Atypical Parkinsonism, PARKINSON DISEASE (Disorder)
Conditions
Keywords
Parkinson Disease, Parkinson_Plus Syndrome, Stem Cells, MSCs, Epigenetics, Metagenomics
Brief summary
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.
Detailed description
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.
Interventions
BIOLOGICALAutologous Bone Marrow Aspirate (BMA) and Bone Marrow Aspirate Concentrate (BMAC)
Same-day autologous bone marrow aspirate (BMA) administered intravenously and bone marrow aspirate concentrate (BMAC) administered intranasally via mucosal atomization. Both products derived from a single posterior superior iliac spine aspiration. No ex vivo expansion, genetic modification, or cryopreservation performed.
Sponsors
Apeiron Research Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Masking description
No masking was applied. Participants, investigators, and outcome assessors were all aware of the intervention.
Intervention model description
Within-subject pre/post design. Each participant serves as their own control, with baseline (Day 0) measurements compared to 6-month and 12-month follow-up assessments. No placebo or sham arm was included in this pilot phase. The single-arm design was selected because the primary objective is safety and feasibility characterization, for which an internal control is appropriate and a concurrent control group is not required.
Eligibility
Sex/Gender
ALL
Age
40 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
General: * 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: (DLB) * 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 (PSP) * 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 (MSA) * 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 (CBD) * 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
Exclusion criteria
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Treatment-Emergent Adverse Events (TEAEs) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change from Baseline in GrimAge Biological Age | Baseline and 6 months | Whole-blood DNA methylation will be analyzed using the Clock Foundation GrimAge assay. GrimAge biological age will be estimated in years at baseline and Month 6. The outcome will be reported as the mean participant-level change from baseline to Month 6. Negative values indicate a reduction in estimated biological age. |
| Bone Marrow Mesenchymal Stromal Cell (MSC) Concentration | Day 0 | Bone marrow mesenchymal stromal cell (MSC) concentration in the administered bone marrow aspirate (intravenous) and bone marrow aspirate concentrate (intranasal), quantified by multiparameter flow cytometry using a Sysmex XF-1600 analyzer. MSCs are identified by sequential gating of singlets, viable cells (7-AAD negative), CD45-negative cells, and CD271-positive/CD73-positive cells. Outcome reported as MSC concentration (cells/mL). |
| Change in Movement Disorder Society Non-Motor Rating Scale (MDS-NMS) Total Score | Baseline, Month 3, Month 6, and Month 12 | Change from baseline to Months 3, 6, and 12 in the Movement Disorder Society Non-Motor Rating Scale (MDS-NMS). The MDS-NMS assesses the frequency and severity of non-motor symptoms in Parkinson's disease. Higher total scores indicate greater non-motor symptom burden and worse disease severity. |
| Change in Parkinson's Disease Questionnaire-39 (PDQ-39) Summary Index | Baseline, Month 3, Month 6, and Month 12 | Change from baseline to Months 3, 6, and 12 in the Parkinson's Disease Questionnaire-39 (PDQ-39) Summary Index, a measure of health-related quality of life. Scores range from 0 to 100, with higher scores indicating poorer health-related quality of life. |
| Change in Non-Motor Symptoms Questionnaire (NMSQ) Score | Baseline, Month 3, Month 6, and Month 12 | Change from baseline to Months 3, 6, and 12 in the Non-Motor Symptoms Questionnaire (NMSQ). Scores range from 0 to 30, with higher scores indicating more non-motor symptoms. |
| Change in SCOPA-Autonomic (SCOPA-AUT) Score | Baseline, Month 3, Month 6, and Month 12 | Change from baseline to Months 3, 6, and 12 in the SCales for Outcomes in Parkinson's Disease-Autonomic (SCOPA-AUT). Total scores range from 0 to 69. Higher scores indicate greater autonomic symptom burden and worse autonomic dysfunction. |
| Change in SCOPA-Cognition (SCOPA-COG) Score | Baseline, Month 3, and Month 6 | Change from baseline to Months 3, 6, and 12 in the Scales for Outcomes in Parkinson's Disease-Cognition (SCOPA-COG). Total scores range from 0 to 43, with higher scores indicating better cognitive function. |
| Change in Five Times Sit-to-Stand Test (FTSTS) | Baseline and Month 6 | Change from baseline to Month 6 in time required to complete the Five Times Sit-to-Stand Test. Outcome reported in seconds. Lower values indicate better lower extremity functional performance. |
| Change in 10-Meter Walk Test (10MWT) | Baseline and Month 6 | Change from baseline to Month 6 in gait speed measured using the 10-Meter Walk Test. Outcome reported as walking speed (meters/second). Higher values indicate better walking performance. |
| Change in Unified Multiple System Atrophy Rating Scale (UMSARS) | Baseline and Month 6 | Change from baseline to Month 6 in the Unified Multiple System Atrophy Rating Scale (UMSARS). Higher scores indicate greater disease severity. |
| Change in Progressive Supranuclear Palsy Clinical Deficits Scale (PSP-CDS) | Baseline and Month 6 | Change from baseline to Month 6 in the Progressive Supranuclear Palsy Clinical Deficits Scale (PSP-CDS). Scores range from 0 to 21. Higher scores indicate greater disease severity. |
| Change in Hoehn and Yahr Stage | Baseline and Month 6 | Change from baseline to Month 6 in Hoehn and Yahr stage. Stages range from 1 to 5. Higher stages indicate greater disease severity. |
| Change in Short Parkinson's Evaluation Scale/Scales for Outcomes in Parkinson's Disease-Motor (SPES/SCOPA-Motor) Score | Baseline and Month 6 | Change from baseline to Month 6 in the SPES/SCOPA-Motor score. Scores range from 0 to 42. Higher scores indicate worse motor impairment. |
| Change in Montreal Cognitive Assessment (MoCA) Score | Baseline, Month 3, and Month 6 | Change from baseline to Months 3, 6, and 12 in the Montreal Cognitive Assessment (MoCA), a validated screening instrument for global cognitive function. Total scores range from 0 to 30, with higher scores indicating better cognitive performance. |
| 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 from baseline to Month 6 in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS Part III) Motor Examination score. Scores range from 0 to 132. Higher scores indicate greater motor impairment. |
| Change in Gut Microbiota Composition | Baseline and Month 6 | Exploratory descriptive analysis of gut microbiota composition using shotgun metagenomic sequencing of stool specimens. Analyses include microbial taxonomic composition, alpha diversity, beta diversity, relative microbial abundance, and microbial community structure |
| Change in Nasopharyngeal Microbiota Composition | Baseline and 6 months | Exploratory descriptive analysis of nasopharyngeal microbiota composition using shotgun metagenomic sequencing. Analyses include microbial taxonomic composition, alpha diversity, beta diversity, relative microbial abundance, and microbial community structure. |
| Change in White Blood Cell Count | Day 0 and 6 months | Change in total white blood cell count measured by automated hematology analyzer. Results summarized descriptively using observed values and change from baseline. |
| TNAP-Positive Mesenchymal Stromal Cell Concentration | Day 0 | Concentration of tissue non-specific alkaline phosphatase (TNAP/MSCA-1)-positive mesenchymal stromal cells within the CD271-positive/CD73-positive MSC population, quantified by multiparameter flow cytometry. Outcome reported as TNAP-positive MSC concentration (cells/mL). |
| Mesenchymal Stromal Cell Frequency | Day 0 | Frequency of mesenchymal stromal cells among viable nucleated bone marrow cells, quantified by multiparameter flow cytometry. Outcome reported as the percentage of viable nucleated cells identified as CD271-positive/CD73-positive MSCs. |
| Total Mesenchymal Stromal Cell Dose | Day 0 | Total number of mesenchymal stromal cells delivered to each participant through intravenous bone marrow aspirate and intranasal bone marrow aspirate concentrate administration. Absolute cell counts are calculated using volumetric counting beads. |
| Mesenchymal Stromal Cell Viability | Day 0 | Percentage of viable mesenchymal stromal cells in the administered cell product as determined by 7-aminoactinomycin D (7-AAD) exclusion using multiparameter flow cytometry. |
| Change in Hemoglobin Concentration | Baseline to Month 6 | Change in hemoglobin concentration measured by automated hematology analyzer. Results will be summarized descriptively to evaluate hematologic safety. |
| Change in Platelet Count | Baseline to Month 6 | Change in platelet count measured by automated hematology analyzer. Results will be summarized descriptively. |
| Change in Serum Creatinine | Baseline to Month 6 | Change in serum creatinine concentration measured by standard clinical chemistry methods. Results will be summarized descriptively to evaluate renal safety. |
| Change in Alanine Aminotransferase (ALT) | Baseline to Month 6 | Change in serum alanine aminotransferase concentration measured by standard clinical chemistry methods. Results will be summarized descriptively to evaluate hepatic safety. |
| Change in Aspartate Aminotransferase (AST) | Baseline to Month 6 | Change in serum aspartate aminotransferase concentration measured by standard clinical chemistry methods. Results will be summarized descriptively. |
| Change in High-Sensitivity C-Reactive Protein (hs-CRP) | Baseline to Month 6 | Change in serum high-sensitivity C-reactive protein concentration measured using a high-sensitivity immunoassay. Results will be summarized descriptively to evaluate changes in systemic inflammation following treatment. |
| Change in Erythrocyte Sedimentation Rate (ESR) | Baseline to Month 6 | Change in erythrocyte sedimentation rate measured using the Westergren method. Results will be summarized descriptively to evaluate systemic inflammatory activity following treatment. |
| Mean Change from Baseline in Cellular Systems Age | Baseline and Month 6 | Whole-blood DNA methylation will be analyzed using the Clock Foundation Systems Age algorithm. Cellular Systems Age will be estimated in years at baseline and Month 6 and summarized as the mean participant-level change from baseline. |
| Mean Change from Baseline in Brain Systems Age | Baseline and Month 6 | Whole-blood DNA methylation will be analyzed using the Clock Foundation Systems Age algorithm. Brain Systems Age will be estimated in years at baseline and Month 6 and summarized as the mean participant-level change from baseline. |
| Mean Change from Baseline in Kidney Systems Age | Baseline and Month 6 | Whole-blood DNA methylation will be analyzed using the Clock Foundation Systems Age algorithm. Kidney Systems Age will be estimated in years at baseline and Month 6 and summarized as the mean participant-level change from baseline. |
| Mean Change from Baseline in Muscle Systems Age | Baseline and Month 6 | Whole-blood DNA methylation will be analyzed using the Clock Foundation Systems Age algorithm. Muscle Systems Age will be estimated in years at baseline and Month 6 and summarized as the mean participant-level change from baseline. |
| Mean Change from Baseline in Immune Systems Age | Baseline and Month 6 | Whole-blood DNA methylation will be analyzed using the Clock Foundation Systems Age algorithm. Immune Systems Age will be estimated in years at baseline and Month 6 and summarized as the mean participant-level change from baseline. |
| Mean Change from Baseline in Lung Systems Age | Baseline and Month 6 | Whole-blood DNA methylation will be analyzed using the Clock Foundation Systems Age algorithm. Lung Systems Age will be estimated in years at baseline and Month 6 and summarized as the mean participant-level change from baseline. |
| Mean Change from Baseline in Vascular Systems Age | Baseline and Month 6 | Whole-blood DNA methylation will be analyzed using the Clock Foundation Systems Age algorithm. Vascular Systems Age will be estimated in years at baseline and Month 6 and summarized as the mean participant-level change from baseline. |
| Mean Change from Baseline in Extracellular Matrix (ECM) Systems Age | Baseline and Month 6 | Whole-blood DNA methylation will be analyzed using the Clock Foundation Systems Age algorithm. Extracellular Matrix Systems Age will be estimated in years at baseline and Month 6 and summarized as the mean participant-level change from baseline. |
| Mean Change from Baseline in Metabolic Systems Age | Baseline and Month 6 | Whole-blood DNA methylation will be analyzed using the Clock Foundation Systems Age algorithm. Metabolic Systems Age will be estimated in years at baseline and Month 6 and summarized as the mean participant-level change from baseline. |
| Mean Change from Baseline in Inflammation Systems Age | Baseline and Month 6 | Whole-blood DNA methylation will be analyzed using the Clock Foundation Systems Age algorithm. Inflammation Systems Age will be estimated in years at baseline and Month 6 and summarized as the mean participant-level change from baseline. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORJason W Glowney, MD, MSc
Apeiron Research Center
Outcome results
None listed