## Protocol Section
### Identification Module
**NCT ID:** NCT06422208

**Brief Title:** Autologous iPSC-Derived Dopamine Neuron Transplantation for Parkinson's Disease

**Official Title:** A Phase 1 Clinical Trial of Autologous iPSC-Derived Dopamine Neuron Transplantation for Parkinson's Disease

#### Organization Study ID Info
**ID:** 2023P003609
#### Organization
**Class:** OTHER
**Full Name:** Mclean Hospital
#### Secondary ID Infos
**ID:** U01NS109463
**Link:** https://reporter.nih.gov/quickSearch/U01NS109463
**Type:** NIH
### Status Module
#### Completion Date
**Date:** 2027-08

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-22

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-21

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2026-08

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-06

**Type:** ESTIMATED

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-20
**Type:** ACTUAL
**Study First Submit Date:** 2024-05-15
**Study First Submit QC Date:** 2024-05-15
### Sponsor Collaborators Module

#### Collaborators

**Class:** NIH

**Name:** National Institute of Neurological Disorders and Stroke (NINDS)

#### Lead Sponsor

**Class:** OTHER

**Name:** Penelope J. Hallett, Ph.D.

#### Responsible Party

**Investigator Affiliation:** Mclean Hospital

**Investigator Full Name:** Penelope J. Hallett, Ph.D.

**Investigator Title:** Associate Professor

**Type:** SPONSOR_INVESTIGATOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** True

**Oversight Has DMC:** True

### Description Module

**Brief Summary:** This research study is evaluating an investigational cell product called autologous induced pluripotent stem cell (iPSC)-derived dopamine neurons. This research study is a single-center Phase 1 clinical trial, which will test the safety of injecting the investigational cell product into the brain of subjects with Parkinson's disease.

**Detailed Description:** The goal of this research study is to test a new treatment for Parkinson's disease. Parkinson's disease is a progressive disease that causes people to lose specific brain cells called midbrain dopamine neurons. When these dopamine neurons are lost, it leads to a lack of dopamine in the brain. When there is not enough dopamine, people with Parkinson's disease experience problems with their movement. This trial will test whether new dopamine neurons made from blood cells from subjects with Parkinson's disease are safe when surgically injected into the area of the brain affected (called the putamen) of the same subjects (called autologous transplantation). The trial will assess the safety of the injected cells and will also measure the effects of the transplanted autologous dopamine neurons on Parkinson's disease symptoms.

### Conditions Module

**Conditions:**

- Parkinson Disease

### Design Module

#### Design Info

**Allocation:** NA

**Intervention Model:** SINGLE_GROUP

##### Masking Info

**Masking:** NONE

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 6

**Type:** ESTIMATED

**Phases:**

- PHASE1

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Intervention Names:**

- Biological: Autologous midbrain dopamine neurons

**Label:** Autologous midbrain dopamine neurons

**Type:** EXPERIMENTAL

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Autologous midbrain dopamine neurons

**Description:** The autologous midbrain dopamine neurons are a experimental cryopreserved cell product derived from human autologous induced pluripotent stem cells. The autologous midbrain dopamine neurons will be surgically administered into the putamen, unilaterally, in a single surgical session.

**Name:** Autologous midbrain dopamine neurons

**Type:** BIOLOGICAL

### Outcomes Module

#### Primary Outcomes

**Description:** To assess the safety of autologous transplantation of cryopreserved midbrain dopamine neurons into the putamen of subjects with Parkinson's disease by measuring (1) the incidence of serious adverse events at 12 months and 18 months post-transplantation and (2) the incidence and severity of all intervention emergent adverse events.

**Measure:** Safety: number and severity of adverse events and serious adverse events

**Time Frame:** Baseline to 12 months post-transplant and baseline to 18 months post-transplant

#### Secondary Outcomes

**Description:** Change in Movement Disorder Society Unified Parkinson's Disease Rating Scale (UPDRS) motor (Part III) compared to the baseline. UPDRS Part III assesses motor function and is measured in both "Off" and "On" states. UPDRS Part III score range: 0-132. A lower score is associated with milder Parkinson's disease motor symptoms.

**Measure:** Change in UPDRS Part III

**Time Frame:** 18 months following transplantation

**Description:** Change in ON time without troublesome dyskinesia is measured using a Parkinson's disease patient diary card.

**Measure:** Change in ON time without troublesome dyskinesia

**Time Frame:** 18 months following transplantation

**Description:** Change in OFF time is measured using a Parkinson's disease patient diary card.

**Measure:** Change in OFF time

**Time Frame:** 18 months following transplantation

**Description:** Change in Levodopa Equivalent Daily Dose (LEDD) which measures Parkinson's medications.

**Measure:** Change in baseline Levodopa Equivalent Daily Dose

**Time Frame:** 18 months following transplantation

**Description:** The Unified Dyskinesia Rating Scale evaluates dyskinesia in patients with Parkinson's disease (range 0-104). A lower score indicates less dyskinesia.

**Measure:** Change in Unified Dyskinesia Rating Scale

**Time Frame:** 18 months following transplantation

**Description:** Change in Movement Disorder Society Unified Parkinson's Disease Rating Scale (UPDRS) Part II, which assesses the motor aspects of experiences of daily living in the week prior to the visit. Score range: 0-52. A lower score is associated with less disability.

**Measure:** Change in UPDRS Part II

**Time Frame:** 18 months following transplantation

**Description:** Change in Montreal Cognitive Assessment (MoCA), which measures various aspects of cognitive function. Score range 0-30. A higher score is associated with better cognitive function.

**Measure:** Change in MoCA

**Time Frame:** 18 months following transplantation

**Description:** DaTscan (SPECT neuroimaging for dopamine transporter, DAT) imaging is performed to assess changes in dopamine neuron function in the putamen (the transplanted area of the brain).

**Measure:** Change in DaTscan

**Time Frame:** Baseline to 18 months following transplantation

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

* Males and females between ages 55 to eighty.
* Diagnosis of Parkinson's disease with motor symptoms by neurologist according to Movement Disorder Society (MDS) 2015 Clinical Diagnostic Criteria for Parkinson's disease.
* Diagnosis of Parkinson's disease for at least 5 years.
* Dopamine drug responsiveness demonstrated by a positive "on/off" test with at least a 30% improvement on UPDRS III (motor) scale.
* No gross abnormalities on MRI, including hydrocephalus or extensive white matter disease.
* No significant cognitive impairment (Montreal Cognitive Assessment).
* No significant untreated depression (Beck Depression Inventory 2).
* Up to date cancer screening per primary MD.
* Able to understand trial requirements and intervention procedures and provide written informed consent.

Exclusion Criteria:

* History of intracranial surgeries.
* Any previous thalamotomy, pallidotomy or deep brain stimulation.
* Atypical Parkinsonism (Parkinsonism-Plus syndrome, secondary parkinsonism, hereditary parkinsonism)
* History of psychiatric disorders including schizophrenia or psychosis likely to compromise with ability to comply with trial protocol requirements.
* Prior history of intracerebral, subdural, or epidural hemorrhage.
* History of malignancy within 5 years.
* Inability to have an MRI.
* Life expectancy \< 6 months due to concomitant illnesses.
* Ingestion of investigational drug or recipient of investigational procedure within 6 months prior to trial.
* Subjects with active cardiovascular and cerebrovascular disease within 6 months prior to signing the informed consent form:

  1. History of severe heart failure (congestive heart failure of New York Heart Association Class II or above or left ventricular ejection fraction \< 35% by any examination method), unstable angina pectoris and myocardial infarction
  2. Severe arrhythmia
  3. History of cardiovascular surgery (cardiac, vascular stent surgery, angioplasty);
  4. History of stroke or transient ischemic attack
  5. History of subarachnoid hemorrhage
  6. Subjects with major vascular diseases (aortic aneurysm, aortic dissecting aneurysm, internal carotid artery stenosis)
* Hypertensive subjects with poorly controlled blood pressure (defined as blood pressure above 160/100 mmHg despite treatment with antihypertensive drugs) and subjects with severe postural hypotension.
* Abnormal pre-operative coagulation labs.
* Any necessary chronic anticoagulation medication in use (not including antiplatelet therapy and chronic NSAID).
* Diabetic subjects with poorly controlled blood glucose (glycosylated hemoglobin \> 9.0%, or fasting plasma glucose (FPG) ≥ 11.1 mmol/L).
* Active infectious disease. Subjects known to have tested positive for HIV, Human T-lymphotropic Virus, Hepatitis B Virus, Hepatitis C Virus, Cytomegalovirus (IgM \> IgG) and/or syphilis will be evaluated by an expert as to subject eligibility based on the subject's infectious status.
* Any illness which, in the Investigator's judgment, will interfere with the subject's ability to comply with the protocol, compromise subject safety, or interfere with the interpretation of the trial results.
* Active clinical infection being treated by antibiotics within one week of enrollment.
* Known drug or alcohol dependence or any other clinical factors or conditions (for example, history of seizures) which will interfere with the trial conduct or interpretation of the results or who in the opinion of the investigator are not suitable to participate.
* Unwilling and/or not able to give written informed consent.

**Maximum Age:** 80 Years

**Minimum Age:** 55 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** Neurosurgerycrc@bwh.harvard.edu

**Name:** Penelope Hallett, Ph.D.

**Phone:** 617-732-6564

**Role:** CONTACT

#### Locations

**Location 1:**

**City:** Boston

**Country:** United States

**Facility:** Brigham & Women's Hospital

**State:** Massachusetts

**Zip:** 02215

### IPD Sharing Statement Module

**IPD Sharing:** NO

### References Module

#### References

**Citation:** Osborn TM, Hallett PJ, Schumacher JM, Isacson O. Advantages and Recent Developments of Autologous Cell Therapy for Parkinson's Disease Patients. Front Cell Neurosci. 2020 Apr 3;14:58. doi: 10.3389/fncel.2020.00058. eCollection 2020.

**PMID:** 32317934

**Citation:** Hallett PJ, Deleidi M, Astradsson A, Smith GA, Cooper O, Osborn TM, Sundberg M, Moore MA, Perez-Torres E, Brownell AL, Schumacher JM, Spealman RD, Isacson O. Successful function of autologous iPSC-derived dopamine neurons following transplantation in a non-human primate model of Parkinson's disease. Cell Stem Cell. 2015 Mar 5;16(3):269-74. doi: 10.1016/j.stem.2015.01.018. Epub 2015 Feb 26.

**PMID:** 25732245

**Citation:** Hallett PJ, Cooper O, Sadi D, Robertson H, Mendez I, Isacson O. Long-term health of dopaminergic neuron transplants in Parkinson's disease patients. Cell Rep. 2014 Jun 26;7(6):1755-61. doi: 10.1016/j.celrep.2014.05.027. Epub 2014 Jun 6.

**PMID:** 24910427

**Citation:** Cooper O, Hallett P, Isacson O. Using stem cells and iPS cells to discover new treatments for Parkinson's disease. Parkinsonism Relat Disord. 2012 Jan;18 Suppl 1(0 1):S14-6. doi: 10.1016/S1353-8020(11)70007-4.

**PMID:** 22166414

**Citation:** Hargus G, Cooper O, Deleidi M, Levy A, Lee K, Marlow E, Yow A, Soldner F, Hockemeyer D, Hallett PJ, Osborn T, Jaenisch R, Isacson O. Differentiated Parkinson patient-derived induced pluripotent stem cells grow in the adult rodent brain and reduce motor asymmetry in Parkinsonian rats. Proc Natl Acad Sci U S A. 2010 Sep 7;107(36):15921-6. doi: 10.1073/pnas.1010209107. Epub 2010 Aug 23.

**PMID:** 20798034

**Citation:** Cooper O, Astradsson A, Hallett P, Robertson H, Mendez I, Isacson O. Lack of functional relevance of isolated cell damage in transplants of Parkinson's disease patients. J Neurol. 2009 Aug;256 Suppl 3:310-6. doi: 10.1007/s00415-009-5242-z.

**PMID:** 19711122

**Citation:** Mendez I, Vinuela A, Astradsson A, Mukhida K, Hallett P, Robertson H, Tierney T, Holness R, Dagher A, Trojanowski JQ, Isacson O. Dopamine neurons implanted into people with Parkinson's disease survive without pathology for 14 years. Nat Med. 2008 May;14(5):507-9. doi: 10.1038/nm1752. Epub 2008 Apr 6.

**PMID:** 18391961

**Citation:** Fink JS, Schumacher JM, Ellias SL, Palmer EP, Saint-Hilaire M, Shannon K, Penn R, Starr P, VanHorne C, Kott HS, Dempsey PK, Fischman AJ, Raineri R, Manhart C, Dinsmore J, Isacson O. Porcine xenografts in Parkinson's disease and Huntington's disease patients: preliminary results. Cell Transplant. 2000 Mar-Apr;9(2):273-8. doi: 10.1177/096368970000900212.

**PMID:** 10811399

**Citation:** Schumacher JM, Ellias SA, Palmer EP, Kott HS, Dinsmore J, Dempsey PK, Fischman AJ, Thomas C, Feldman RG, Kassissieh S, Raineri R, Manhart C, Penney D, Fink JS, Isacson O. Transplantation of embryonic porcine mesencephalic tissue in patients with PD. Neurology. 2000 Mar 14;54(5):1042-50. doi: 10.1212/wnl.54.5.1042.

**PMID:** 10720272

**Citation:** Mendez I, Sanchez-Pernaute R, Cooper O, Vinuela A, Ferrari D, Bjorklund L, Dagher A, Isacson O. Cell type analysis of functional fetal dopamine cell suspension transplants in the striatum and substantia nigra of patients with Parkinson's disease. Brain. 2005 Jul;128(Pt 7):1498-510. doi: 10.1093/brain/awh510. Epub 2005 May 4.

**PMID:** 15872020

**Citation:** Wernig M, Zhao JP, Pruszak J, Hedlund E, Fu D, Soldner F, Broccoli V, Constantine-Paton M, Isacson O, Jaenisch R. Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson's disease. Proc Natl Acad Sci U S A. 2008 Apr 15;105(15):5856-61. doi: 10.1073/pnas.0801677105. Epub 2008 Apr 7.

**PMID:** 18391196

**Citation:** Cooper O, Hargus G, Deleidi M, Blak A, Osborn T, Marlow E, Lee K, Levy A, Perez-Torres E, Yow A, Isacson O. Differentiation of human ES and Parkinson's disease iPS cells into ventral midbrain dopaminergic neurons requires a high activity form of SHH, FGF8a and specific regionalization by retinoic acid. Mol Cell Neurosci. 2010 Nov;45(3):258-66. doi: 10.1016/j.mcn.2010.06.017. Epub 2010 Jul 24.

**PMID:** 20603216

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000020734

- Term: Parkinsonian Disorders

- ID: D000001480

- Term: Basal Ganglia Diseases

- ID: D000001927

- Term: Brain Diseases

- ID: D000002493

- Term: Central Nervous System Diseases

- ID: D000009422

- Term: Nervous System Diseases

- ID: D000009069

- Term: Movement Disorders

- ID: D000080874

- Term: Synucleinopathies

- ID: D000019636

- Term: Neurodegenerative Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC10

- Name: Nervous System Diseases

- Abbrev: All

- Name: All Conditions

- Abbrev: BC04

- Name: Neoplasms

- Abbrev: BC17

- Name: Skin and Connective Tissue Diseases

- Abbrev: BC18

- Name: Nutritional and Metabolic Diseases

### Condition Browse Module - Browse Leaves

- ID: M13213

- Name: Parkinson Disease

- Relevance: HIGH

- As Found: Parkinson's Disease

- ID: M22494

- Name: Parkinsonian Disorders

- Relevance: LOW

- As Found: Unknown

- ID: M25603

- Name: Ganglion Cysts

- Relevance: LOW

- As Found: Unknown

- ID: M16358

- Name: Synovial Cyst

- Relevance: LOW

- As Found: Unknown

- ID: M4774

- Name: Basal Ganglia Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M5204

- Name: Brain Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M5742

- Name: Central Nervous System Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M12029

- Name: Movement Disorders

- Relevance: LOW

- As Found: Unknown

- ID: M2217

- Name: Synucleinopathies

- Relevance: LOW

- As Found: Unknown

- ID: M21558

- Name: Neurodegenerative Diseases

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000010300

- Term: Parkinson Disease

### Intervention Browse Module - Ancestors

- ID: D000002316

- Term: Cardiotonic Agents

- ID: D000013566

- Term: Sympathomimetics

- ID: D000001337

- Term: Autonomic Agents

- ID: D000018373

- Term: Peripheral Nervous System Agents

- ID: D000045505

- Term: Physiological Effects of Drugs

- ID: D000015259

- Term: Dopamine Agents

- ID: D000018377

- Term: Neurotransmitter Agents

- ID: D000045504

- Term: Molecular Mechanisms of Pharmacological Action

- ID: D000020011

- Term: Protective Agents

### Intervention Browse Module - Browse Branches

- Abbrev: CaAg

- Name: Cardiotonic Agents

- Abbrev: All

- Name: All Drugs and Chemicals

### Intervention Browse Module - Browse Leaves

- ID: M7473

- Name: Dopamine

- Relevance: HIGH

- As Found: Insight

- ID: M5572

- Name: Cardiotonic Agents

- Relevance: LOW

- As Found: Unknown

- ID: M16345

- Name: Sympathomimetics

- Relevance: LOW

- As Found: Unknown

- ID: M17962

- Name: Dopamine Agents

- Relevance: LOW

- As Found: Unknown

- ID: M20504

- Name: Neurotransmitter Agents

- Relevance: LOW

- As Found: Unknown

- ID: M21869

- Name: Protective Agents

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: D000004298

- Term: Dopamine

### Misc Info Module

- Version Holder: 2024-05-31
