Part 2 Of 2 Comment/Reply on ACT/Ocata Lancet Report (Oct. 2014) Reply by, *Steven D Schwartz, Eddy Anglade, Robert Lanza, on behalf of the Ocata Macular Disease Investigator Group schwartz@jsei.ucla.edu Jules Stein Eye Institute Retina Division, and David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA (SDS); and Ocata Therapeutics Inc, Marlborough, MA, USA (EA, RL) Source Material: http://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(15)61203-X.pdf

1. Correspondence
30 www.thelancet.com Vol 386 July 4, 2015
Third, because the progression
of the disease has already led
to photoreceptor-cell death and
irreversible vision loss for a substantial
number of patients, an ideal solution
to this issue would be the generation
of photoreceptor cells for use in
conjunction with retinal pigment
epithelium graft.
Finally, although the subretinal area
is privileged, researches have shown
that the transplanted cells in the host
eye still need long-term immune
suppression for survival.2
Therefore,
the duration of immunosuppression
and the recommended dose remains
to be discussed in detail.
We declare no competing interests.
Guo-You Zhang,Tian Liao,
Xiao-Bing Fu, *Qing-Feng Li
dr.liqingfeng@yahoo.com
Department of Plastic and Reconstructive Surgery,
Shanghai Ninth People’s Hospital, Shanghai
JiaoTong University School of Medicine, Shanghai,
200011, China (G-YZ, Q-FL); Department of Head
and Neck Surgery, Fudan University Shanghai
Cancer Center, Shanghai, China (TL); andWound
Healing and Cell Biology Laboratory, Institute of
Basic Medical Science, First Hospital Affiliated to the
PLA General Hospital, Beijing, China (X-BF)
1 Schwartz SD, Regillo CD, Lam BL, et al. Human
embryonic stem cell-derived retinal pigment
epithelium in patients with age-related
macular degeneration and Stargardt’s macular
dystrophy: follow-up of two open-label phase
1/2 studies. Lancet 2015; 385: 509–16.
2 West EL, Pearson RA, Barker SE, et al.
Long-term survival of photoreceptors
transplanted into the adult murine neural
retina requires immune modulation. Stem Cells
2010; 28: 1997–2007.
Authors’ reply
We thank Janet Sunness and
Guo-You Zhang and colleagues fortheir
comments on our Article.1
Sunness
asserts that transplantation of human
embryonic stem cell-derived retinal
pigment epithelium (hESC-RPE) into
patients with advanced dry age-related
macular degeneration and Stargardt’s
disease needs to be tested. We report
only visual improvements as noted
during the course of a phase 1 safety
trial.As mentioned inourArticle,1
many
potential explanations are available
for these observations other than
an actual functional improvement,
including those suggested by
Sunness. However, the area of the
macula transplanted in our patients
intentionally excluded the foveal
centre to which Sunness refers, and
instead targeted a transition zone that
included undetectable, compromised,
and healthy photoreceptors. This
choice of transplant site was guided
with multimodal imaging done
preoperatively and intended to
transplant an area that recapitulated
the central macula earlier in the course
of the disease. Again, safety was the
primary endpoint studied. All vision
improvements came as surprise to the
investigators. All patient assessments
were assessed by masked vision
examiners with expertise in low vision
rehabilitation.
Perhaps more importantly,
accumulating evidence suggests that
photoreceptor inner segments or cell
bodies might survive in a state that
is difficult to detect in some forms
of macular degeneration.2
Thus, if
biological plausibility of transplanted
stem-cell progeny conferring a
regenerative signal to neighbouring
tissues is discounted, a rescue effect of
dormant celltypes might still be noted.
Therefore,we respectfullydisagreewith
the statement that transplantation
of stem-cell-derived retinal pigment
epithelium cells cannot restore vision;
we are confident that this is an open
question and are hopeful that future
studies will help answer it.
We agree with the potential value
of microperimetric assessment. Many
of our patients have undergone many
microperimetric tests before and
after transplantation and some even
seemed to show improved thresholds
and fixation in the transplant sites.
However, after further scrutiny and
consultation with renowned experts in
the specialty, the results were deemed
tobeimmaterialandultimatelywithout
meaning. Microperimetry is an evolving
science and is very difficultto accurately
studyineyeswithpoorfixation.Despite
these hurdles, microperimetry will be
partof future clinicaltrial protocols.
We agree with Zhang and colleagues
that our phase 1 safety trial studying
hESC-RPE contained 18 patients and,
thus, assumptions of absolute safety
should be avoided. Furthermore, we
appreciate and agree that a complete
dose–response curve has not been
generated in this phase 1 safety trial,
and thank them for the common
suggestion that stem-cell-derived
photoreceptors should be combined
with hESC-RPE. Finally, we agree that
immunosuppression regimens have to
be optimised.
SDS has received research support and consultancy
fees from Alcon, Bausch and Lomb, Allergan,
Genentech, Regeneron, and Avalanche. EA, and RL
are employees of OcataTherapeutics Inc.
*Steven D Schwartz, Eddy Anglade,
Robert Lanza, on behalf of the Ocata
Macular Disease Investigator Group
schwartz@jsei.ucla.edu
Jules Stein Eye Institute Retina Division, and David
Geffen School of Medicine, University of California,
Los Angeles, CA 90095, USA (SDS); and Ocata
Therapeutics Inc, Marlborough, MA, USA (EA, RL)
1 Schwartz SD, RegilloCD, Lam BL, et al. Human
embryonic stem cell-derived retinal pigment
epithelium in patients with age-related macular
degeneration and Stargardt’s macular
dystrophy: follow-up oftwo open-label phase
1/2 studies. Lancet 2015; 385: 509–16.
2 WangQ,TutenWS, Lujan BJ, et al.Adaptive
optics microperimetry andOCT images show
preserved function and recoveryof cone visibility
in maculartelangiectasiatype 2 retinal lesions.
InvestOphthalmolVisSci 2015; 56: 778–86.
Department of Error
RTS,S ClinicalTrials Partnership. Efficacy and
safety of RTS,S/AS01 malaria vaccine with or
without a booster dose in infants and children in
Africa: final results of a phase 3, individually
randomised, controlled trial. Lancet 2015;
386: 31–45—The Acknowledgments section
of the appendix of this Article has been
updated.This correction has been made to
the online version as of July 3, 2015, and the
printed version is correct.
The AVERTTrial Collaboration group. Efficacy and
safety of very early mobilisation within 24 h of
stroke onset (AVERT): a randomised controlled
trial. Lancet 2015; 386: 46–55—The column
headings of figure 2 in the appendix of this
Article have been changed from “OR [odds
ratio]” to “ES [effect size]”.This correction has
been made to the online version as of
May 7, 2015, and the printed version is correct.
Published Online
May 7, 2015
http://dx.doi.org/10.1016/
S0140-6736(15)60643-2