Journal of Parkinson’s Disease xx (2021) x–xx 1

DOI 10.3233/JPD-212685
IOS Press

1 Review

2 Bringing Advanced Therapies for

Parkinson’s Disease to the Clinic:

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3

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4 The Scientist’s Perspective

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5 Mark Tomishimaa and Agnete Kirkebyb,c,∗
6
a BlueRock Therapeutics, New York, NY, USA
7
b Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark
c Wallenberg Center for Molecular Medicine (WCMM) and Department of Experimental Medical Science,

Lund University, Lund, Sweden

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8
11

10 Accepted 14 June 2021

Pre-press 3 July 2021 Au
12 Abstract. After many years of preclinical development, cell and gene therapies have advanced from research tools in the
13 lab to clinical-grade products for patients, and today they constitute more than a quarter of all new Phase I clinical trials for
14 Parkinson’s disease. Whereas efficacy has been convincingly proven for many of these products in preclinical models, the
15 field is now entering a new phase where the functionality and safety of these products will need to stand the test in clinical
16 trials. If successful, these new products can have the potential to provide patients with a one-time administered treatment
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17 which may alleviate them from daily symptomatic dopaminergic medication.

Keywords: ATMP, clinical trial, dopaminergic neurons, regenerative therapy, stem cells, transplantation
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18
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19 INTRODUCTION: WHY DO WE NEED treatments to halt or slow progression of PD. Despite 30

20 ADVANCED REGENERATIVE promising data from animal models, not a single 31

21 THERAPIES FOR PARKINSON’S disease-modifying therapy for PD has until now 32

22 DISEASE? passed through Phase III clinical trial with positive 33

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outcome. Recently, there has been much anticipation 34

23 Ever since the discovery of Parkinson’s disease to antibody therapies which can block propagation 35

24 (PD) in the early 19th century, there has been intense of a-Synuclein (a-Syn) pathology in the brain. How- 36

25 focus on trying to identify the underlying cause of ever, in April 2020 Prothena/Roche announced that 37
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26 the disease as well as the mechanism of disease pro- their therapy Prasinezumab had failed to meet the 38

27 gression. However, while the development of early primary endpoint of UPDRS reduction from the first 39

28 symptomatic treatments for the disease has been suc- such a phase II antibody trial [1]. More phase II trial 40

29 cessful, we have yet to develop disease-modifying results are expected this year to uncover the clin- 41

ical efficacy of a-Syn antibody technologies. The 42

∗ Correspondence
depressing conclusions so far likely reflect the fact 43
to: Agnete Kirkeby, Wallenberg Center for
Molecular Medicine (WCMM), and Department of Experimen-
that we still do not understand what triggers PD 44

tal Medical Science, Lund University, 22184 Lund, Sweden. Tel.: at its infancy, or why patients display such vari- 45

+45 5168 5353; E-mail: agnete.kirkeby@med.lu.se. able patterns of spread of pathology throughout the 46

ISSN 1877-7171/$35.00 © 2021 – IOS Press. All rights reserved.

 2 M. Tomishima and A. Kirkeby / The Scientist’s Perspective to PD Therapies

47 brain. Furthermore, the pathogenesis of PD is highly non-DA neurons to produce DA by supplying key 96

48 complex, involving damaging effects due to protein DA enzymes (ProSavin: AADC, TH and CH1) or 97

49 aggregation, inflammation, mitochondrial dysfunc- by increasing inhibitory signals from the subthalmic 98

50 tion, impaired autophagy and reactive oxygen species nucleus (STN) through AAV-GAD expression. Both 99

51 just to mention a few [2], and it may be naive to approaches have shown moderate efficacy on UPDRS 100

52 think that a single molecule can halt this multitude of scores in clinical trials and are being explored further 101

53 deleterious processes. It is thought-provoking that the in new trials [8, 9]. However, an initiated Phase-II 102

54 drugs which are currently showing most promising gene therapy trial with AAV-AADC (VY-AADC02) 103

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55 disease-slowing effects in clinical trials are GLP- was halted by the FDA in December 2020, and the 104

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56 1 agonists, which have an unclear mechanism of future development of this product is currently uncer- 105

57 action proposed to involve modulation of several cell tain [7, 10]. Evolving from these early efforts with 106

58 types including neurons, glia and immune cells [3, ATMPs, more advanced products are being devel- 107

59 4]. While refined and efficacious disease-modifying oped and cell and gene therapies now constitute 27% 108

60 treatments are still struggling to reach the market, of all ongoing Phase I studies in PD (14 out of 51 tri- 109

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61 patients are in dire need of therapies which pro- als by January 2020), thereby clearly marking a new 110

62 vide better quality of life and which are effective era of advanced therapies moving in larger numbers 111

63 beyond the initial period after diagnosis. Compared from the lab into the clinic [7]. New on this stage 112

64 to symptomatic dopamine (DA)-modifying medica- is the emergence of DA cell replacement products 113

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65 tions, gene and cell therapies have the potential to based on pluripotent stem cells (PSCs), which have 114

66 provide more refined solutions to a complex prob- the potential to yield authentic and fully functional 115

67 lem by restoring neuronal signaling and in some midbrain DA neurons, the type which is lost in PD. 116

68 cases even circuits in the diseased brain. As such,

69 cell therapies such as DA cell replacement have the
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70 potential to significantly minimise the need for DA CLINICAL TRANSLATION OF DA CELL 117

71 medications, relieving the patients not only of pri- REPLACEMENT THERAPIES: WHERE 118

72 mary motor symptoms, but also of the severe side ARE WE NOW? 119

73 effects accompanying the ever-increasing doses of

74 medication required to keep the progressing disease The concept of DA cell replacement therapy 120

in check. has a rich clinical history based on allografting of

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75 121

human fetal ventral mesencephalic tissue, with esti- 122

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mates of over 300 PD patients transplanted over 123

76 ADVANCED THERAPIES FOR the past 30 years [11]. Patient outcomes have been 124

77 PARKINSON’S DISEASE PASSING variable, with some patients able to reduce or dis- 125

78 THROUGH THE PIPELINE continue medications for years while others suffered 126

from graft-induced dyskinesias. Two double-blinded, 127

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79 Until now, only few advanced therapeutic medic- placebo-controlled trials failed to meet their endpoint 128

80 inal products (ATMPs) have been tested beyond which led to a re-evaluation of fetal cell therapies for 129

81 initial Phase I/II clinical trials for PD. Overall, tri- Parkinson’s, eventually leading to the initiation of the 130

82 als involving delivery of neurotrophic factors for EU-funded TRANSEURO trial using improved pro- 131
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83 supporting DA neuron survival, i.e., AAV-Neurturin tocols for fetal tissue preparation and more rigorous 132

84 (CERE-120) and GDNF infusion have shown dis- patient selection [12]. This trial has recently com- 133

85 appointing outcomes on efficacy parameters [5, 6]. pleted transplantation of all 11 patients included in the 134

86 This likely reflects the fact that damaged DA neu- trial with fetal tissue, and clinical results are expected 135
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87 rons are difficult to rescue from cell death when during 2021/22 [12]. Along with earlier fetal cell 136

88 disease pathology is ongoing. A novel gene therapy work, results from this trial will provide an important 137

89 trial relying on supplying GBA1 to GBA mutation framework for stem cell-based therapies to come. 138

90 carriers is currently in Phase-I clinical trial, and Clinical trials using PSC-based therapies have 139

91 will provide important information on whether GBA only just begun (see summary in Table 1). The first 140

92 mutations alone are central in driving the progres- PSC-based trial for PD (ISCO trial) was initiated 141

93 sion of the disease in already diagnosed patients [7]. in Australia in 2016, using parthenogenetic PSC- 142

94 Other gene therapies are based on strategies to alter derived neural progenitor cells of a non-DA fate 143

95 neurotransmitter production, either through hijacking [13]. These cells are proposed to have a more 144
 M. Tomishima and A. Kirkeby / The Scientist’s Perspective to PD Therapies 3

indirect mechanism of action, working potentially

MoA, Mechanism of Action; NSC, Neural stem cell; DA-CRT, Dopamine cell replacement therapy; N/A, not available. ∗ Patient numbers in brackets are total no. of planned patients in trials which
145

EudraCT 2021-001366-38
through trophic support. However, multiple groups 146
Clinical data trial ID

have shown through genetic engineering in preclin- 147

UMIN000033564
ical models that it is specifically the midbrain DA 148

IND No. 17145

NCT02452723

NCT03119636

NCT04802733
neurons which are responsible for reverting symp- 149

toms in animal models of PD [14–16]. 150

Following this rationale, Jun Takahashi and col-

N/A

N/A

N/A

N/A

N/A
151
[29]

leagues launched the first PSC-based midbrain DA 152

f
neuron cell replacement in Japan in 2018 using an
Patients included∗

153

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allogenic iPSC approach [17, 18]. Just recently, a 154

collaborative effort between Weill Cornell, Memo-

(50)

(10)
(7)

(8)
12

155
1

rial Sloan Kettering, and BlueRock Therapeutics was 156

granted permission by the FDA to advance to Phase 157

1 clinical trial in the US with an hESC-based mid- 158

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Trial start

Est. 2021

Est. 2022

brain DA product (MSK-DA01) originally developed 159

2016

2017

2017

2018

by Lorenz Studer [19–21]. This trial is anticipated to 160

begin later this year. In an equivalent European effort, 161

Malin Parmar and colleagues have provided strong

[16, 19, 20, 44]
Pluripotent stem cell products in the clinical trial pipeline for PD

162
Preclin. data

[13, 38, 39]

[17, 42, 43]

[30, 45–50]

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proof of concept for their hESC-based product and are 163
[40]

[41]

aiming to begin clinical trials in the EU in 2022. These 164

groups working on PSC-based products have been 165

meeting annually since 2014 in the research-based 166

Sweden UK

network GForce-PD with the aim of sharing expe- 167

Australia
Trial site

Au
China

Japan
USA

USA

riences to bring the best treatments forward for the 168

PD community. Building on these academically led 169

Table 1

advancements, three additional companies, Sumit- 170

Trophic support

omo Dainippon Pharma, FujiFilm Cellular Dynamics 171

are not yet completed. Patient numbers without brackets are completed, transplanted patients.
DA-CRT

DA-CRT

DA-CRT

DA-CRT

DA-CRT

Inc. and Novo Nordisk have also announced the 172

MoA

development of PSC-based cell products for treat-

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173

ment of PD. 174

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The trials mentioned above are based on allogeneic 175

cell transplantation strategies. Induced pluripotent

Immune matching

176
Allogeneic, HLA

Allogeneic, HLA

stem cell technology could provide an autologous

non-matched

non-matched

non-matched

non-matched

non-matched
matched and

matched and

177
Autologous
Allogeneic,

Allogeneic,

Allogeneic,

approach with the benefit of genetic matching at 178

the cost of time, logistic complexity and potential 179

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variability. For intracerebral therapies, it is not clear 180

that autologous approaches will be advantageous in 181

BlueRock Therapeutics

the immunoprivileged brain since fetal cell allografts 182

(Company/Institution)

Cambridge University
Weill Cornell/Memorial
International Stem Cell
Corporation (ISCO)

have demonstrated robust and long-lived survival, up

Chinese Academy of

183
Site of development

Sciences, Beijing

Harvard University

co
Sloan Kettering/

to 24 years without long term immune suppression

Kyoto University

Lund University/

184

[22–28]. Relying on autologous grafting could limit 185

the accessibility of stem cell therapies due to the cost 186

and the complication of batch-to-batch variation in 187

Un

differentiation efficacy. Nevertheless, one cannot dis- 188

count the possibility that the immune response to 189

STEM-PD (hESC-derived

grafted allogeneic cells can limit efficacy. A recent

(hESC-derived ventral
Human parthenogenetic

midbrain progenitors)
hESC-derived ventral

190
hESC-derived NSCs)

midbrain progenitors

midbrain progenitors

midbrain progenitors
hiPSC-derived ventral

hiPSC-derived ventral
ISC-hpNSC (Human

single patient case led by the group of Kwang-Soo 191

ventral midbrain
parthenogenetic

Kim at Harvard demonstrated proof of concept for the 192

progenitors)

autologous transplantation approach [29]. The Kim

Cell product

MSK-DA01

193

group, as well as the US-based company Aspen Neu- 194

roscience, is now pursuing further clinical trials using 195

autologous iPSCs for transplantation.

 4 M. Tomishima and A. Kirkeby / The Scientist’s Perspective to PD Therapies

196 LOOKING TOWARDS THE FUTURE OF transplantation to achieve optimal clinical function 247

197 PSC-BASED CELL THERAPIES from cell replacement therapies. This makes the 248

choice of a clinical endpoint critical to assure the 249

198 It has taken around twenty years of intensive strongest clinical signal and reduced chance for 250

199 preclinical work to produce clinically acceptable placebo effects. Another key piece to the puzzle 251

200 pluripotent stem cell-derived human DA neurons that remains the patients themselves. PD has been increas- 252

201 function efficiently in PD animal models. While this ingly recognized as a syndrome with a range of 253

202 is great progress, much remains to be learned from clinical courses. Increasing knowledge of PD sub- 254

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203 clinical trials to improve cell products further. Careful types and results from stem cell trials will allow us 255

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204 work by the Parmar lab [30] has shown equiva- to better understand which patients will truly benefit 256

205 lence between fetal cell and PSC-based dopamine from cell replacement therapies. 257

206 neurons in animal models of PD, but clinical data

207 will be crucial to assess this equivalence in patients. ACKNOWLEDGMENTS 258
208 Another unresolved question is whether transplanted

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209 DA neurons are “self-regulating.” That is, DA neu- The authors would like to thank Joachim Frue- 259
210 rons might receive feedback from the brain that bis and Seth Ettenberg for critical and constructive 260
211 naturally balances and limits dopamine release. This comments to the manuscript. 261
212 is important since excessive dopamine release might

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213 result in dyskinesias (involuntary movement) [31].
CONFLICT OF INTEREST 262
214 Understanding this biology in humans will inform
215 our strategy for patient dosing.
Mark Tomishima holds several patent agreements 263
216 Another factor affecting dose is the observation
and is an employee of BlueRock Therapeutics, a com- 264
217 that many neurons die after transplantation. It is not
pany that plans to commercially develop the DA01
Au 265
218 known why this occurs, and excess cells must be
product. Agnete Kirkeby holds several patent agree- 266
219 transplanted to account for this loss and assure ade-
ments and is a consultant for Novo Nordisk A/S on 267
220 quate dosing. The delivery device itself creates an
the development of the STEM-PD product. 268
221 injury and a localized immune reaction, and large
222 numbers of dead cells could alert the immune system
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