Safety, Tolerability, and Efficacy Study of Intrathecally Administered Gene Therapy AMT-162 in ALS Patients With SOD1 Mutations

Inclusion Criteria: Subjects diagnosed with mutant SOD1-mediated ALS experiencing signs and/or symptoms of lower motor neuron dysfunction, with or without upper motor neuron symptoms. Subjects with rapidly progressing disease ("fast" progressors), defined as average ALS Functional Rating Scale - Revised decline ≥1.0 per month calculated from score at onset of symptoms compared to score at Screening ALSFRS-R. ALSFRS-R score ≥ 25 at Screening. Slow vital capacity (SVC) ≥65% of predicted normal value. King's stage ≤3 at Screening Capable of providing informed consent and complying with trial procedures, in the documented opinion of the Investigator. Titer for neutralizing antibodies (NAb) to AAV rh10 >[1:50] at Screening Normal renal clearance at Screening. Normal coagulation function. Platelet count >150 10^3/mm^3. For subjects on anticoagulant or antiplatelet therapy: able to temporarily stop or bridge therapy for the AMT-162/placebo administration procedures. Exclusion Criteria: SOD1 mutation in positions 2-12 of the MiR targeting sequence, also defined as complementary deoxyribonucleic acid (cDNA) position 128-139, which also corresponds to amino acid regions 43-47. (Position 1 is defined as the start codon ATG.). Homozygosity for the D91A (formerly D90A) SOD1 gene mutation. History of significant chronic pain or sensory syndrome. Presence of unstable psychiatric illness. Active suicidal ideation within 6 months prior to screening. Reproductive status that includes any of the following: Women who are pregnant or have positive pregnancy test at Screening or during Lead-in period Women who are breastfeeding Women of childbearing potential (WOCBP) who are unwilling or unable to use birth control to avoid pregnancy for the entire study period Men who are unwilling to use birth control for the entire study period History of structural CNS disease, may impact intrathecal infusion or cause difficulty placing the catheter. Known allergy or sensitivity to immunosuppression regimens in this protocol Unstable cardiac function. Uncontrolled blood pressure, defined as systolic ≥ 180 millimeters of mercury (mmHg) or diastolic ≥ 120 mmHG Malignancy within 5 years prior to first dose of immunosuppression unless treated definitively without evidence of recurrence Known immunocompromised status including individuals who have undergone organ transplantation; who test positive at Screening for the human immunodeficiency virus (HIV), HCV antibody (anti-HCV) or hepatitis B surface antigen (HBsAg); or who have history of active tuberculosis (TB) or a positive tuberculosis blood test during Screening Anticipated survival, per Investigator judgment, that is shorter than the duration of Screening plus Lead-in plus 6 months after treatment in Part 1 or Part 2 Presence of tracheostomy and/or dependent on mechanically assisted ventilation, defined as being unable to lay supine without it, unable to sleep without it, or continuous daytime use- with exception of continuous positive airway pressure (CPAP) and bilevel positive airway pressure (BiPAP) for obstructive sleep apnea. Presence of an implanted shunt for the drainage of CSF or an implanted CNS catheter Laboratory test values during Screening or during the Lead-in period that are clinically significant in the opinion of the Investigator. Any of the following prior or concomitant treatments: Change in dose of riluzole (RILUTEK®, TIGLUTIK®) or edaravone (RADICAVA®) within 30 days prior to immunosuppression (i.e., riluzole and/or edaravone are allowed if dose is stable). Concomitant medications contraindicated for use with rituximab or sirolimus, including strong inducers and strong inhibitors of CYP3A4 and P-glycoprotein. Chronic systemic corticosteroid use, defined as >10 mg of prednisone or equivalent systemic corticosteroid taken for more than 2 consecutive weeks within 2 months prior to first dose of immunosuppression. Treatment with stem cells for any indication within 6 months prior to first dose of immunosuppression. Any prior treatment with SOD suppression therapy (viral microRNA or antisense oligonucleotide (ASO) mediators). Any prior administration of an AAV gene therapy. Treatment with any other investigational study medication within 90 days prior to signing IC.F Planned treatment with live vaccines during Lead-in period or at any time after receipt of AMT-162/placebo. Warfarin within 30 days prior to Screening labs. If a subject switches to a different anticoagulant for the sole purpose of meeting criteria for participation in the study, ICF should be signed before the switch. Presence of any other condition or clinically significant laboratory values which, in the opinion of the Investigator (by its nature or by being inadequately controlled), might put the subject at significantly higher risk due to participation in the study or might influence the results of the study or the subject's ability to complete the study