Parkinsons Treatmeant
Parkinsons Treatmeant
Parkinsons Treatmeant
Brief Report
Sum m a r y
From the Departments of Neurosurgery We report the implantation of patient-derived midbrain dopaminergic progenitor
(J.S.S., B.S.C.), Neurology (T.M.H.), and cells, differentiated in vitro from autologous induced pluripotent stem cells (iPSCs),
Radiology (K.K., Q.L.), the Gordon Cen-
ter for Medical Imaging (K.K., Q.L.), and in a patient with idiopathic Parkinson’s disease. The patient-specific progenitor
the Division of Neuroradiology (O.R.), cells were produced under Good Manufacturing Practice conditions and character-
Massachusetts General Hospital, the De- ized as having the phenotypic properties of substantia nigra pars compacta neurons;
partment of Pediatrics, Computational
Health Informatics Program, Boston Chil- testing in a humanized mouse model (involving peripheral-blood mononuclear
dren’s Hospital (I.-H.L., S.-W.K.), and the cells) indicated an absence of immunogenicity to these cells. The cells were im-
Connell and O’Reilly Families Cell Manip- planted into the putamen (left hemisphere followed by right hemisphere, 6 months
ulation Core Facility, Dana–Farber/Harvard
Cancer Center (J.R.), Boston, and the apart) of a patient with Parkinson’s disease, without the need for immunosuppres-
Department of Psychiatry (B.M.C.) and sion. Positron-emission tomography with the use of fluorine-18-L-dihydroxyphe-
the Molecular Neurobiology Laboratory nylalanine suggested graft survival. Clinical measures of symptoms of Parkinson’s
(B.S., T.-Y.P., N.L., S.K., J.J., Y.C., H.S.,
J.K., T.K., P.L., K.-S.K.), McLean Hospital, disease after surgery stabilized or improved at 18 to 24 months after implantation.
Belmont — all in Massachusetts; the De- (Funded by the National Institutes of Health and others.)
partments of Neurology (C.H.) and Neuro-
surgery (M.K.) and the Brain and Mind
T
Research Institute (G.A.P.), Weill Cornell
Medical College, New York; the Depart- issue transplantation in patients with Parkinson’s disease to
ment of Neurology, Kaiser Permanente, replace the lost dopaminergic neurons of the substantia nigra pars com-
Irvine, CA (C.N.); and the Department of
Molecular and Life Sciences, Hanyang pacta has been studied since the 1980s. Sources of these cells have includ
University, Seoul, South Korea (H.S.). ed adrenal medulla1,2 and fetal midbrain tissues from allogeneic or xenogeneic
Address reprint requests to Dr. Schweitzer sources.3-7 Inconsistent symptomatic benefit of various durations has been reported
or Dr. Carter at the Department of Neuro-
surgery, Massachusetts General Hospital, with these approaches.8-11 Fetal cell–based therapies have been considered imprac-
55 Fruit St., White Bldg., Rm. 502, Boston, tical because of ethical constraints, difficulty in producing a defined cell product,
MA 02114, or at jschweitzer1@mgh.harvard and graft-induced dyskinesias, which may be caused by contaminating serotonergic
.edu or bcarter@mgh.harvard.edu; or to
Dr. Kwang-Soo Kim at the Molecular Neu- neurons, excess dopamine production, or both.8,12 Pluripotent stem cell–derived
robiology Laboratory, Rm. 216, McLean midbrain dopaminergic progenitor cells (mDAPs) represent a possible cell source
Hospital, 115 Mill St., Belmont, MA that can be produced with greater consistency.13,14 Advances in the technology for
02478, or at kskim@mclean.harvard.edu.
creating induced pluripotent stem cells (iPSCs) and for guiding their in vitro dif-
Drs. Schweitzer, Song, Herrington, Park,
and N. Lee and Drs. Carter and K.-S. Kim
ferentiation toward a midbrain dopaminergic fate offer the hope of achieving the
contributed equally to this article. benefits of fetal-tissue transplantation without its inherent practical and ethical
This article was updated on May 20, 2020, concerns.15-17 An autologous cell source may additionally obviate the need for im-
at NEJM.org. munosuppression. We report data from a patient treated by our group with this
N Engl J Med 2020;382:1926-32. method; no other patients were similarly treated.
DOI: 10.1056/NEJMoa1915872
Copyright © 2020 Massachusetts Medical Society.
Parkinson’s Disease Rating Scale (MDS-UPDRS), The patient underwent two MRI-guided stereo-
part III (scores range from 0 to 132, with higher tactic surgical procedures for implantation in
scores indicating worse parkinsonian motor the putamen, left hemisphere followed by right
signs),19 and the 39-item Parkinson’s Disease hemisphere, separated by 6 months, conforming
Questionnaire (PDQ-39; scores range from 0 to to regulatory guidance from the FDA. At each
156, with higher scores indicating worse quality operation, three trajectories were made in the
of life).20 (A complete list of clinical assessments putamen posterior to the level of the anterior
is provided in Table S3.) commissure, each spanning the superior–inferior
extent of the nucleus.21 A total of 4 million cells
Brain Imaging were delivered at each operative procedure, divid-
Computed tomographic (CT) scans were per- ed equally among the three tracks. Intravenous
formed intraoperatively to confirm accurate place- cefazolin was administered perioperatively. No
ment of the cell injection in the putamen and immunosuppressants, glucocorticoids, or anticon-
immediately postoperatively for hemorrhage vulsants were used at any time. After each sur-
screening at or near the site of implantation. Se- gery, the patient was monitored overnight and
rial magnetic resonance imaging (MRI) scans discharged the following day.
and magnetic resonance spectroscopic findings
were reviewed for any evidence of tumor, stroke, R e sult s
or hemorrhage. Serial fluorine-18-L-dihydroxy-
phenylalanine (18F-DOPA) positron-emission to- Immunogenicity of Grafts after
mography (PET)–CT was performed to assess Implantation in Humanized Mice
for the presence of presynaptic dopamine termi- As shown in Figure 1A and Figure S5, both patient-
nal activity in the engrafted putaminal regions. derived mDAPs (C4-mDAPs) and allogeneic mDAPs
Changes in radioisotope uptake were judged (H9-mDAPs) survived in NOD SCID gamma
semiquantitatively by 18F-DOPA standardized up- mice, and both graft types were rejected when
take value ratios. transplanted to allogeneic humanized mice
(K1-hu). Patient-humanized mice (C4-hu) per-
Safety Monitoring mitted the survival of autologous C4-mDAPs,
Serial clinical neurologic examination to detect with grafts staining positively for hNCAM+ cells
adverse neurologic events, along with imaging and containing TH+ neurons at 2 weeks after
reviews, was performed by two study neurolo- implantation, whereas C4-hu mice rejected allo-
gists and a study radiologist (all of whom are geneic H9-mDAPs, with prominent CD4+ lym-
authors). The patient continued to be treated phocytic infiltrates (Fig. 1B and 1C).
independently by an author who is his commu-
nity neurologist. Imaging at 0 to 24 Months after Implantation
in the Patient
At 3 months after the first implantation, 18F-DOPA
C a se R ep or t
PET–CT imaging showed an initial decline in
The patient was a 69-year-old right-handed man 18
F-DOPA uptake from baseline in the putamina,
with a 10-year history of progressive idiopathic followed by small increases in 18F-DOPA uptake
Parkinson’s disease. He was receiving extended- at subsequent times up to 18 months and 24
release carbidopa–levodopa (in capsules contain- months after implantations on the right side and
ing 23.75 mg and 95 mg, respectively, at a dose left side, respectively. Increased activity was
of three capsules four times daily), rotigotine greater on the right (second implant) than on
(4 mg daily), and rasagiline (1 mg daily) (total the left and was most prominent in the posterior
daily dose, 904 mg of levodopa equivalents). He putamen near the graft sites, as seen on the
reported poor control of his symptoms, with color intensity scale and on quantitative com-
3 hours of “off” time per day, characterized by parisons of selected subregions (Fig. 2A and Fig.
worsening tremor, posture, and fine motor con- S6). Semiquantitative changes from baseline in
trol; increases in the levodopa dose beyond these uptake of the radioisotope are shown in Figure 2
doses caused orthostatic hypotension. The pa- and varied from −4.0% to 13.5% on the right and
tient had not had dyskinesias. from −4.8% to 9.8% on the left.
A
C4-mDAPs H9-mDAPs
NSG
C4-hu
K1-hu
B
NSG C4-hu K1-hu
C4-mDAPs H9-mDAPs C4-mDAPs H9-mDAPs C4-mDAPs H9-mDAPs
TH hNCAM TH hNCAM TH hNCAM TH hNCAM TH hNCAM TH hNCAM
C
NSG+C4-mDAPs C4-hu+C4-mDAPs C4-hu+H9-mDAPs
CD4/Hoechst
Figure 2. Imaging.
Panel A shows axial fluorine-18-L-dihydroxyphenylalanine (18F-DOPA) positron-emission tomographic images at the
level of the basal ganglia at the time points indicated: baseline (4 months before first surgery), 3 months after the
left implantation, 12 months after the left implantation and 6 months after the right implantation, and 24 months
after the left implantation and 18 months after the right implantation. A decrease in 18F-DOPA uptake 3 months after
the initial left implantation was followed by a modest increase in dopamine uptake on both sides (right greater than
left), mainly in the posterior putamen near the graft sites. The table below the images shows the percentage change
in 18F-DOPA uptake (by standardized uptake value [SUV] ratio) with respect to baseline before surgery or to the low-
est uptake measured 3 months after the first (left side) implantation, as indicated by the timeline arrows. Anterior
and posterior denote the position of the measured region of interest within the putamen. Panel B is a T2-weighted
BLADE magnetic resonance image at 18 months after the left implantation and 12 months after the right implanta-
tion. Arrows indicate the location of the implants. Hyperintensity on T2-weighted imaging was associated with the
graft sites, more prominently on the right.
MRI at 6 months after the first implantation ment therapy (“off”) were not measured before
and subsequent time points showed areas of in- the first implantation because the patient declined
creased T2-weighted signal intensity approximat- to cease medications owing to worsened symp-
ing the locations of the graft sites in the pu- toms. Scores in the off period were 43 at 4 weeks
tamina, as well as along parts of the surgical after the first implantation, 33 to 41 at subse-
tracts within the white matter, more pronounced quent follow-up times, and 33 at 24 months.
on the right (Fig. 2B and Fig. S7). No contrast Scores on the MDS-UPDRS, part III, at the peak
enhancement was seen at the six putaminal im- dose of dopamine replacement therapy (“on”)
plantation sites. At 6 months after the second were 38 at the time of implantation, 19 to 35
surgery, a 4-mm region of enhancement was during follow-up, and 29 at 24 months. PDQ-39
observed 3 cm above the target in one tract; CT scores (assessing Parkinson’s disease–related
and MRI including arterial spin labeling mag- quality of life, with lower scores indicating bet-
netic resonance perfusion imaging and magnetic ter quality) were 62 at the time of implantation,
resonance spectroscopy showed changes consis- 2 to 34 during follow-up, and 2 at 24 months
tent with postsurgical gliosis (Fig. S7). (Fig. 3 and Table S3).
At 24 months, the patient’s Parkinson’s dis-
Clinical Assessments ease medications were extended-release carbidopa–
At 24 months after the first (left) implantation levodopa (in capsules containing 23.75 mg and
and 18 months after the second (right) implan- 95 mg, respectively, at a dose of three, three,
tation, the patient reported no adverse events or two, and three capsules four times daily), rotigo-
decline in function. Scores on the MDS-UPDRS, tine (4 mg daily), rasagiline (1 mg daily), and
part III (assessing parkinsonian motor signs), droxidopa (100 mg daily) (total daily dose, 847
after overnight withdrawal of dopamine replace- mg of levodopa equivalents); this represented a
with clinical and imaging results suggesting pos- We thank present and past members of the molecular neu-
robiology laboratory (including Melissa Feitosa, Dabin Hwang,
sible benefit over a period 24 months. Further Yeahan Kim, Shibo Cao, Jacob W. Feldmann, María José Luna,
studies are warranted to address how this ap- and Jin Hyuk Jung) for their technical assistance; Philip E.
proach will perform in a variety of patients with Stieg of the Weill Cornell Brain and Spine Center at the New
York–Presbyterian/Weill Cornell Medical Center and staff (Aly-
diverse genetic backgrounds and disease pheno- son Hignight, Mary O’Hehir, and Kristin Strybing); Blagovest
types over a period longer than 24 months. Nikolov for his help in filing the application to the Cornell in-
Supported by grants (K23NS099380, NS070577, NS084869, stitutional review board; Stephen M. Kaminsky and Hyunmi
and OD024622) from the National Institutes of Health and by Lee, directors of the Belfer Gene Therapy Core Facility; and
philanthropic support, partly funded by the patient described the personnel of the Dana–Farber/Harvard Cancer Center Cell
in this report, of the Parkinson’s Cell Therapy Research Fund at Manipulation Core Facility, especially Sarah Nikiforow, Hélène
McLean Hospital and Massachusetts General Hospital and the Nègre, and Laëtitia Pinte, for their technical and administrative
William and Elizabeth Sweet Endowed Professorship in Neuro- help in setting up the cell production in accordance with Good
science at Harvard Medical School. Manufacturing Practice conditions.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
References
1. Lindvall O, Backlund EO, Farde L, et al. neurons for severe Parkinson’s disease. 17. Kriks S, Shim JW, Piao J, et al. Dopa-
Transplantation in Parkinson’s disease: N Engl J Med 2001;344:710-9. mine neurons derived from human ES
two cases of adrenal medullary grafts to 9. Olanow CW, Goetz CG, Kordower JH, cells efficiently engraft in animal models
the putamen. Ann Neurol 1987;22:457-68. et al. A double-blind controlled trial of of Parkinson’s disease. Nature 2011;480:
2. Goetz CG, Olanow CW, Koller WC, bilateral fetal nigral transplantation in 547-51.
et al. Multicenter study of autologous Parkinson’s disease. Ann Neurol 2003;54: 18. Song B, Cha Y, Ko S, et al. Human
adrenal medullary transplantation to the 403-14. autologous iPSC-derived dopaminergic
corpus striatum in patients with advanced 10. Kefalopoulou Z, Politis M, Piccini P, progenitors restore motor function in
Parkinson’s disease. N Engl J Med 1989; et al. Long-term clinical outcome of fetal Parkinson’s disease models. J Clin Invest
320:337-41. cell transplantation for Parkinson disease: 2020;130:904-20.
3. Lindvall O, Brundin P, Widner H, et al. two case reports. JAMA Neurol 2014;71: 19. Goetz CG, Tilley BC, Shaftman SR,
Grafts of fetal dopamine neurons survive 83-7. et al. Movement Disorder Society-spon-
and improve motor function in Parkin- 11. Li W, Englund E, Widner H, et al. sored revision of the Unified Parkinson’s
son’s disease. Science 1990;247:574-7. Extensive graft-derived dopaminergic in- Disease Rating Scale (MDS-UPDRS):
4. Freed CR, Breeze RE, Rosenberg NL, nervation is maintained 24 years after scale presentation and clinimetric test-
et al. Survival of implanted fetal dopa- transplantation in the degenerating par- ing results. Mov Disord 2008; 23:
2129-
mine cells and neurologic improvement kinsonian brain. Proc Natl Acad Sci U S A 70.
12 to 46 months after transplantation for 2016;113:6544-9. 20. Peto V, Jenkinson C, Fitzpatrick R,
Parkinson’s disease. N Engl J Med 1992; 12. Politis M, Wu K, Loane C, et al. Sero- Greenhall R. The development and valida-
327:1549-55. tonergic neurons mediate dyskinesia side tion of a short measure of functioning
5. Spencer DD, Robbins RJ, Naftolin F, effects in Parkinson’s patients with neu- and well being for individuals with Par-
et al. Unilateral transplantation of human ral transplants. Sci Transl Med 2010; 2: kinson’s disease. Qual Life Res 1995; 4:
fetal mesencephalic tissue into the cau- 38ra46. 241-8.
date nucleus of patients with Parkinson’s 13. Lindvall O. Clinical translation of stem 21. Schweitzer JS, Song B, Leblanc PR,
disease. N Engl J Med 1992;327:1541-8. cell transplantation in Parkinson’s dis- Feitosa M, Carter BS, Kim KS. Columnar
6. Widner H, Tetrud J, Rehncrona S, et al. ease. J Intern Med 2016;279:30-40. injection for intracerebral cell therapy.
Bilateral fetal mesencephalic grafting in 14. Barker RA, Drouin-Ouellet J, Parmar Oper Neurosurg (Hagerstown) 2019;18:
two patients with parkinsonism induced M. Cell-based therapies for Parkinson dis- 321-8.
by 1-methyl-4-phenyl-1,2,3,6-tetrahydro- ease — past insights and future potential. 22. Brooks DJ. Neuroimaging in Parkin-
pyridine (MPTP). N Engl J Med 1992;327: Nat Rev Neurol 2015;11:492-503. son’s disease. NeuroRx 2004;1:243-54.
1556-63. 15. Sonntag KC, Song B, Lee N, et al. Pluri 23. Ma Y, Tang C, Chaly T, et al. Dopa-
7. Deacon T, Schumacher J, Dinsmore J, potent stem cell-based therapy for Parkin- mine cell implantation in Parkinson’s dis-
et al. Histological evidence of fetal pig son’s disease: current status and future ease: long-term clinical and (18)F-FDOPA
neural cell survival after transplantation prospects. Prog Neurobiol 2018;168:1-20. PET outcomes. J Nucl Med 2010;51:7-15.
into a patient with Parkinson’s disease. 16. Kikuchi T, Morizane A, Doi D, et al. 24. Zhao T, Zhang ZN, Rong Z, Xu Y. Im-
Nat Med 1997;3:350-3. Human iPS cell-derived dopaminergic munogenicity of induced pluripotent stem
8. Freed CR, Greene PE, Breeze RE, et al. neurons function in a primate Parkinson’s cells. Nature 2011;474:212-5.
Transplantation of embryonic dopamine disease model. Nature 2017;548:592-6. Copyright © 2020 Massachusetts Medical Society.