A Study to Assess the Safety and Tolerability of Nusinersen (ISIS 396443) in Participants With Spinal Muscular Atrophy (SMA).

Part 2 is an Open Label extension phase.

Key Inclusion Criteria:

- Genetic documentation of 5q SMA homozygous gene deletion, mutation, or compound
heterozygote.

- Onset of clinical signs and symptoms consistent with SMA at ≤6 months of age and have
documentation of 3 SMN2 copies OR onset of clinical signs and symptoms consistent with
SMA at ≤6 months of age, >7 months of age (211 days) at screening, and have
documentation of 2 SMN2 copies OR onset of clinical signs and symptoms consistent with
SMA at >6 months of age, are ≤18 months of age at screening, and have documentation of
2 or 3 SMN2 copies.

- Meets age-appropriate institutional criteria for use of anesthesia/sedation, if use is
planned for study procedures.

- Medical care, such as routine immunizations meets and is expected to continue to meet
guidelines set out in the Consensus Statement for Standard of Care in SMA, in the
opinion of the Investigator.

- Participants with 2 SMN2 copies must reside within approximately 9 hours'
ground-travel distance from a participating study site for the duration of the study.

Key Exclusion Criteria:

- Meets additional study related criteria.

- Any previous exposure to ISIS 396443; previous dosing in this study or previous
studies with ISIS 396443.

- Signs or symptoms of SMA present at birth or within the first week after birth.

- Ventilation for ≥16 hours per day continuously for >21 days at screening.

- Permanent tracheostomy, implanted shunt for CSF drainage, or implanted central nervous
system (CNS) catheter at screening.

- History of brain or spinal cord disease that would interfere with the LP procedure,
CSF circulation, or safety assessments.

- Hospitalization for surgery (e.g., scoliosis surgery), pulmonary event, or nutritional
support within 2 months prior to screening, or hospitalization for surgery planned
during the study.

- Clinically significant abnormalities in hematology or clinical chemistry parameters or
Electrocardiogram (ECG), as assessed by the Investigator.

- Treatment with an investigational drug for SMA (e.g., albuterol/salbutamol, riluzole,
carnitine, sodium phenylbutyrate, valproate, hydroxyurea), biological agent, or device
within 30 days prior to screening. Any history of gene therapy, prior antisense
oligonucleotide (ASO) treatment, or cell transplantation.

For Part 2 only:

To be eligible to participate in Part 2 of this study, participants must meet the following
eligibility criteria at the time of consent to participate in Part 2:

Participation in Part 1 and completion of the End of Part 1 Evaluation assessments.

Ability of parent(s) or legal guardian(s) to understand the purpose and risks of the study
and to provide signed and dated informed consent on the Part 2 informed consent form (ICF)
and authorization to use confidential health information in accordance with national and
local participant privacy regulations.

Able to complete all study procedures, measurements, and visits, and parent or legal
guardian/participant has adequately supportive psychosocial circumstances, in the opinion
of the Investigator.

Participants will be excluded from the Part 2 if they meet the following exclusion
criterion at the time of consent into Part 2 of the study:

Any significant change in clinical status, including laboratory tests that, in the opinion
of the Investigator, would make them unsuitable to participate in Part 2. The Investigator
must reassess the subject's medical fitness for participation and consider any diseases
that would preclude treatment.

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