an iit clinical study to evaluate the safety, tolerability, and preliminary efficacy of a single intrathecal injection of snug01 in patients with amyotrophic lateral sclerosis

Conditions: Amyotrophic Lateral Sclerosis (ALS)

Summary: this is a multicenter, open-label, single-arm investigator-initiated clinical study designed to evaluate the safety, tolerability, and preliminary efficacy of snug01 in patients with amyotrophic lateral sclerosis (als).

snug01 is a gene therapy designed to deliver a protective protein gene to the central nervous system. safety will be the primary focus during the initial 24 weeks post-treatment (primary study period). after the primary study period, participants will be assessed for both safety and efficacy for up to a total of 5 years following snug01 treatment.

Eligibility criteria:
inclusion criteria: 1.able to understand and voluntarily sign the informed consent form, the informed consent form must be signed before performing any clinical trail procedures. 2.18\~80 years old (including 18 and 80 years old), both male and female. 3.must have been diagnosed with clinically probable als, clinically possible laboratory-supported als, or clinically definite als according to the revised version of the el escorial world federation of neurology criteria. 4.less than or equal to 36 months (inclusive) after the onset of symptoms of amyotrophic lateral sclerosis. 5.body mass index (bmi) ≥19 kg/m2. 6.the forced vital capacity (fvc) in the screening period is greater than or equal to 70% of the estimated vital capacity. 7.amyotrophic lateral sclerosis functional rating scale-revised (alsfrs-r) score ≥ 26 during the screening period, with scores of ≥ 4 in the three respiratory items (dyspnea, orthopnea, and respiratory insufficiency) on the alsfrs-r. 8. adequate organ function: hematological: neutrophil count≥1.5 × 10⁹/l, platelet count≥ 100 × 10⁹/l, hemoglobin ≥90 g/l. renal: creatinine ≤1.5×uln or creatinine clearance (ccr) ≥50 ml/min using the cockcroft-gault formula. hepatic: total bilirubin (tbil), alanine aminotransferase (alt), aspartate aminotransferase (ast)≤2 × uln, alkaline phosphatase (alp) ≤ 3 × uln. coagulation: international normalized ratio (inr), prothrombin time (pt), activated partial thromboplastin time (aptt) ≤1.5 × uln. 9.subjects are not currently receiving riluzole or have been receiving a stable dose of riluzole for at least 4 weeks prior to the screening visit. subjects treated with riluzole are expected to remain on the same dose throughout the study period. 9.subjects are not currently treated with edaravone or are being treated with the approved standard regimen of edaravone. subjects being treated with edaravone must have completed at least 1 cycle of treatment prior to the screening visit and are expected to continue treatment with edaravone throughout the study period. 10.women of childbearing age must have a negative blood pregnancy test during the screening period and be non-lactating. female subjects of childbearing age (women of childbearing age include premenopausal women and women within 2 years after menopause, except those who have undergone bilateral tubal ligation, complete oophorectomy or hysterectomy.) and male subjects whose partners are women of childbearing age must agree to use effective contraceptive methods throughout the study period, such as abstinence, double barrier contraceptive methods, condoms, intrauterine devices and other non-drug contraceptive measures, and are not allowed to donate sperm or eggs. exclusion criteria: 1. serum anti-aav9 neutralizing antibody (nab) titer \&gt; 1:100 at the time of screening. 2. there are contraindications to lumbar puncture during the screening period (including but not limited to skin infection at the administration site and signs or symptoms of increased intracranial pressure), receiving any active intrathecal therapy, and having implants for drainage of cerebrospinal fluid (csf). inserted shunt, presence of implanted central nervous system (cns) cannula, or any condition that prevents csf collection. 3. there are other diseases related to motor neuron dysfunction (progressive bulbar palsy, primary lateral sclerosis, cervical spondylosis, lumbar spondylosis, etc., idiopathic inflammatory myopathy), which may confuse or cover up the diagnosis of als. 4. previously required invasive ventilation or tracheotomy due to als disease, or currently using non-invasive ventilation support with an average of ≥16 hours/day. 5. previous history of gene therapy, hematopoietic stem cell transplantation, and solid organ transplantation. 6. the patient has poorly controlled acute or chronic respiratory diseases, including but not limited to: chronic obstructive pulmonary disease, severe asthma, severe pneumonia, active tuberculosis. 7. those who have been implanted or the researchers estimate that they will need to implant a diaphragmatic pacing system during the study period. 8. any thromboembolic events occurred within 6 months before the first administration, such as deep vein thrombosis, pulmonary arteriovenous embolism, jugular vein embolism, etc.. 9. received another drug for the treatment of als disease (including but not limited to sodium phenylbutyrate (pb), taurine diol (turso), tauroursodeoxycholic acid (tudca) within 4 weeks before the first dose ) or ursodeoxycholic acid (udca), biologics, etc. except riluzole and edaravone). 10. autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, scleroderma, inflammatory myopathies, mixed connective tissue disease, overlap syndrome, etc.) within 30 days prior to the screening period, or ongoing immune-related therapy (e.g., corticosteroids, cyclosporine, tacrolimus, methotrexate, cyclophosphamide, intravenous immunoglobulin, rituximab, leflunomide, hydroxychloroquine, interleukin 2 antagonists, etc.), except for intranasal, inhaled, ocular, topical topical, intra-articular corticosteroid therapy, or physiologic replacement therapy with corticosteroids. 11. suffering from active or uncontrolled infection (including but not limited to: infectious pneumonia, sepsis, herpes zoster infection) within 4 weeks before the first administration, or chronic bacterial infection that is considered unacceptable according to the investigator\&#39;s judgment ( medical history such as tuberculosis). 12. have undergone major surgery within 4 weeks before the first administration, or have not recovered from previous treatment-related adverse events (ae) to ≤ grade 1 (ctcae 5.0), except alopecia. 13. participated in another clinical study within 4 weeks before the first administration, unless it is an observational (non-intervention) clinical study. 14. any febrile illness occurred within 14 days before the first administration. 15. have been vaccinated within 14 days before the first dose. 16. patients with poorly controlled hypertension (refers to resting blood pressure after treatment: systolic blood pressure (sbp) \&gt; 160 mmhg or diastolic blood pressure (dbp) \&gt; 100 mmhg). 17. arterial oxygen saturation and/or finger pulse oxygen saturation \&lt;93% after treatment with oxygen therapy or noninvasive respiratory support (\&lt;16 hrs/day) at the time of screening, as determined by the investigator. 18. hypersensitivity to prednisolone, other glucocorticoids or their excipients. 19. positive hepatitis b surface antigen (hbsag) or positive hepatitis b core antibody (anti-hbcab) with peripheral blood hbv dna titer ≥ 1.0e+02 iu/ml.; positive hepatitis c virus (hcv) antibody with positive hcv rna results; positive human immunodeficiency virus (hiv) antibody; or positive treponemal antibody for syphilis. 20. the following cardiovascular and cerebrovascular diseases, including but not limited to: qtc interval (corrected using fridericia formula) average value: males qtc \&gt; 450 ms, females qtc \&gt; 470 ms. echocardiogram showing left ventricular ejection fraction (lvef) \&lt; 50% or below the lower limit of normal (whichever is higher). history of heart failure of class iii-iv (nyha classification). myocardial infarction, unstable angina, poorly controlled arrhythmia, cerebrovascular accident or transient ischemic attack occurred within 6 months before the first administration; 21. mental illness that may affect compliance with the test requirements: unstable mental illness, cognitive dysfunction, dementia or alcohol dependence, etc. 22. other conditions that the researcher thinks are not suitable for participating in this study.

Keywords: gene therapy aav (adeno-associated virus) als neuromuscular diseases motor neuron disease nervous system diseases