A Single-Arm, Open-Label, Within-Subject Pilot Study (Phase I/IIa) Evaluating the Safety, Tolerability, and Exploratory Epigenetic Outcomes of a Single Same-Day Administration of Autologous Bone Marrow Aspirate (Intravenous) and Autologous Bone Marrow Aspirate Concentrate (Intranasal) in Adults With Parkinson's Disease or Parkinson-Plus Syndromes
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- Incidence of Treatment-Emergent Adverse Events (TEAEs)
研究概览
简要总结
This pilot study evaluated the safety, tolerability, and exploratory epigenetic outcomes of a single same-day autologous bone marrow procedure in adults with Parkinson's disease (PD) or Parkinson-plus syndromes (PPS). Ten participants underwent posterior superior iliac spine bone marrow aspiration under local anesthesia. The unprocessed aspirate (BMA) was filtered and administered intravenously via normal saline infusion on the same day. A portion of the aspirate was centrifuged to produce a bone marrow aspirate concentrate (BMAC), which was atomized intranasally using a mucosal atomization device. Cells were not expanded in culture or genetically modified. The procedure was performed under the Same Surgical Procedure exception (21 CFR 1271.15(b)); an investigational new drug application (IND 31770) was submitted to the FDA Center for Biologics Evaluation and Research (CBER).
The primary outcome was safety and tolerability, assessed by treatment-emergent adverse events (TEAEs) graded per CTCAE v5.0 criteria through 12 months post-treatment. Exploratory outcomes included DNA methylation biological age (GrimAge-based composite and organ/system Systems Age clocks) measured from peripheral blood at baseline and approximately 6 months, and characterization of the delivered cell product by automated hematology and multiparameter flow cytometry.
详细描述
Parkinson's disease (PD) and Parkinson-plus syndromes (PPS), including progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal syndrome (CBS), and Lewy body dementia (LBD), are progressive neurodegenerative disorders characterized by motor dysfunction, non-motor symptoms, and progressive disability. Currently available therapies are primarily symptomatic and do not alter the underlying neurodegenerative process.
Autologous bone marrow aspirate contains mesenchymal stromal cells (MSCs), hematopoietic progenitor cells, and numerous trophic, immunomodulatory, and anti-inflammatory bioactive factors that may support neuronal repair and tissue homeostasis. Preclinical studies suggest these cells and associated soluble factors may promote neuroprotection by modulating inflammation, oxidative stress, mitochondrial dysfunction, and neurotrophic signaling. Because the cell product is autologous and minimally manipulated, it avoids ex vivo culture expansion and genetic modification and is expected to have low immunogenic potential.
Intranasal administration may facilitate transport of cells and soluble factors to the central nervous system through olfactory and trigeminal pathways, while intravenous administration provides systemic exposure. Combining both delivery routes may provide complementary central nervous system and peripheral biologic effects using a single same-day autologous procedure.
This pilot study was designed primarily to evaluate the safety and tolerability of combined intravenous bone marrow aspirate (BMA) and intranasal bone marrow aspirate concentrate (BMAC) administration in adults with PD or PPS. Exploratory objectives include evaluation of changes in DNA methylation-derived biological age biomarkers and characterization of the administered autologous cell product.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
盲法说明
No masking was applied. Participants, investigators, and outcome assessors were all aware of the intervention.
入排标准
- 年龄范围
- 40 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants diagnosed with PD or PPS by a licensed medical professional
- •Documented diagnosis of PD or PPS ≤ 6 years
- •Participants with an anticipated survival of at least 3 years in the investigator's opinion
- •Participants who are willing and able to give informed consent
- •Participants who can comply with the study protocol over the 6-month duration
- •Stable medical profile for 60 days prior to the initial intake screening
- •Participants can ambulate at least 25m without assistance
- •No known history of heparin-induced thrombocytopenia
- •Willingness to comply with study requirements and provide informed consent
- •Participants have no history of adverse reactions to heparin, e.g., HIT, local numbing medications, adhesives, or skin sterilizing agents
- •PD Inclusion Criteria:
- •Idiopathic Parkinson's disease patients who meet the MDS's Clinical Diagnostic Criteria for Parkinson's disease
- •Responsive to levodopa or dopamine agonists defined by 33% improvement in "Off"/"On" symptoms by MDS-UPDRS-III
- •A modified Hoehn and Yahr stage of 3 or less
- •Neuroimaging findings are consistent with PD and absent of atrophy or other brain pathology inconsistent with PD
- •"Normal" cognition as assessed by Montreal Cognitive Assessment (MoCA), with a value 26
- •PPS Inclusion Criteria:
- •High probability of cognitive capacity to give informed consent by the Montreal - Cognitive Assessment (MoCA), with a value 23
- •Probable DLB - DLB consortium: Two or more core clinical features are present (including features of parkinsonism for the study), or only one core clinical feature is present, but with one or more indicative biomarkers
- •Core clinical features:
- •Fluctuating cognition with pronounced variations in attention and alertness
- •Recurrent visual hallucinations that are typically well-formed and detailed
- •Rapid eye movement (REM) sleep behavior disorder (RBD), which may precede cognitive decline
- •One or more spontaneous cardinal features of parkinsonism: bradykinesia, resting tremor, or rigidity
- •Indicative biomarkers:
- •Reduced dopamine transporter uptake in basal ganglia demonstrated by SPECT/PET
- •Abnormal (low uptake) I-MIBG myocardial scintigraphy
- •Polysomnographic confirmation of REM sleep without atonia
- •MDS Diagnostic Criteria for probable PSP with predominant parkinsonism (PSP-P)
- •Ocular motor dysfunction: vertical supranuclear gaze palsy or slow velocity of vertical saccades or frequent macro square wave jerks ("eyelid-opening apraxia")
- •Ocular motor dysfunction + akinetic-rigid, axial predominant, levodopa resistant or with tremor and/or asymmetric and/or levodopa responsive (akinesia)
- •"Normal" cognition as assessed by Montreal Cognitive Assessment (MoCA), with a value 26
- •MDS Diagnostic Criteria for clinically probable MSA
- •Autonomic dysfunction
- •Parkinsonism
- •Cerebellar syndrome, including at least one of gait ataxia, limb ataxia, cerebellar dysarthria, or oculomotor features
- •"Normal" cognition as assessed by Montreal Cognitive Assessment (MoCA), with a value 26
- •Chronic progressive course
- •Asymmetric onset
- •Higher cortical dysfunction: apraxia, speech apraxia, non-fluent aphasia, alien limb phenomena, or cortical sensory loss
- •Movement disorder: rigid/akinetic syndrome and either dystonic limb posturing or focal myoclonus in limb, and levodopa-resistant
- •"Normal" cognition as assessed by Montreal Cognitive Assessment (MoCA), with a value 26
排除标准
- •Other non-PD/PPS Parkinsonism (e.g., drug-induced, vascular parkinsonism)
- •No strong familial history of PD/PPS not attributable to environmental exposure or any known genetic predisposition to PD/PPS
- •Unable to maintain/tolerate supine position with cervical neck extension
- •Active systemic infection or local infection near the lumbar pelvis region
- •Any bone marrow aspiration from the pelvis within 6 months of initial screening
- •Any musculoskeletal-pelvis contraindications to BMA harvest from the PSIS
- •Concurrent enrollment in another PD/PPS study or having taken/received another investigational intervention within 6 weeks of initial screening
- •Malignancy diagnosed 2 years prior to initial screening
- •History of intracranial or nasopharyngeal surgery deemed detrimental to the participant during the trial, including brain surgery/stereotactic procedure for PD/PPS
- •History of electroconvulsive therapy
- •Chronic Kidney Disorder (CKD) > Stage II or eGFR <60 mL/min
- •Autoimmune disease, including:
- •Rheumatoid Arthritis (RA)
- •Systemic Lupus Erythematosus (SLE)
- •Any disorders of glucocorticoid excess or diseases requiring systemic steroids or immune-modulating therapies
- •Cardiac disease deemed significant:
- •Poorly controlled hypertension (BP 140/90)
- •NYHA class III or IV congestive heart failure
- •History of a significant ventricular arrhythmia
- •Obesity class II or higher (BMI 35)
- •Moderate-to-uncontrolled diabetes HbA1c 7%
- •Osteoporosis
- •A history of other severe systemic disorders, including significant CVA, TBI, seizure, encephalitis, meningitis, or psychiatric disorder that is deemed potentially harmful to the participant by the PI
- •Positive for HIV, HBV, HCV, or syphilis
- •Any of the following lab abnormalities:
- •Hematology: Hgb < 10 g/dl, ANC < 1.550/L, platelets < 100,000 /L
- •Chemistry: albumin < 3.0 g/dL, serum creatine > 1.5 x ULN, total bilirubin > 1.5 x ULN, AST/ALT/ALP > 2.0 x ULN
- •Female or another gender with childbearing potential not willing to adopt barrier method(s) of contraception, plus one other form, including:
- •Intrauterine system (IUS)
- •Intrauterine device (IUD)
- •Oral, injected, or implanted hormonal contraception
- •Female or another gender who is lactating/breastfeeding or has a positive urine or serum pregnancy test at intake screening
- •Any disorder that compromises the participant's ability to give appropriate informed consent or hinders the ability to perform the assessment and receive the study's interventions
- •Any other condition not listed above that is deemed potentially harmful to the participant by the PI
研究组 & 干预措施
Autologous BMA (IV) and BMAC (Intranasal)
Participants received a single same-day autologous bone marrow procedure consisting of: (1) intravenous infusion of filtered, unprocessed bone marrow aspirate (BMA) in normal saline; and (2) intranasal atomization of bone marrow aspirate concentrate (BMAC). Both products were derived from a single posterior superior iliac spine (PSIS) aspiration performed under local anesthesia on the same day. Cells were not expanded in culture or genetically modified.
干预措施: Autologous Bone Marrow Aspirate (BMA) and Bone Marrow Aspirate Concentrate (BMAC) (Biological)
结局指标
主要结局
Incidence of Treatment-Emergent Adverse Events (TEAEs)
时间窗: Baseline through Month 12
Incidence, severity, and relationship to study treatment of treatment-emergent adverse events (TEAEs) following a single same-day autologous bone marrow procedure consisting of intravenous bone marrow aspirate (BMA) and intranasal bone marrow aspirate concentrate (BMAC). Adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 (Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life-threatening, Grade 5=death related to adverse event). Serious adverse events (SAEs) include death, life-threatening events, hospitalization or prolongation of hospitalization, persistent or significant disability, congenital anomaly, or other important medical events. TEAEs will be recorded throughout the study and assessed by the investigator for relationship to study treatment.
次要结局
- Mean Change from Baseline in GrimAge Biological Age(Baseline and 6 months)
- Bone Marrow Mesenchymal Stromal Cell (MSC) Concentration(Day 0)
- Change in Movement Disorder Society Non-Motor Rating Scale (MDS-NMS) Total Score(Baseline, Month 3, Month 6, and Month 12)
- Change in Parkinson's Disease Questionnaire-39 (PDQ-39) Summary Index(Baseline, Month 3, Month 6, and Month 12)
- Change in Non-Motor Symptoms Questionnaire (NMSQ) Score(Baseline, Month 3, Month 6, and Month 12)
- Change in SCOPA-Autonomic (SCOPA-AUT) Score(Baseline, Month 3, Month 6, and Month 12)
- Change in SCOPA-Cognition (SCOPA-COG) Score(Baseline, Month 3, and Month 6)
- Change in Five Times Sit-to-Stand Test (FTSTS)(Baseline and Month 6)
- Change in 10-Meter Walk Test (10MWT)(Baseline and Month 6)
- Change in Unified Multiple System Atrophy Rating Scale (UMSARS)(Baseline and Month 6)
- Change in Progressive Supranuclear Palsy Clinical Deficits Scale (PSP-CDS)(Baseline and Month 6)
- Change in Hoehn and Yahr Stage(Baseline and Month 6)
- Change in Short Parkinson's Evaluation Scale/Scales for Outcomes in Parkinson's Disease-Motor (SPES/SCOPA-Motor) Score(Baseline and Month 6)
- Change in Montreal Cognitive Assessment (MoCA) Score(Baseline, Month 3, and Month 6)
- Change in Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS Part III) Motor Examination Score(Baseline and Month 6)
- Change in Gut Microbiota Composition(Baseline and Month 6)
- Change in Nasopharyngeal Microbiota Composition(Baseline and 6 months)
- Change in White Blood Cell Count(Day 0 and 6 months)
- TNAP-Positive Mesenchymal Stromal Cell Concentration(Day 0)
- Mesenchymal Stromal Cell Frequency(Day 0)
- Total Mesenchymal Stromal Cell Dose(Day 0)
- Mesenchymal Stromal Cell Viability(Day 0)
- Change in White Blood Cell Count(Baseline to Month 6)
- Change in Hemoglobin Concentration(Baseline to Month 6)
- Change in Platelet Count(Baseline to Month 6)
- Change in Serum Creatinine(Baseline to Month 6)
- Change in Alanine Aminotransferase (ALT)(Baseline to Month 6)
- Change in Aspartate Aminotransferase (AST)(Baseline to Month 6)
- Change in High-Sensitivity C-Reactive Protein (hs-CRP)(Baseline to Month 6)
- Change in Erythrocyte Sedimentation Rate (ESR)(Baseline to Month 6)
- Mean Change from Baseline in Cellular Systems Age(Baseline and Month 6)
- Mean Change from Baseline in Brain Systems Age(Baseline and Month 6)
- Mean Change from Baseline in Kidney Systems Age(Baseline and Month 6)
- Mean Change from Baseline in Muscle Systems Age(Baseline and Month 6)
- Mean Change from Baseline in Immune Systems Age(Baseline and Month 6)
- Mean Change from Baseline in Lung Systems Age(Baseline and Month 6)
- Mean Change from Baseline in Vascular Systems Age(Baseline and Month 6)
- Mean Change from Baseline in Extracellular Matrix (ECM) Systems Age(Baseline and Month 6)
- Mean Change from Baseline in Metabolic Systems Age(Baseline and Month 6)
- Mean Change from Baseline in Inflammation Systems Age(Baseline and Month 6)