SOD1 Kinetics Measurements in ALS Patients

Background: Novel targeted therapeutic strategies are being developed for genetic subsets of
ALS, such as those caused by dominantly inherited mutations in the superoxide dismutase 1
gene (SOD1). Investigators have developed an antisense oligonucleotide (ASO) inhibitor of
SOD1 biosynthesis for ALS patients who carry mutations in SOD1. This ASO is now ready for
clinical trial (ClinicalTrials.gov #NCT02623699). The initial success of the ASO will depend
on showing a pharmacodynamics result on SOD1 in participants, and thus a key challenge in
applying this targeted therapy involves rigorous examination of pharmacodynamics markers.

The Investigator's previous data suggest that SOD1 in the cerebral spinal fluid (CSF) will be
an excellent pharmacodynamics marker for an SOD1-focused therapeutic approach. However, one
of the central missing components in understanding SOD1 as a marker is SOD1 CSF half-life
data. The half-life of this protein will aid in clinical trial planning since half-life
influences the amount of SOD1 protein reduction by ASO and thus dictates the optimal timing
of drug administration and CSF collection for pharmacodynamics measures.

Objectives:

- Enroll a total of 86 ALS participants

- Determine the kinetics for total SOD1 protein, as well as the wild type and mutant
protein separately

- Determine this in patients with known SOD1 mutation as well as sporadic ALS patients
Eligibility

- Adults over age 18

- fALS with confirmed genetic testing showing a mutation in the SOD1 gene; asymptomatic
SOD1 gene carriers and sporadic ALS patients.

Measures: The key outcome of this study is to determine the half-life of the SOD1 protein in
symptomatic and asymptomatic ALS patients which will provide critical information to inform
future therapeutic studies in ALS. For ALS patients, The Investigators will also perform Slow
Vital Capacity testing and the ALSFRS-R at the screening visit and at each lumbar puncture
visit.

Measures: Participants will have up to 7 in-person visits over 4 months. The study involves
labeling or marking SOD1 with a special type of leucine. Leucine is an essential amino acid
that is found in the foods we eat. This method involves an overnight stay for a 16 hour
intravenous infusion of labeled leucine along with a collection blood and urine followed by 5
lumbar punctures scheduled over the period of 4 months.

At each subsequent visit, subjects will undergo a blood draw, urine collection, lumbar
puncture, a questionnaire (ALS Functional Rating Scale) which measures motor function, and a
breathing test to determine Slow Vital Capacity (SVC) measurements.

Analysis: In addition to determining the half-life of the SOD1 protein in ALS patients, the
Investigators will also analyze the kinetics of wild type SOD1 protein separately from mutant
SOD1 protein to determine differences in half life. The Investigators will also compare CSF
Tau half-life between ALS patients and controls as a disease specificity control. The
Investigators hope to correlate this data with clinical measures which may reveal other
important hypotheses regarding SOD1 kinetic rates and disease manifestations.

Inclusion Criteria (with exceptions for each group):

- Males or females of any race aged 18 or older

- Positive for SOD1 mutation (SOD1 ALS only)

- Diagnosed with Definite, Probable or Possible ALS in accordance with El Escorial
criteria (ALS and SOD1 Positive ALS only)

- Able to hold position and breathe comfortably for the duration of the LP procedure as
determined by the LP physician or Nurse Practitioner

- Subjects must be able to provide informed consent

Exclusion Criteria for all groups:

- Invasive ventilator dependence, such as tracheostomy

- Medically unable to undergo lumbar puncture (LP) as determined by the investigator
(i.e.,bleeding disorder, allergy to local anesthetics, a skin infection at or near the
LP site, or evidence of high intracranial pressure).

- Any active dermatologic disease.

- Any connective tissue disease including systemic lupus erythematous, Sjögren's
syndrome, scleroderma or mixed connective tissue disease.

- Any known or suspected abnormal CSF pressure or intracranial/intraspinal tumors.

- Use of anticoagulant medication (eg. warfarin, dalteparin, enoxaparin, rivaroxaban,
fondaparinux, dabigatran) that cannot be safely withheld until coagulation parameters
have normalized prior to lumbar puncture and for up to a week following the lumbar
puncture.

- Blood dyscrasia, abnormal bleeding diathesis, or the use of dialysis for renal
failure.

- Clinical judgment of the Site Investigator that the subject would be unable to undergo
multiple lumbar punctures.

- Safety lab values greater than 2X the upper limit of normal

- Allergy to Lidocaine

- Pregnancy

- Any contraindication for lumbar puncture