Unrelated Umbilical Cord Blood Transplantation for the Treatment of Amyotrophic Lateral Sclerosis (ALS)

A Single-Arm, Open-Label, Single-Center Clinical Study on Unrelated Umbilical Cord Blood Transplantation for the Treatment of Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder. Its global prevalence is approximately 0.73-1.89 per 100,000 individuals. In China, there are about 200,000 ALS patients, with approximately 25,000 new cases diagnosed annually. Microglia, the resident immune cells of the central nervous system (CNS), rapidly transition from a resting state to a pro-inflammatory phenotype (M1) in ALS. This activation leads to the release of a large number of inflammatory factors (such as TNF-α, IL-1β, IL-6, NO, ROS) and chemokines (such as MCP-1/CCL2), and triggers the NLRP3 inflammasome. Furthermore, systemic immune dysregulation plays a significant role in the pathogenesis of ALS. ALS patients exhibit reduced numbers of regulatory T cells (Tregs), alterations of activated CD8+ T cell infiltrates, and a shift in the helper T cell (Th1/Th2) balance towards the pro-inflammatory Th1 phenotype. In recent years, therapeutic strategies targeting novel pathways such as neuroinflammation, immune dysregulation, and energy metabolism have emerged, including the infusion of Tregs, mesenchymal stem cells (MSCs), and neural stem cells. However, these approaches have still failed to halt disease progression [NCT05695521, NCT03280056, NCT06973629, NCT02290886]. Recent research suggests that hematopoietic stem cell transplantation (HSCT) may disrupt the activation cycle between astrocytes and microglia, alleviate chronic inflammatory states in the CNS, partially mitigate mitochondrial dysfunction, and thereby slow neurodegeneration. Unrelated umbilical cord blood transplantation offers advantages such as low HLA-matching requirements, a lower risk of graft-versus-host disease (GVHD), a potent graft-versus-leukemia (GVL) effect, and immediate availability. Investigators plan to conduct an exploratory clinical trial to evaluate the safety and efficacy of umbilical cord blood transplantation for ALS patients. The preliminary plan is to enroll 8 adult subjects. Following successful neutrophil engraftment (defined as an absolute neutrophil count ≥0.5×10⁹/L for three consecutive days) and confirmation of complete donor chimerism. The trial will focus on assessing transplantation-related complications and patient tolerance. A 3-month post-transplantation follow-up will be conducted for a comprehensive evaluation of safety and efficacy for ALS patients.

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Inclusion Criteria:

• Patients with a confirmed diagnosis of ALS, with an ALSFRS-R score ≥35 and a maximum vital capacity ≥65%
• Aged >35 years and <50 years, with no gender restrictions
• Karnofsky Performance Status (KPS) score ≥70, and Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2
• Unrelated umbilical cord blood and the recipient demonstrate high-resolution HLA (-A, -B, Cw, DR, DQ) matching at ≥4/6, 5/8, or 7/10 loci, and the post-thaw CD34+ cell count in the cord blood unit is ≥1.2×10⁵/kg (recipient body weight)
• Willing and able to comply with the study procedures and conditions, demonstrating good compliance
• Willing to receive at least two years of treatment and follow-up, with detailed medical records maintained
• The patient and/or their legal guardian voluntarily participate in this clinical trial, sign the informed consent form, and are capable of completing all follow-up assessments as required by the protocol

Exclusion Criteria:

• Patients with positive results in the following etiological tests: Human Immunodeficiency Virus (HIV-1/2), Human Cytomegalovirus DNA (HCMV-DNA), Epstein-Barr Virus DNA (EBV-DNA), Hepatitis B (positive for Hepatitis B surface antigen (HBsAg) or Hepatitis B virus DNA (HBV-DNA)), Hepatitis C antibody (HCV-Ab), or Treponema pallidum antibody (TP-Ab)
• Clinically significant active bacterial, viral, fungal, or parasitic infections as judged by the investigator during screening
• Patients who have previously received gene therapy or allogeneic hematopoietic stem cell transplantation
• First-degree relatives with known or suspected familial cancer syndromes (including but not limited to hereditary breast and ovarian cancer syndrome, hereditary nonpolyposis colorectal cancer syndrome, familial adenomatous polyposis, etc.)
• Diagnosis of major psychiatric disorders or predisposition to such conditions that would significantly impair the ability to participate in the clinical study
• History of major organ impairment, including: Liver disorders: Liver function tests showing AST or ALT >3 × ULN; total serum bilirubin >2.5 × ULN; for cases consistent with Gilbert syndrome, total bilirubin >3 × ULN and direct bilirubin >2.5 × ULN; history of hepatic bridging fibrosis, cirrhosis, or active hepatitis; Cardiac disorders: Left ventricular ejection fraction (LVEF) <45% at screening; New York Heart Association (NYHA) Class III or IV congestive heart failure; severe arrhythmias requiring treatment; poorly controlled hypertension (systolic blood pressure >160 mmHg and/or diastolic blood pressure >100 mmHg despite antihypertensive therapy), or prior history of hypertensive emergencies, hypertensive encephalopathy, or unstable angina; history of myocardial infarction, coronary artery bypass graft surgery, peripheral arterial bypass graft implantation, or stent placement within 12 months prior to enrollment; clinically significant valvular disease; calculated eGFR <60 mL/min/1.73m²; Pulmonary function: FEV1/FVC <60% and/or diffusing capacity less than 60% of predicted; clinically significant evidence of pulmonary hypertension requiring medical intervention
• Uncorrectable coagulation dysfunction or history of severe bleeding disorders
• Any other condition deemed by the physician to render the subject unsuitable for hematopoietic stem cell transplantation
• Known hypersensitivity to the investigational drug or its components
• Participation in or ongoing participation in other interventional clinical studies within 3 months prior to screening
• Vaccination with live vaccines within 6 weeks prior to screening
• Pregnant or breastfeeding women
• History of solid organ transplantation
• Poor compliance of the subject with the study protocol
• Any other condition considered by the investigator as unsuitable for participation in this clinical trial
• Unwillingness of the subject to provide pre-existing valid diagnostic evidence before treatment or to undergo bone marrow, lumbar puncture, blood tests, and other examinations after treatment