An Open-label Safety, Tolerability and Dose-range Finding Study of Multiple Doses of ISIS SMNRx in Patient With Spinal Muscular Atrophy

This study will test the safety, tolerability, and pharmacokinetics of escalating doses of
ISIS-SMNRx administered multiple times over the duration of the trial, as intrathecal
injections. Four dose levels will be evaluated sequentially. Each dose level will be
studied in a cohort of 8 patients, where all patients will receive active drug.

Inclusion Criteria:

- Genetic documentation of 5q SMA (homozygous gene deletion or mutation)

- Clinical signs attributable to Spinal Muscular Atrophy

- Males and females 2 to 15 years of age

- Able to complete all study procedures, measurements, and visits and parent/patient
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

Exclusion Criteria:

- Respiratory insufficiency defined by the medical necessity for invasive or
non-invasive ventilation during a 24 hour period

- Medical necessity for a gastric feeding tube, where the majority of feeds are given
by this route, as assessed by the Site Investigator

- Previous scoliosis surgery that would interfere with the lumbar puncture injection
procedure

- Hospitalization for surgery (i.e. scoliosis surgery) or pulmonary event within 2
months of screening or planned during the duration of the study

- 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 lumbar puncture
procedures or CSF circulation

- Presence of an implanted shunt for the drainage of CSF or an implanted CNS catheter

- History of bacterial meningitis

- Dosing with ISIS 396443 in clinical study ISIS 396443-CS1 Cohorts 2, 3, or 4

- Dosing with ISIS 396443 in clinical study ISIS 396443 - CS10

- Clinically significant abnormalities in hematology or clinical chemistry parameters

- Treatment with investigational drug, biological agent, or device within 1-month of
Screening or 5 half-lives of study agent, whichever is longer. Treatment with
valproate or hydroxyurea within 3-months of screening. 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 compromise the
ability of the patient to undergo study procedures.