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

Overview

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 1/2a 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.

At this time, autologous iPSC-derived midbrain dopamine neurons are available only through participation in the ongoing Phase 1/2a clinical trial. Expanded access or compassionate use outside of the trial is not available.

Interventions

• Biological Autologous midbrain dopamine neurons
  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.

Primary outcome measures

• 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 outcome measures (8)

• Change in UPDRS Part III [Time frame: 18 months following transplantation]
• Change in ON time without troublesome dyskinesia [Time frame: 18 months following transplantation]
• Change in OFF time [Time frame: 18 months following transplantation]
• Change in baseline Levodopa Equivalent Daily Dose [Time frame: 18 months following transplantation]
• Change in Unified Dyskinesia Rating Scale [Time frame: 18 months following transplantation]
• Change in UPDRS Part II [Time frame: 18 months following transplantation]
• Change in MoCA [Time frame: 18 months following transplantation]
• Change in DaTscan [Time frame: Baseline to 18 months following transplantation]

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:

• 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
• Severe arrhythmia
• History of cardiovascular surgery (cardiac, vascular stent surgery, angioplasty);
• History of stroke or transient ischemic attack
• History of subarachnoid hemorrhage
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Brigham & Women's Hospital — Boston

Publications

• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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

Identifiers

NCT: NCT06422208 · 2023P003609 · U01NS109463

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗