Idiopathic Parkinson Disease Clinical Trial
Official title:
Human OK99 Allogeneic Stem Cell Transplantation for Patients With Severe Parkinson's Disease
Implantation of Celavie human stem cells (OK99) is intended to address the underlying pathology of the disease by replacing damaged/destroyed cells of the brain, and/or stimulating the patient's brain to repair itself.
This trial is a longitudinal, prospective, interventional, uncontrolled study designed to
test, firstly, the safety and secondly, the potential efficacy of intraputaminal grafting of
undifferentiated hfSC for the treatment of PD. Patients were monitored carefully for any
adverse effects. All patients underwent baseline and 6- and 12-month post-surgery
neurological, neuropsychological, MRI, and PET evaluations.
Procurement, isolation, expansion, and characterization of hfSC, as well as assessment of
patients' immune response to hfSC grafting, were performed at Celavie Biosciences, LLC
(Oxnard, CA USA). Patient selection, pre- and post-surgery neurological, neuropsychological,
and MRI evaluations, as well as stereotactic surgery and post-surgery care, were performed
at Hospital Angeles del Pedregal (Mexico City, Mexico). Synthesis of radiopharmaceuticals
and PET imaging were carried out at the Radiopharmacy-Cyclotron Unit of the Faculty of
Medicine, Universidad Nacional Autonoma de Mexico (Mexico City, Mexico). Eight patients with
moderate to advanced PD were selected for this trial. One of the patients was lost to follow
up due to reasons unrelated to this study. Subjects that completed follow up were 2 females
and 5 males, with ages ranging between 43-74 years (mean age 56 years).
Procurement and expansion of hfSC
Human fetal brain tissue was procured via routine sterile manual aspiration methods with
informed consent from the donor in accordance with NIH guidelines for use of fetal tissue as
well as federal, and state laws. Tissue donor and hfSC recipients remained unknown to each
other.
Maternal blood samples (sera) were tested for: HIV (Abbott Laboratories, Abbott Park IL,
USA) hepatitis A, B and C (Abbott); HTLVI (Abbott); VDRL (Baxter Agglutination Slide Test
and reflex FTA), and cytomegalovirus (Quest, Oxnard CA). Women with a history of genital
herpes, cancer, asthma, lupus, rheumatoid arthritis, allergies, vasculitis of autoimmune
origin, and drug abuse were excluded. Gestation was determined according to Carnegie stages.
Fetal tissue was harvested at the sixth week of gestation after elective abortion. Fetal
brain was dissected, minced and triturated to a single cell suspension. Cells were cultured
in flasks incubated at 37°C under hypoxic conditions (5% O2 and 5% CO2) through 4 doublings.
At the second doubling (D2) cell culture was tested for sterility (USP <71>) and at D4
culture was karyotyped and PCR tested for presence of adventitious agents: HTLV-1, HTLV-2,
HIV-1 (A, B, D, F, H, N), hepatitis A, B and C, T. p. pallidum, CMV, HSV-1, HSV-2, HPV.
Cells were then transferred to a closed bioreactor system (GE WAVE Bioreactor 2/10 System,
Uppsala SWE), operating under the same physical and chemical conditions. The bioreactor was
used to create the Master Cell Bank (MCB), which was harvested, tested, characterized and
rate-control cryopreserved after a total of seven doublings (D7).
After the MCB was safety tested and characterized, a portion of the batch was thawed and
used to seed the bioreactor for the Working Cell Bank (WCB) production. Cells were cultured
in the bioreactor until they reached D13. They were harvested (Centritech LAB-III, Carr
Centritech Separation System, Rancho Cucamonga, CA, USA), aliquoted (Fill-It; TAP
Biosystems, Wilmington, DE, USA), and cryopreserved to create a WCB. The WCB was subjected
to release testing for safety and characterization assays. Safety testing included sterility
(USP <71>), mycoplasma (USP <63), endotoxin (USP <85>), and karyotyping (Cell Line Genetics,
Madison WI, USA). Characterization included flow cytometry testing for: Oct-4 >90% (10H11.2,
EMD Millipore, Billerica, MA, USA; AF488 conjugated), Sox-2 >90% (Btjce, eBioscience, San
Diego CA, USA; AF488 conjugated), MHC-I <10% (A4, eBioscience; APC conjugated), MHC-II <10%
(CVS20, Novus Biologicals, Littleton CO, USA; AF488 conjugated), CD105 <10% (SN6,
eBioscience; PE-Cy7 conjugated), and tyrosine hydroxylase <10% (EP1532Y, Abcam, Cambridge,
UK; FITC conjugated goat anti-rabbit IgG; Abcam; polyclonal). Both MCB and WCB were stored
in gas phase LN2 at -196°C.
All procedures were performed under aseptic conditions in an ISO 8 clean room, utilizing ISO
5 bio-safety cabinets and laminar airflow hoods, according to validated protocols. Cells
were shown to have a normal karyotype and did not produce teratomas in immunocompromised
rodents (unpublished data).
Pharmacotherapy
Immunosuppression via cyclosporine A at a dose of 15 mg/kg/day was started 10 days prior to
surgery and continued for one month thereafter. Patients also received Indomethacin
225mg/day, starting at 10 days prior to implantation and for six months postoperatively
thereafter. Wide spectrum antibiotic (Zannat 700mg) was given preoperatively and 48 hours
post-operatively. Antiparkinsonian medications were adjusted to patient's requirements.
Stereotactic surgery
MRI-guided stereotactic intraputaminal cell implantation into PD patients was performed
using a Leksell Stereotactic System and Stealth Station Surgical Navigation System (Fridley,
Minnesota, USA). Ropivacaine was used as a local anesthetic for frame placement. For target
locations, measurements were made using CT-scan images fused with previous MR images (both
in DICOM format, in axial sections 1.0 mm thick). With the patient under general anesthesia,
the stereotactic frame was fixed to the operating table with a Mayfield head holder.
Bilateral parasagittal incisions and corresponding 14 mm burr holes (one for each
hemisphere) were made in preparation for cell suspension injections. Two different needle
tracks through the same burr hole were selected for each side. Target locations were
determined by height and length of putaminal nuclei. The lowest Z-coordinates of each track
were located in the dorsal putamen and spaced 4mm apart in the X-direction. Each needle
track received 1X106 cells in 1 cc of culture medium. To ensure complete cell suspension
delivery, injections were carried out slowly for 2 min with reciprocal withdrawal of the
delivery needle to avoid both damage to stem cells and brain tissue, as well as to avert
reflux or bubble formation. After surgery, patients were kept in a conventional
post-operative care unit for 1 h. The day following surgery, MR images were obtained to
confirm correct placement of cell suspensions. All patients were discharged 24 h after
surgery.
Neurological evaluations
Neurological endpoints of this study included evaluation of the number and severity of
adverse events after cell grafting, and the efficacy in the improvement of motor responses,
as assessed on the UPDRS part I (mentation, behavior and mood), part II (motor activities of
the daily living), part III (motor performance), and part IV (complications of therapy), as
well as the modified Höehn and Yahr Scale, and the modified Schwab and England Activities of
the Daily Living Scale. Patients were clinically evaluated with these scales at screening
(as baseline, before surgery), and then after the procedure at six and 12 months. At every
visit, patients were asked to discontinue antiparkinsonian medications at least 12 hours
before the UPDRS assessment (for practical purposes, "OFF" state was defined as overnight
drug withdrawal) in order to be rated in their "OFF" state and then, UPDRS "ON" medication
evaluations were performed 1 hour after receiving their usual dose of levodopa. Each patient
received the same preoperative levodopa dose for each assessment. Adverse events, including
those reported by the patients spontaneously and those observed during the evaluations were
recorded. After obtaining signed informed consent from all patients that completed the
study, all "OFF" and "ON" UPDRS evaluations, were videotaped.
Neuropsychological evaluations
Cognitive performance was evaluated using the following instruments: Mexican adaptations of
Beck and Steer's anxiety [25] and depression [26] inventories; our brief neuropsychological
(NEUROPSI)[27,28] and computerized neuropsychological test batteries, and the Mini-mental
Parkinson State Examination (MMPSE)[29]. Patients reported on their quality of life as
related to their daily living activities; physical and mental well-being (health status);
cognition and communication, and one summary index.
Immunogenicity testing
Patient's blood was evaluated for increase in titers of hfSC specific antibodies and for
increase in antibody-dependent cell-mediated cytotoxicity after implantation as compared to
baseline values. Samples were drawn one month prior to cell implantation, and then one month
and six months after surgery. Whole blood specimens were collected from each patient and
processed as serum one and six months post-grafting using the lipophilic membrane dye PKH67
(Sigma-Aldrich) as described by the manufacturer for cell tracking in immune response and
cytotoxicity assays by flow cytometry [30,31]. Cytotoxicity assay was performed with 100:1,
50:1, and 25:1 effector to target ratios.
MRI
MR images were obtained before surgery (baseline) and three times after cell implantation at
24 h, and six and 12 months post-surgery. They were acquired with a 3 Tesla magnet, MR
Systems Achieva release 2.6.3.8 Philips (Best, The Netherlands).
PET molecular imaging
Patients underwent PET molecular imaging at baseline, at six months (data not presented),
and at one year after hfSC implantation. Radiopharmaceuticals utilized were
(+)-alpha-[11C]Dihidrotetrabenazine (DTBZ), 6-[18F]Fluoro-L-DOPA (FDOPA), and
[11C]Raclopride (RAC). All patients underwent DTBZ-PET scans and one additional study with
either FDOPA or RAC, at least one week apart. Patients were asked to discontinue
antiparkinsonian medications at least 12h before each study. Scans were acquired on a
Siemens Biograph 64 PET/CT. Thirty-minute brain emission scans were acquired 20 minutes
post-injection of DTBZ or RAC, while 15 min scans were acquired for FDOPA 75 min
post-injection. All patients studied with FDOPA were pre-medicated with 150 mg of carbidopa
to prevent peripheral decarboxylation. Images were reconstructed using an OSEM-2D algorithm
and analyzed with the software Statistical Parametric Mapping (SPM v.12). Each individual
PET brain image was normalized on an anatomical MRI atlas to be evaluated within a standard
space. Following normalization, FSL structural atlases were used for definition of the
regions of interest. To facilitate the quantitative analysis, specific uptake ratios (SUR)
in the caudate and putamen were calculated by subtracting the background signal of a
reference region with nonspecific uptake from striatal activity and dividing by reference
region activity [(target uptake - reference uptake)/reference uptake], using occipital
cortex (DTBZ and FDOPA) and cerebellum (RAC), as reference regions.
Statistical analysis
Comparisons between baseline and 12-month follow-up measurements for anxiety, depression,
NEUROPSI, MMPSE examinations, right and left finger tapping in "ON" and "OFF" medication
states were performed using the Wilcoxon test. All other end measures were reported as
individual results for each patient.
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Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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