. corticosteroids, cyclosporine, tacrolimus, methotrexate, cyclophosphamide, intravenous immunoglobulin, rituximab)
* Patients with Anti-AAV9 antibody titers \>1:50 as determined by ELISA binding immunoassay.
* Abnormal laboratory values considered clinically significant (GGT \> 3XULN, bilirubin ≥ 3.0 mg/dL , creatinine ≥ 1.8 mg/dL, Hgb \< 8 or \> 18 g/Dl; WBC \> 20,000 per cmm) Participation in a recent SMA treatment clinical trial that in the opinion of the PI creates unnecessary risks for gene transfer.
* Family does not want to disclose patient's study participation with primary care physician and other medical providers.
* Patient with signs of aspiration based on a swallowing test and unwilling to use an alternative method to oral feeding.
* Patients with a single base substitution in SMN2 (c.859G\>C in exon 7) will be excluded based on predicted mild phenotype.

Answer: A