Please select the eligibility criteria that correspond to the clinical trial below.
Title: An Open-Label Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of Multiple Doses of ISIS 396443 Delivered Intrathecally to Subjects With Genetically Diagnosed and Presymptomatic Spinal Muscular Atrophy
Brief Summary: The primary objective of the study is to examine the efficacy of multiple doses of Nusinersen administered intrathecally in preventing or delaying the need for respiratory intervention or death in infants with genetically diagnosed and presymptomatic spinal muscular atrophy (SMA). Secondary objectives of this study are to examine the effects of Nusinersen in infants with genetically diagnosed and presymptomatic SMA.


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:

* Age ≤ 6 weeks at first dose.
* Genetic documentation of 5q SMA homozygous gene deletion or mutation or compound heterozygous mutation.
* Genetic documentation of 2 or 3 copies of survival motor neuron 2 (SMN2).
* Ulnar compound muscle action potential (CMAP) ≥ 1 mV at Baseline.
* Gestational age of 37 to 42 weeks for singleton births; gestational age of 34 to 42 weeks for twins.
* Meet additional study related criteria.

Key Exclusion Criteria:

* Hypoxemia (oxygen saturation \<96% awake or asleep without any supplemental oxygen or respiratory support).
* Any clinical signs or symptoms at Screening or immediately prior to the first dosing (Day 1) that are, in the opinion of the Investigator, strongly suggestive of SMA.
* Clinically significant abnormalities in hematology or clinical chemistry parameters.
* Treatment with an investigational drug given for the treatment of SMA biological agent, or device. Any history of gene therapy, prior antisense oligonucleotide (ASO) treatment, or cell transplantation.
* Meet additional study related criteria.

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

Cohort 1

* Confirmed genetic diagnosis of 5q SMA
* SMA 2 or non-ambulatory SMA 3: all subjects must be able to sit independently for at least 3 seconds without support
* Age 2 to 8 years at time of enrollment

Cohort 2

* Confirmed genetic diagnosis of 5q SMA
* SMA subjects (SMA types 2 or 3) who can stand independently without braces or other support for up to 2 seconds, or walk independently
* Age 3 to 17 years at time of study enrollment

Exclusion Criteria:

Cohort 1

* Need for BiPAP support \> 12 hours per day
* Spinal rod or fixation for scoliosis or anticipated need within six months of enrollment
* Inability to meet study visit requirements or cooperate reliably with functional testing
* Coexisting medical conditions that contraindicate travel, testing or study medications
* Use of medications or supplements which interfere with valproic acid or carnitine metabolism within 3 months of study enrollment.
* Current use of either VPA or carnitine. If study subject is taking VPA or carnitine then patient must go through a washout period of 12 weeks before enrollment into the study
* Body Mass Index \> 90th % for age

Cohort 2

* Spinal rod or fixation for scoliosis or anticipated need within six months of enrollment
* Inability to meet study visit requirements or cooperate with functional testing
* Transaminases, amylase or lipase \> 3.0 x normal values, WBC \< 3.0 or neutropenia \< 1.0, platelets \< 100 K, or hematocrit \< 30 persisting over a 30 day period.
* Coexisting medical conditions that contraindicate travel, testing or study medications
* Use of medications or supplements which interfere with valproic acid or carnitine metabolism within 3 months of study enrollment.
* Current use of either VPA or carnitine. If study subject is taking VPA or carnitine then patient must be go through a washout period of 12 weeks before enrollment in the study.
* Body Mass Index \> 90th % for age
* Pregnant women/girls, or those intending to try to become pregnant during the course of the study.
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: B