Page 17 - MSC手冊 20220831

OA

退化性關節炎

臍帶間質幹細胞(MSC)治療退化性關節炎第I/II期人體臨床試驗顯
示，患者有顯著的疼痛與功能改善並且是安全的治療方式

6
˙ 實驗作法：MSC-1 治療組的患者 (9 名 ) 接受單劑量每公斤 20×10 個細胞 ;
6
MSC-2 治療組的患者 (9 名 ) 接受兩次單劑量每公斤 20×10 個細胞
˙ 實驗結果：利用 WOMAC 退化性關節炎量表做為成效指標，只有 MSC 治療的
患者有顯著的疼痛和功能改善且 MSC-2 治療組的疼痛水平明顯較低。
且在第一階段 / 第二階段試驗 (NCT02580695)，重複施打臍帶間質幹
HUMANCLINICALARTICLE
細胞的治療是安全的。

Umbilical Cord-Derived Mesenchymal Stromal Cells
(MSCs) for Knee Osteoarthritis: Repeated MSC
Dosing Is Superior to a Single MSC Dose
and to Hyaluronic Acid in a Controlled
a Department of Orthopedic Randomized Phase I/II Trial
Surgery, Universidad de los
Andes, Santiago, Chile; a a a b
b JOSE MATAS, MARIO ORREGO, DIEGO AMENABAR, CATALINA INFANTE,
Cells for Cells & Consorcio
b
Regenero, Santiago, Chile; RAFAEL TAPIA-LIMONCHI, b,c MARIA IGNACIA CADIZ, FRANCISCA ALCAYAGA-MIRANDA, b,c,d
c d e b,c,d c,d,f
Program for Translational PAZ L. GONZÁLEZ, EMILIO MUSE, MAROUN KHOURY, FERNANDO E. FIGUEROA ,
Research in Cell Therapy, Matas, Orrego, Amenabar et b,c,f 221
FRANCISCO ESPINOZA al.
Universidad de los Andes, Matas, Orrego, Amenabar et al. 221
d
Santiago, Chile; Laboratory Key Words. Osteoarthritis • Knee • Mesenchymal stromal cells • Pain • Disability
of Nano-Regenerative
Medicine, Universidad de
los Andes, Santiago, Chile; ABSTRACT
e
Department of Radiology, Knee osteoarthritis (OA) is a leading cause of pain and disability. Although conventional treat-
Clínica Universidad de los ments show modest benefits, pilot and phase I/II trials with bone marrow (BM) and adipose-
Andes, Santiago, Chile; derived (AD) mesenchymal stromal cells (MSCs) point to the feasibility, safety, and occurrence of
f Department of clinical and structural improvement in focal or diffuse disease. This study aimed to assess the
Rheumatology, Universidad safety and efficacy of the intra-articular injection of single or repeated umbilical cord-derived
de los Andes, Santiago, (UC) MSCs in knee OA. UC-MSCs were cultured in an International Organization for Standardiza-
Chile tion 9001:2015 certified Good Manufacturing Practice-type Laboratory. Patients with symptom-
atic knee OA were randomized to receive hyaluronic acid at baseline and 6 months (HA, n = 8),
6
Correspondence: Francisco single-dose (20 × 10 ) UC-MSC at baseline (MSC-1, n = 9), or repeated UC-MSC doses at baseline
6
Espinoza, M.D., Department of and 6 months (20 × 10 × 2; MSC-2, n = 9). Clinical scores and magnetic resonance images
Rheumatology, Universidad de (MRIs) were assessed throughout the 12 months follow-up. No severe adverse events were
los Andes, Avenida Monseñor reported. Only MSC-treated patients experienced significant pain and function improvements
Alvaro del Portillo 12455, from baseline (p = .001). At 12 months, Western Ontario and Mc Master Universities Arthritis
Santiago 7620086, Chile. Index (WOMAC-A; pain subscale) reached significantly lower levels of pain in the MSC-2-treated
Telephone: 56 2 26181008; group (1.1 1.3) as compared with the HA group (4.3 3.5; p = .04). Pain Visual Analog scale
e-mail: fespinoza@uandes.cl
was significantly lower in the MSC-2 group versus the HA group (2.4 2.1 vs. 22.1 9.8,
Received March 13, 2018; p = .03) at 12 months. For total WOMAC, MSC-2 had lower scores than HA at 12 months
accepted for publication (4.2 3.9 vs. 15.2 11, p = .05). No differences in MRI scores were detected. In a phase I/II trial
October 20, 2018; first (NCT02580695), repeated UC-MSC treatment is safe and superior to active comparator in knee
published December 28, 2018. OA at 1-year follow-up. STEM CELLS TRANSLATIONAL MEDICINE 2019;8:215–224
http://dx.doi.org/ 15
10.1002/sctm.18-0053 Figure 3. Efficacy outcomes. (A–C): Comparison with baseline in each group. (A): WOMAC-A pain subscale. (B): WOMAC-C function sub-
Figure 3. Efficacy outcomes. (A–C): Comparison with baseline in each group. (A): WOMAC-A pain subscale. (B): WOMAC-C function sub-
scale. (C): Total WOMAC. (D): OMERACT-OARSI Responder Index Criteria. Abbreviation: HA, hyaluronic acid; MSC, mesenchymal stromal
SIGNIFICANCE STATEMENT
資料來源 : Stem Cells Transl Med. 2019 Mar; 8(3): 215-224.
scale. (C): Total WOMAC. (D): OMERACT-OARSI Responder Index Criteria. Abbreviation: HA, hyaluronic acid; MSC, mesenchymal stromal
This is an open access article cell; WOMAC, Western Ontario and Mc Master Universities Arthritis Index.
cell; WOMAC, Western Ontario and Mc Master Universities Arthritis Index.
under the terms of the Creative Osteoarthritis is the main disabling musculoskeletal disorder in adults, for which presently avail-
Commons Attribution- able treatments are only of marginal benefit. This trial provides evidence of safety and efficacy
NonCommercial-NoDerivs effects in OA have been revised given the more recent evi- Table 4. Structural assessment by magnetic resonance
of a highly accessible allogeneic cell source that had not been tested in knee osteoarthritis, in imaging
effects in OA have been revised given the more recent evi-
License, which permits use and Table 4. Structural assessment by magnetic resonance imaging
dence suggesting that paracrine and anti-inflammatory actions
spite of its well-known biological advantages. Even if these results should be confirmed in larger
distribution in any medium, dence suggesting that paracrine and anti-inflammatory actions HA MSC-1 MSC-2
MSC-2
MSC-1
HA
are crucial with respect to the tissue-restoring effects of MSC
trials, they point the way to a simple, scalable cell-based therapy open to repeated applications
provided the original work is are crucial with respect to the tissue-restoring effects of MSC group group group p value
group
group
p value
group
treatments [35].
properly cited, the use is non- with no need for invasive surgical procedures. WORMS at baseline
treatments [35].
For example, Ichiseki et al. [36] have examined the role
commercial and no modifica- For example, Ichiseki et al. [36] have examined the role WORMS at baseline 30.9 25.1 46.1 18.1 40.1 25.7 .21
Total (0–332)
of MSCs in an enzymatic rat OA model. When cells were
tions or adaptations are made. MSCs in an enzymatic rat OA model. When cells were Total (0–332) 30.9 25.1 46.1 18.1 40.1 25.7 .21
of
injected intra-articularly, an increase in the expression of TNF-α- Articular cartilage 16.5 13.4 23.2 10.9 21 14 .3
injected intra-articularly, an increase in the expression of TNF-α- Articular cartilage 16.5 13.4 23.2 10.9 21 14 .3
INTRODUCTION (TSG-6) was observed in the joint car-
stimulated gene/protein 6 disease-modifying OA drugs are described, and
stimulated gene/protein 6 (TSG-6) was observed in the joint car- Meniscal integrity 1.7 1.3 1.1 1.2 2.7 1.9 .15
1.1 1.2
2.7 1.9
Meniscal integrity
1.7 1.3
.15
tilage, with no expression in the control group. A reduction of
clinical effects of pharmacological interventions
tilage, with no expression in the control group. A reduction of WORMS at 6 months
Osteoarthritis (OA) is the most common joint dis-
metalloprotease A disintegrin and metalloproteinase with WORMS at 6 months
metalloprotease A disintegrin and metalloproteinase with remain of short duration. In consequence, cur- .3
Total (0–332)
33.2 25.7 46.6 18.1 40.6 21.4
ease, leading to chronic pain, poor quality of life,
thrombospondin motifs 5 (ADAMTS5) levels was evidenced as Total (0–332) 33.2 25.7 46.6 18.1 40.6 21.4 .3
thrombospondin motifs 5 (ADAMTS5) levels was evidenced as
Articular cartilage 16.7 14.5 22.4 10.8 21.3 14.1
well. TSG-6 has been reported as a mediator of the beneficial rent aims have been directed toward the devel- .28
and increased mortality [1–3]. This imposes a
well. TSG-6 has been reported as a mediator of the beneficial Articular cartilage 16.7 14.5 22.4 10.8 21.3 14.1 .28
effect of MSCs in both cardiac and lung injury models of tissue opment of newer cell-based therapies. Initial .13
Meniscal integrity
1.7 1.6
2.7 2.1
0.9 1.2
major social burden due to elevated health care
effect of MSCs in both cardiac and lung injury models of tissue Meniscal integrity 1.7 1.6 0.9 1.2 2.7 2.1 .13
damage. On the other hand, the expression of anti-Calcitonin
attempts aiming at joint repair with autologous
damage. On the other hand, the expression of anti-Calcitonin WORMS at 12 months
costs and premature workforce retirement [4, 5].
Gene-Related Peptide in the C5 dorsal horn of the OA animals WORMS at 12 months
Gene-Related Peptide in the C5 dorsal horn of the OA animals chondrocytes [6, 7], thus requiring surgical .15
However, despite decades of research, no true
33.6 26.3 41.5 14.3 40.5 23.9
Total (0–332)
was also significantly decreased, indicating a suppressive effect Total (0–332) 33.6 26.3 41.5 14.3 40.5 23.9 .15
was also significantly decreased, indicating a suppressive effect
on the central sensitization component of pain. Saulnier Articular cartilage 16.8 14.5 23.1 10.2 21.3 13.8 .3
on the central sensitization component of pain. Saulnier Articular cartilage 16.8 14.5 23.1 10.2 21.3 13.8 .3
et al. [37] confirmed the reduced expression of metalloprotei-
0.9 1.2
2.7 2.1
Meniscal integrity
1.7 1.6
et al. [37] confirmed the reduced expression of metalloprotei-
1.7
STEM CELLS TRANSLATIONAL MEDICINE 2019;8:215–224 www.StemCellsTM.com 1.6 © 2018 The Authors .13
Meniscal integrity
.13
0.9 1.2
2.7 2.1
nases (1, 3, and 13) after MSC injection, but describe that MSC-
STEM CELLS TRANSLATIONAL MEDICINE published by Wiley Periodicals, Inc. on behalf of AlphaMed Press
nases (1, 3, and 13) after MSC injection, but describe that MSC-
conditioned medium can also convey these anti-inflammatory Data are presented as n (%) or mean SD.
conditioned medium can also convey these anti-inflammatory Data are presented as n (%) or mean SD.
Abbreviations: HA, hyaluronic acid; MSC, mesenchymal stromal cells;
effects on OA synoviocytes. In sum, MSC treatments are known Abbreviations: HA, hyaluronic acid; MSC, mesenchymal stromal cells;
effects on OA synoviocytes. In sum, MSC treatments are known WORMS, Whole-Organ Magnetic Resonance Imaging Score.
WORMS, Whole-Organ Magnetic Resonance Imaging Score.
to induce potent anti-inflammatory, tissue-restoring, and analge-
to induce potent anti-inflammatory, tissue-restoring, and analge-
sic effects that could explain the clinical findings described in
sic effects that could explain the clinical findings described in
recent trials as well as in the present phase I/II study. the OARSI clinical responder status was achieved by all (100%)
recent trials as well as in the present phase I/II study. the OARSI clinical responder status was achieved by all (100%)
Indeed, the size of the effect for clinical response of the MSC-2 group patients at 6 and 12 months. This is usually
MSC-2 group patients at 6 and 12 months. This is usually
Indeed, the size of the effect for clinical response of the
VAS score in this trial reached 0.81 for cell therapy, evidencing achieved only in 50%–60% of patients receiving intra-articular
VAS score in this trial reached 0.81 for cell therapy, evidencing achieved only in 50%–60% of patients receiving intra-articular
a high symptomatic impact, leading to a number needed-to- steroids or HA during initial (3–6 months) follow-up [41, 42].
a high symptomatic impact, leading to a number needed-to- steroids or HA during initial (3–6 months) follow-up [41, 42].
treat of only 2.1. Such an effect surpasses the usual findings Our own data confirmed this trend, but without reaching sig-
treat of only 2.1. Such an effect surpasses the usual findings Our own data confirmed this trend, but without reaching sig-
reported for intra-articular placebo or HA according to recent nificance (100% vs. 62%, p = .08; Fig. 3). Taken together, our
reported for intra-articular placebo or HA according to recent nificance (100% vs. 62%, p = .08; Fig. 3). Taken together, our
meta-analyses [38–40]. Somehow underscoring these effects, findings suggest that clinical impact of UC-MSC treatment is
meta-analyses [38–40]. Somehow underscoring these effects, findings suggest that clinical impact of UC-MSC treatment is
www.StemCellsTM.com © 2018 The Authors. STEM CELLS TRANSLATIONAL MEDICINE published by
www.StemCellsTM.com © 2018 The Authors. STEM CELLS TRANSLATIONAL MEDICINE published by
Wiley Periodicals, Inc. on behalf of AlphaMed Press
Wiley Periodicals, Inc. on behalf of AlphaMed Press