Progress in clinical applications
of PSCs in 2017
Trounson A. et al. Nature Reviews Molecular Cell Biology 17, 194–200 (2016) doi:10.1038/nrm.2016.10
Robust strategies have been developed to differentiate pluripotent stem cells into
retinal pigment epithelium, A9 dopaminergic neurons, oligodendrocyte, pancreatic βislet
cells and cardiomyocytes. Clinical trials are underway for embryonic stem cell (ES
cell) derivatives for age-related macular degeneration (AMD), type I diabetes, spinal
cord injury, myocardial infarct and Parkinson disease (using parthenogenetic embryonic
stem cells (pES cells)).
Induced pluripotent stem cells (iPSCs) are in a clinical trial for AMD. Rigorously tested,
abundant sources of these cell types are needed for preclinical research to generate
data for regulatory approval for human studies. The cells also need to be manufactured
in large quantities for clinical trials.
These clinical studies in humans begin with regulatory approval for Phase I trials, which
demonstrate safety. They are followed by Phase II studies showing proof of concept for
cell therapy in human patients. Sometimes, Phase I–II studies are designed to
demonstrate both safety and efficacy. Larger-scale Phase III clinical trials aim to
demonstrate the statistical significance of the therapeutic benefit.
The bench to bedside pathway
Knoepfler PS Adv Drug Deliv Rev. 2015 Mar;82-83:192-6.
Diagram of the evolving clinical trials process and other mechanisms of therapy
translation to the bedside. The traditional, multi-phasic FDA clinical trials process is
shown in black with a black arrow from bench to bedside. Evolving FDA mechanisms for
accelerating the clinical trial process are shown in orange. Compassionate Use (also
known as “Expanded Access”) and Right To Try (RTT) are shown in green with a loop
reflecting the bypassing of Phase 2 and Phase 3. It is notable that the requirements for
Compasionate Use are evolving and there are diverse stakeholder views. The precise
pre-requisites (e.g. Phase 1 versus Phase 2 data) obtainable from FDA guidance are not
completely clear and may vary on a case-by-case basis. The common stem cell clinic
approach of entirely avoiding the clinical trials approval process is shown in red. Note
that for some non-more than minimally manipulated stem cell products used in a
homologous manner, direct use by stem cell clinics or other physicians may be
appropriate with only a relatively minor role for the FDA.
• 41,054 studies (total)
•
• 28849 studies: heart, cardiac, coronary
• 6240 studies : heart failure
• 210 studies: heart failure stem cell
• 4 studies: heart human embryonic
• 4 studies: heart human induced pluripotent
• 1 study: heart failure induced pluripotent
- diagnostic
https://clinicaltrials.gov/ct2/results?term=heart+failure+human+embryonic
https://clinicaltrials.gov/ct2/show/NCT02057900?term=heart+failure+human+embryoni
c&rank=1 PATCH
http://www.onlinejacc.org/highwire/markup/28281/expansion?width=1000&height=50
0&iframe=true&postprocessors=highwire_figures%2Chighwire_math%2Chighwire_inlin
e_linked_media%2Chighwire_embed
https://clinicaltrials.gov/ct2/results?term=heart+human+induced+pluripotent&type=&r
slt=&recr=&age_v=&gndr=&cond=&intr=&titles=&outc=&spons=&lead=&id=&state1=&
cntry1=&state2=&cntry2=&state3=&cntry3=&locn=&rcv_s=&rcv_e=&lup_s=&lup_e=
Why?
• human heart has limited potential for
regeneration, the loss of cardiomyocytes
during course of cardio-myopathy and
ischaemic injury can result in heart failure
and death
What to do?
• current status
– prevention – non smoking, education, lifestyle, lipids…
– AC Inhibitor – lowe blood pressure, reverse remodeling
– Betablocker – reduces adrenergic stimulation = lower
oxygen consumption / need
– Diuretics – reduces volume overload
– etc… symptomatic treatment
– Bypass / Angioplasty / Transplantation… in time?
• cardiac repair is strategy to regenerate functionally
viable myocardium after insult as myocardial infarction to
prevent or heal heart failure…
How?
• cells/ tissues / vessels
• growth factors / cytokines
• origin:
endogenouse repair– original tissue
autologouse – other organs
allogenic – other human(s)
xenogenic – other species
• number of different strategies…
Bosniak Z. 3rd Dubrovni Cardiology Highlihts lecture
Source
?
––
Sanganalmath S Bolli R Circ Res. 2013 Aug 30; 113(6): 810–834.
Skeletal Myoblasts?
• precursors of satellite cells (SKMs)
• muscle biopsies, proliferative + resistant to
ischaemia and hypoxia
• no functional coupling of SKMs with the
myocardium in vivo = fail to contract
synchronously with the native myocardium
• the MAGIC trial - no significant
improvement in LV function = discontinued
P. Menasch´e, O. Alfieri, S. Janssens et al., “The myoblast
autologous grafting in ischemic cardiomyopathy (MAGIC)
trial: first randomized placebo-controlled study of myoblast
transplantation,” Circulation, vol. 117, no. 9, pp. 1189–1200, 2008.
[41] H. Reinecke, V. Poppa, and C. E. Murry, “Skeletal muscle stem
cells do not transdifferentiate into cardiomyocytes after cardiac
grafting,” Journal of Molecular and Cellular Cardiology, vol. 34,
no. 2, pp. 241–249, 2002.
Bone Marrow-Derived Stem Cells
(BMCs) unselected ?
• in circulation- contribute to myocytes renewal
(cell fusion and transdifferentiation)
haematopoietic stem cells (HSCs)
mesenchymal stem cells (MSCs)
endothelial progenitor cells (EPCs)
- is optimal the mixture of stem-like cells ?
• harvested from pelvic bones of patients
• TheTOPCARE-AMI,
• BALANCE trial - intracoronary BMMNCs showed 10-11% inc. LVEF (5Y)
• meta- analysis: over 3000 patients have been treated with BMCs
– overall LVEF (+3.96%)
– smaller infarct size ( −4.03%)
– clinical significance?
– limited data on mortality, recurrence of MI, and rehospitalization for heart failure
– no of carcinogenesis, arrhythmias, or any other adverse effects
D. M. Leistner, U. Fischer-Rasokat, J. Honold et al., “Transplantation
of progenitor cells and regeneration enhancement
in acute myocardial infarction (TOPCARE-AMI): final 5-year
results suggest long-term safety and efficacy,” Clinical Research
in Cardiology, vol. 100, no. 10, pp. 925–934, 2011.
M. Yousef, C.M. Schannwell, M. K¨ostering, T. Zeus, M. Brehm,
and B. E. Strauer, “The BALANCE Study: clinical benefit
and long-term outcome after intracoronary autologous bone
marrow cell transplantation in patients with acute myocardial
infarction,” Journal of the American College of Cardiology, vol.
53, no. 24, pp. 2262–2269, 2009.
Bone Marrow-Derived Stem Cells
clinical trial in Brno
Long-term results of intracoronary bone marrow cell transplantation: the potential of
gated sestamibi SPECT/FDG PET imaging to select patients with maximum benefit from
cell therapy. Kaminek M, Meluzin J, Panovský R, Metelkova I, Budikova M, Richter M.
Clin Nucl Med. 2010 Oct;35(10):780-7. doi: 10.1097/RLU.0b013e3181e4d9c5.
Autologous transplantation of mononuclear bone marrow cells in patients with acute
myocardial infarction: the effect of the dose of transplanted cells on myocardial
function.
Meluzín J, Mayer J, Groch L, Janousek S, Hornácek I, Hlinomaz O, Kala P, Panovský R,
Prásek J, Kamínek M, Stanícek J, Klabusay M, Korístek Z, Navrátil M, Dusek L,
Vinklárková J. Am Heart J. 2006 Nov;152(5):975.e9-15.
Mesenchymal Stem Cells
(MSCs) selected?
• Bone Marrow - LVEF was increased by approximately
6.7% at 6 months, an inverse dose response, 20 million
better than 200 million cells, - the POSEIDON-pilot
• Umbilical cord matrix in 18-month follow-up, global LVEF
improved by 5% no arrhythmias or immuno side effects
• Adipose-Derived Mesenchymal Stem Cells.
harvested and expanded
o MHC class II antigens,
differentiate in to cardiomyocytes and endothelial cells
upon induction
the PRECISE study cells stabilized the scar size in
patients with advanced ischaemic heart disease (not
reduction of scar size or increase LVEF)
J. M. Hare, J. E. Fishman, G. Gerstenblith et al., “Comparison of allogeneic vs autologous
bonemarrow-derivedmesenchymal stem cells delivered by transendocardial injection in
patients with ischemic cardiomyopathy: the POSEIDON randomized trial,” JAMA, vol.
308, no. 22, pp. 2369–2379, 2012.
The TRansendocardial Stem Cell Injection Delivery Effects on Neomyogenesis STudy (The
TRIDENT Study) (Trident) (NCT02013674)
E. C. Perin, R. Sanz-Ruiz, P. L. S´anchez et al., “Adipose-derived regenerative cells in
patients with ischemic cardiomyopathy: the PRECISE Trial,” American Heart Journal, vol.
168, no. 1, pp. 88.e2–95.e2, 2014.
Cardiac Stem Cells
(CSCs )?
• resident stem-like cells, self-renewing cells able to differentiate into
a 3 cell lineages
• low proportion (0.01%) of native cardiomyocytes = low turnover rate
• meta-analysis 1970 animals improvement in LVEF by approximately
12%
• SCIPIO study phase I, c-kit+ CSCs - ischaemic MI, CSCs from right
atrial appendage CABG
– 1 million of cells administered to 16 patients intracoronary 4 months after CABG
increase in LVEF 12.3% at 12 months injection / no tumour formation
– 4–8% of transplanted CSCs colonized / persisted in the myocardium 1y
– effect of paracrine factors released by injected cells modulating the
proliferation of the host cardiac cells?
R. Bolli, A. R. Chugh, D. D’Amario et al., “Cardiac stem cells in patients with ischaemic
cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial,” The Lancet, vol.
378, no. 9806, pp. 1847–1857, 2011.
Cardiosphere-Derived Cells
(CSps)?
• in vitro cultured myocardial biopsies form spheroids
• self-renewal, positive for progenitor cell markers (c-kit,
CD-34, Sca-1, and Nkx2.5)
• heterogeneous mixture of cardiac stem cells,
differentiating progenitors and differentiated
cardiomyocytes
• enhance cardiac function, angiogenic formation, and
paracrine factor secretion (supporting cells)
• the CADUCEUS - decreased scar size of 12.3% at 12
months - no improvement in global LVEF
• large size may embolize capillary
• lack MHC II antigen = allogeneic CDCs trials
R. R. Makkar, R. R. Smith, K. Cheng et al., “Intracoronary cardiosphere-derived cells for
heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised
phase 1 trial,” The Lancet, vol. 379, no. 9819, pp. 895–904, 2012.
Embryonic Stem Cells
(ESCs)?
• derived from the inner cell mass of the early embryo in the
blastocyst stage
• self-renewing, clonogenic, and capable of differentiating into
any type of cell in the adult
• atrial-like, ventricular-like, sinus nodal-like, Purkinje-like cells
• beat spontaneously and synchronously
• teratomas after transplantation because of the unlimited
differentiation potential of ESCs - need for selection
• ethical concerns, potential genetic instability, risk of immune
rejection - the ESCORT study
Transplantation of Human Embryonic Stem Cell-derived Progenitors in Severe Heart
Failure (ESCORT) (NCT02057900)
induced Pluripotent Stem Cells
(iPSCs)
• forced expression of OCT4, SOX2, KLF4, and c-MYC
transcription factors reprogram terminally differentiated
• cells - resemble embryonic stem cells
• iPSCs can be derived from individual patients for
autologous transplantation
• risk of teratoma formation, the low efficiency of
cardiogenic differentiation, high costs, and timeconsuming
methods
• diagnostic methods – phenotype analyses and on
demand patient specific drugs testing
Derivation of Human Induced Pluripotent Stem (iPS) Cells to Heritable Cardiac
Arrhythmias (NCT02413450),
“Blood Collection From Healthy Volunteers and Patients forthe Production of
ClinicalGrade Induced Pluripotent StemCell (iPSC) Products (NCT02056613),”
Direct reprogramming?
• additional slide according to question :-)
• M. Ieda, J.-D. Fu, P. Delgado-Olguin et al.,
“Direct reprogramming of fibroblasts into
functional cardiomyocytes by defined
factors,” Cell, vol. 142, no. 3, pp. 375–386,
2010.
Medicine paradigm shift!
Gillray J. Bloodletting 1804, World History Archive