Study of Neural Stem Cell-Derived Exosomes in Moderate-to-Severe Early-Onset Alzheimer's Disease

A Phase I, Open-Label, Single-Center, Frequency-Escalation Study of the Safety, Tolerability, and Preliminary Efficacy of Neural Stem Cell-Derived Exosomes in Patients With Moderate-to-Severe Early-Onset Alzheimer's Disease

This is an open-label, single-center, phase I clinical study in patients with moderate-to-severe early-onset Alzheimer's disease. The study aims to evaluate the safety, tolerability, and preliminary efficacy of neural stem cell-derived exosomes (NSC-EVs) administered by the intranasal route. A total of 9 participants will be enrolled in 3 frequency-escalation groups: once every 3 days, once every other day, and once daily, each for 28 days. Participants will undergo screening and baseline assessment, a 28-day treatment period, and follow-up visits at 4, 8, and 24 weeks after the end of treatment.

Study Overview

• Status: Not yet recruiting
• Conditions: Alzheimer Disease (AD)
• Intervention / Treatment: Biological: Neural Stem Cell-Derived Exosomes

Detailed Description

Early-onset moderate-to-severe Alzheimer's disease imposes a substantial burden on patients and families, and there is currently no truly effective treatment capable of reversing the pathological process. Neural stem cell-derived exosomes (NSC-EVs) are considered a promising therapeutic approach because they may have low immunogenicity, the ability to cross the blood-brain barrier, and a more standardized manufacturing pathway than cell-based therapy.

This study is designed as an open-label, single-center, three-group phase I clinical study to explore the safety, tolerability, and preliminary efficacy of intranasal NSC-EVs in patients with moderate-to-severe early-onset Alzheimer's disease. The study uses a 3+3 frequency-escalation design with sentinel-participant monitoring to determine the highest tolerated dosing frequency and to generate preliminary clinical data for future larger-scale studies.

A total of 9 participants are planned for enrollment. Participants will be assigned sequentially to 1 of 3 dosing-frequency groups: low-frequency, medium-frequency, or high-frequency. All groups will receive the same investigational product by intranasal administration for 28 days, with differences only in dosing frequency. The low-frequency group will receive treatment on Days 1, 4, 7, 10, 13, 16, 19, 22, 25, and 28; the medium-frequency group will receive treatment on Days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, and 27; and the high-frequency group will receive treatment daily from Day 1 through Day 28.

After the 4-week treatment period, participants will enter a follow-up phase with visits scheduled at 4 weeks, 8 weeks, and 24 weeks after the end of treatment. Assessments during treatment and follow-up will include safety monitoring, clinical laboratory testing, cognitive and neuropsychiatric evaluations, and protocol-defined biomarker and imaging assessments as applicable. The primary objective is to evaluate safety and tolerability, while secondary and exploratory objectives include preliminary evaluation of cognitive, behavioral, functional, and biomarker changes over time.

• Study Type: Interventional
• Enrollment (Estimated): 9
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Yue Ling 岳玲, MD, PhD; Phone Number: 18017311249; Email: bellinthemoon@hotmail.com

Study Locations

• China
  • Shanghai Municipality
    • Shanghai, Shanghai Municipality, China, 200030
      • Shanghai Mental Health Center
      • Contact: Yue Ling 岳玲, MD, PhD; Phone Number: 18964352661; Email: bellinthemoon@hotmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

• Inclusion Criteria:
• Male or postmenopausal female, aged 50 to 75 years.
• Meets the 2011 NIA-AA criteria for probable Alzheimer's disease dementia.
• Age at onset ≤65 years.
• CMMS score 5-20
• Stable dose for at least 2 months before enrollment if receiving pro-cognitive or psychiatric medications.
• Primary school education or above and able to complete study-required cognitive assessments.
• Hachinski Ischemic Score ≤4.
• GDS-30 total score ≤10.
• Screening brain MRI+DWI+SWI meeting protocol-defined cerebrovascular exclusion thresholds and no major structural abnormalities inconsistent with Alzheimer's disease.
• Positive amyloid pathology confirmed by Aβ-PET at screening or before enrollment.
• Adequate vision and hearing to complete assessments.
• Has a reliable caregiver able to accompany the participant to study visits and provide information for assessments.
• Willing to participate and sign informed consent.

Exclusion Criteria:

• Dementia due to causes other than Alzheimer's disease.
• Brain MRI showing any of the following: Fazekas white matter hyperintensity score >2; more than 2 lacunar infarcts >1.5 cm; lacunar infarcts involving critical regions such as the thalamus, hippocampus, entorhinal cortex, or parahippocampal region; cerebral hemorrhage, subdural hematoma, aneurysm, arteriovenous malformation, intracranial mass lesion, or other clinically significant structural abnormalities.
• Allergy to stem cell-derived exosomes or PET examination.
• Severe psychiatric disorder or symptoms.
• Significant active physical illness, including severe cardiac disease, severe systemic infection, or severe liver/kidney dysfunction.
• Elevated tumor markers or tumor history.
• Immune-related disease.
• Significant nasal obstruction.
• Serious suicide risk.
• Participation in another clinical trial or stem cell therapy within the past 6 months.
• Any other condition judged inappropriate by the investigator.
• Contraindications to MRI or inability to complete MRI examinations, including non-MRI-compatible metallic implants, certain stents, plates, pacemakers, or severe claustrophobia.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low-Frequency NSC-EVs; Participants receive neural stem cell-derived exosomes by intranasal administration once every 3 days for 28 days. The single dose is 6 × 10^9 particles administered into both nostrils. In the low-frequency group, dosing is scheduled on Days 1, 4, 7, 10, 13, 16, 19, 22, 25, and 28, for a total of 10 doses.	Biological: Neural Stem Cell-Derived Exosomes; The investigational product is a neural stem cell-derived exosome preparation administered intranasally. The product specification is 6 × 10^9 particles per 2 mL vial. The product is thawed to room temperature before administration and delivered into both nostrils. The same investigational product is used in all study groups; the groups differ only in dosing frequency.; Other Names: NSC-EVs
Experimental: Medium-Frequency NSC-EVs; Participants receive neural stem cell-derived exosomes by intranasal administration every other day for 28 days. The single dose is 6 × 10^9 particles administered into both nostrils. In the medium-frequency group, dosing is scheduled on Days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, and 27, for a total of 14 doses.	Biological: Neural Stem Cell-Derived Exosomes; The investigational product is a neural stem cell-derived exosome preparation administered intranasally. The product specification is 6 × 10^9 particles per 2 mL vial. The product is thawed to room temperature before administration and delivered into both nostrils. The same investigational product is used in all study groups; the groups differ only in dosing frequency.; Other Names: NSC-EVs
Experimental: High-Frequency NSC-EVs; Participants receive neural stem cell-derived exosomes by intranasal administration once daily for 28 days. The single dose is 6 × 10^9 particles administered into both nostrils. In the high-frequency group, dosing is scheduled daily from Day 1 through Day 28, for a total of 28 doses.	Biological: Neural Stem Cell-Derived Exosomes; The investigational product is a neural stem cell-derived exosome preparation administered intranasally. The product specification is 6 × 10^9 particles per 2 mL vial. The product is thawed to room temperature before administration and delivered into both nostrils. The same investigational product is used in all study groups; the groups differ only in dosing frequency.; Other Names: NSC-EVs

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Related Adverse Events	Number of participants experiencing treatment-related adverse events assessed according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.	Baseline to Week 4
Number of Participants With Treatment-Related Clinical Laboratory Abnormalities	Number of participants with treatment-related clinical laboratory abnormalities during the treatment period.	Baseline to Week 4

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Chinese Mini-Mental Status (CMMS) Score	Cognitive function will be assessed using the Chinese Mini-Mental Status (CMMS), a Chinese-language screening instrument for global cognitive impairment. Total scores range from 0 to 30, with higher scores indicating better cognitive performance.	Baseline, Week 4 (end of treatment), and 4, 8, and 24 weeks after end of treatment
Change in Severe Impairment Battery (SIB) Score	Cognitive function will be assessed using the Severe Impairment Battery (SIB), a validated instrument for cognitive function in moderate-to-severe dementia. Total scores range from 0 to 100, with higher scores indicating better cognitive performance.	Baseline, Week 4 (end of treatment), and 4, 8, and 24 weeks after end of treatment
Change in Neuropsychiatric Inventory (NPI) Score	Neuropsychiatric symptoms will be assessed using the Neuropsychiatric Inventory (NPI), a standardized instrument for behavioral and psychological symptoms in dementia. Total scores range from 0 to 144, with higher scores indicating greater neuropsychiatric symptom burden.	Baseline, Week 4 (end of treatment), and 4, 8, and 24 weeks after end of treatment
Change in Pittsburgh Sleep Quality Index (PSQI) Score	Sleep quality will be assessed using the Pittsburgh Sleep Quality Index (PSQI), a questionnaire that evaluates subjective sleep quality and sleep disturbance. Total scores range from 0 to 21, with higher scores indicating poorer sleep quality.	Baseline, Week 4 (end of treatment), and 4, 8, and 24 weeks after end of treatment
Change in Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) Score	Functional ability will be assessed using the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL), a caregiver-based instrument used to evaluate daily functioning in patients with Alzheimer's disease. Total scores range from 0 to 78, with higher scores indicating better functional ability.	Baseline, Week 4 (end of treatment), and 4, 8, and 24 weeks after end of treatment
Change in Zarit Burden Interview (ZBI) Score	Caregiver burden will be assessed using the Zarit Burden Interview (ZBI), a questionnaire used to evaluate the perceived burden experienced by caregivers. Total scores range from 0 to 88, with higher scores indicating greater caregiver burden.	Baseline, Week 4 (end of treatment), and 4, 8, and 24 weeks after end of treatment
Change in Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) Score	Global dementia severity will be assessed using the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB), which evaluates impairment across multiple cognitive and functional domains. Total scores range from 0 to 18, with higher scores indicating greater dementia severity.	Baseline, Week 4 (end of treatment), and 4, 8, and 24 weeks after end of treatment
Change in Geriatric Depression Scale (GDS) Score	Depressive symptoms will be assessed using the 30-item Geriatric Depression Scale (GDS-30), a questionnaire designed to assess depressive symptoms in older adults. Total scores range from 0 to 30, with higher scores indicating more severe depressive symptoms.	Baseline, Week 4 (end of treatment), and 4, 8, and 24 weeks after end of treatment

Collaborators and Investigators

• Sponsor: Shanghai Mental Health Center
• Collaborators: Shanghai Angecon Biotechnology Co., Ltd.

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2026
• Primary Completion (Estimated): October 20, 2027
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: April 21, 2026
• First Submitted That Met QC Criteria: April 21, 2026
• First Posted (Actual): April 28, 2026

Study Record Updates

• Last Update Posted (Actual): May 15, 2026
• Last Update Submitted That Met QC Criteria: May 13, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Safety; Tolerability; Phase I Clinical Study; Intranasal Administration; Early-Onset Alzheimer's Disease; Moderate-to-Severe Alzheimer's Disease; Neural Stem Cell-Derived Exosomes; Frequency Escalation
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Dementia; Tauopathies; Neurodegenerative Diseases; Alzheimer Disease
• Other Study ID Numbers: SMHC-EOAD-NSCEV-2026-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No