Download The current Status of Stem cells in eye care

Retina
The Current Status of
Stem Cells in Eye Care
By Irv Arons
The following is based on an article that originally ran in the May/June 2012 Retina Today, a sister publication of
Advanced Ocular Care. The author has updated the contents and tables. More information about companies involved in
stem cell research and ongoing clinical trials involving stem cells for ocular applications can be found by following the QR
codes embedded in this article.
F
rom an inauspicious start several years ago, the
use of stem cells in the treatment of several ocular and retinal diseases has picked up steam over
the past year. There are now nearly 30 companies
and institutions involved in research and clinical trials using a variety of stem cells for the treatment of
more than a dozen degenerative problems found in the
eye (Table; Additional Resources), including 14 now in
human clinical trials.
WHAT ARE STEM CELLS?
Every organ and tissue in the human body is made
up of specialized cells that originated from a pool of
stem cells in the very early embryo (embryonic stem
cells). Throughout our lives, we rely, to a much more
limited degree, on rare deposits of stem cells in certain
areas of the body (adult stem cells) to regenerate organs
and tissues that are injured or lost, such as skin, hair,
blood, and the lining of the gut.
Stem cells are like a blank microchip that can be programmed to perform particular tasks. Stem cells’ pluripotency allows them to develop or differentiate under
proper conditions into specialized cells that carry out
a specific function, such as in the skin, muscle, liver, or
in the eye. Additionally, stem cells can grow extensively
without differentiating and give rise to more stem
cells—this is referred to as self-renewal. These two characteristics distinguish stem cells from other cells in the
body and give stem cells their tremendous therapeutic
promise for a wide range of degenerative diseases.
The four most commonly used and described classes
of stem cells are embryonic stem cells (embryonic ESCs,
or human embryonic stem cells hESCs), induced pluripotent stem cells (ipSCs), adult stem cells (adult SCs), and
parthenogenetic stem cells (hpSCs). All four types are
used in medical research, although the popularity of
research involving ipSCs and hpSCs has grown in recent
years.
24 Advanced ocular care march 2013
Additional Resources
Stem Cell/Cell Therapy Companies/Institutions
Active in Ophthalmology
A list of 30 companies and institutions working with stem cells/cell
therapies for ophthalmic applications. The table lists collaborators,
the cell type being used, and the
tinyurl.com/StemCellComp
applications for which the cells will
be used.
Stem Cell/Cell Therapy in Ophthalmology
by Application
A list of 14 ophthalmic applications being studied in clinical trials.
The table includes the companies/
institutions involved, the clinical
trial status, and an active link for
tinyurl.com/StemCellAppl
the clinical trial for those listed.
(Thirty-four active and completed
clinical trials are shown.)
Stem Cell/Cell Therapy in Ophthalmology—
Ongoing and Completed Clinical Trial Details
A list of the 14 ophthalmic applications and the 34 clinical trials
showing the number of patients
to be studied in each trial and the
number studied to date. Active
tinyurl.com/StemCellClncal
links are provided for each ongoing or completed trial.
ESCs are derived from fertilized human eggs (oocytes)
in the very early stages of development. They are truly
pluripotent, in principle enabling them to become
any body tissue, and thus provide tremendous clinical
Retina
Table. Stem Cell/Cell Therapy in Ophthalmology by Applicationa
Application
Company/Institution
Status
Clinical Trialb
Stargardt
Advanced Cell Technology
• UCLA/Jules Stein
• Wills Eye Institute
• Moorfields Eye Hosp.
• Aberdeen Royal Infirm.
Phase 1/2
Phase 1/2
Phase 1/2
Phase 1/2
NCT01345006
CHA Bio & Diostech (S. Korea)
Phase 1
NCT01625559
CNGB3 achromatopsia
National Eye Institute (NEI)
Phase 1/2
NCT01648452
Dry age-related macular
degeneration/geographic
atrophy
Advanced Cell Technology
• UCLA/Jules Stein
• Wills Eye Institute
• Bascom Palmer
• Mass Eye & Ear
Phase 1/2
Phase 1/2
Phase 1/2
Phase 1/2
NCT01344993
• Moorfields Eye Hosp.
IND-Prep
Wet age-related macular
degeneration
CHA Bio & Diostech (S. Korea)
Phase 1/2
NCT01674829
Janssen R&D (J&J)
• Retina Institute of CA
• Wills Eye Institute
Phase 1/2a
NCT01226628
(Re-started 7-13-12)
StemCells Inc.
• Retina Foundation of the Southwest Phase 1/2
NCT01632527
Neurotech
• Multiple
Completed
NCT00447954
Phase 1 not yet recruiting
NCT01691261
Pfizer
• Univ. Col. London
Univ. of San Paulo
Phase 1/2
• Centro de Pesquisa Rubens Siqueira
Corneal surface repair/
limbal cell renewal
NCT01469832
NCT01518127
CellSeed France SARL/FGK
Clinical Reserach GmbH
• Universitatsklinkum, Erlangen,
Germany
Started recruitment April 2012 NCT01489501
Univ. Hosp. Antwerp
Phase 1/2
NCT00845117
Centre Hospitalier d’Ophth. des
Quinze-Vingts, Paris
Phase 2
NCT01619189
Royan Institute (Tehran, Iran)
Completed
NCT00736307
Instit. Univ. De Oftalmobiologia
Aplicada, Valladolid, Spain
Phase 1/2
NCT01562002
march 2013 Advanced ocular care 25
Retina
Table. Stem Cell/Cell Therapy in Ophthalmology by Applicationa (continued)
Glaucoma, primary openangle
Dr. Jeffrey Goldberg
Univ. of Miami
• Bascom Palmer
Phase 1
Not yet recruiting
NCT01408472
Ischemic retinopathy
(diabetic retinopathy)
Univ. of San Paulo
• Centro de Pesquisa Rubens
Siqueira
Phase 1/2
NCT01518842
Macular telangectasia
(MacTel)
Neurotech
• UCLA/Jules Stein
• Retina Assoc. of Cleveland
Phase 1
Not yet recruiting
NCT01327911
Ocular surface repair
Fundacion Clinic per a la Recerca
Biomedica (Spain)
• Hospital Clinic Barcelona
• Instituto Univ. Barraquer
• Instituto de Microcirugia Ocular
Recruiting
Not yet recruiting
Not yet recruiting
NCT01470573
Mahidol Univ. (Thailand)
Completed
NCT01237600
Ministry of Health, Malaysia
NCT01123044
Phase 3
Not yet recruiting
Phase 1
NCT00491959
(Terminated due to unstable
cell sheet quality)
National Taiwan Univ. Hosp.
Corneal epithelial stem
cell deficiency
Dept. Ophth, Tohoku Univ. Grad.
School of Medicine (Japan)
Not yet recruiting
JPRNUMIN000006745
Dept. Ophth, Osaka Univ Grad School
of Medicine (Japan)
Not yet recruiting
JPRNUMIN000005400
National Eye Institute (NEI)
Completed
NCT00063765
Univ. of San Paulo
Completed
• Centro de Pesquisa Rubens Siqueira Phase 2
NCT01068561
NCT01560715
Mahidol Univ. (Thailand)
Phase 1
NCT01531348
Neurotech
• Multiple
• Multiple
Completed
Completed
NCT00447980
NCT00447993
Retinitis Pigmentosa/Usher Neurotech
Syndrome Types 2 & 3
• UCSF
Phase 2 Recruiting
NCT01530659
Optic nerve atrophy
General Hosp. of the Chinese
People’s Armed Police Force (China)
Recruiting
ChiCTRTNRC-11001491
Dr. Jeffrey Goldberg
Univ. of Miami
• Bascom Palmer
Not yet recruiting
NCT00063765
Retinitis pigmentosa
Retinitis pigmentosa/
Usher syndrome types 2
& 3, and choroideremia
aInformation
bClinical
for this table was compiled by Irv Arons, and its use here is courtesy of the author.
trial identifier as registered with ClinicalTrials.gov or the World Health Organization.
26 Advanced ocular care march 2013
Retina
potential. They are, however, associated with significant
ethical, political, and religious controversy, because a
fertilized egg, under the right circumstances, has the
potential to develop into a human being. Of note, one
company, Advanced Cell Technology, has devised a
method to produce human embryonic stem cells from
a blastomere, removing only a few cells without damaging or destroying the embryo.
Another major (albeit much less publicized) issue
with ESCs is that, because they are transplanted from
one person (the fertilized egg) to another person (the
recipient patient) (ie, an allogeneic treatment), therapeutic cells and tissues derived from ESCs may provoke
an immune response from the recipient and be rejected.
In contrast, ipSCs are adult and fully differentiated
cells (eg, skin cells) that are chemically, physically,
genetically, or otherwise driven back to earlier developmental stages. Although creation of such cells does
not involve the use or destruction of a fertilized egg, it
does require dramatic changes in gene expression that
may have an unknown biological impact. As a result,
their use will likely be subject to substantial scrutiny by
regulatory authorities before approval for therapeutic
use. Also, due to immune rejection, ipSCs have to be
derived from the patients themselves (ie, autologous
therapy), which significantly limits clinical use and
adds time and cost that will be increasingly difficult
to implement in cost-contained health care systems
worldwide. Finally, ipSCs cannot be used for hereditary
disease therapy because they bear the same genetic
defects as the donor patient.
Adult SCs are rare cells found in various organs or tissues and have a limited ability to differentiate into cells
with specific functions. They are older and less powerful than other types. Although these stem cells do not
require the use or destruction of a fertilized egg or extensive manipulation of gene expression, they are rare and
hard to identify, and they generally proliferate poorly,
thus making it hard to produce therapeutic amounts.
Another type of stem cell, hpSCs, are derived from
activated human oocytes. Parthenogenesis is a form of
asexual reproduction in some amphibians and plants
but does not occur naturally in mammals, including
humans. Scientists have discovered a process for the
chemical activation of human eggs, similar to what the
sperm does in normal fertilization, but without sperm.
Some companies claim that this process results in
hpSCs which are as pluripotent and proliferate as ESCs,
yet avoid the ethical, political, and religious controversy around the use or destruction of human embryos
with potential for viable human life. Furthermore,
because there is no forced change of gene expression
“Most of the research efforts
involving stem cells appears to be
focused on the back of the eye,
specifically on retinal tissue and
diseases.”
patterns, hpSCs are not likely to face the same safety
and regulatory hurdle as ipSCs. Most importantly and
unique relative to all other stem cell classes, hpSCs can
be produced in a simplified immunogenetic (homozygous) form that enables each line to be an immune
match for many millions of people.
APPLICATIONS FOR STEM CELLS IN
OPHTHALMOLOGY
The Front of the Eye
Scarred and degenerative corneas represent one prime
area of research for the use of stem cells. Because of a
shortage of donated human corneas for transplantation, especially in populous nations such as India and
China (and in developing nations), the use of stem cells
to regenerate corneal tissues could become valuable in
areas of the world where blindness due to damaged corneas is prevalent.
The Middle of the Eye
There are only a few research programs using stem
cells for the middle areas of the eye, specifically in treating glaucoma. NeoStem, Inc., has said that it is working
with Schepens Research Institute in using the company’s
very small embryonic-like stem cells in the treatment
of glaucoma (and age-related macular degeneration
[AMD]). Stemedica Cell Technologies claims to be working with the Fyodorov Eye Institute in Moscow on a
glaucoma program.
The Back of the Eye
Most of the research efforts involving stem cells
appears to be focused on the back of the eye, specifically
on retinal tissue and diseases. I have identified areas of
interest including regeneration of retinal pigment epithelial cells for the treatment of both dry and wet forms
of AMD; replacement of damaged photoreceptors; the
growth of artificial retinas for treating AMD; and direct
treatments for diseases such as retinitis pigmentosa, retinopathy of prematurity, diabetic retinopathy, Stargardt
disease (also known as Stargardt macular dystrophy),
retinal vein occlusions, and optic nerve atrophy.
march 2013 Advanced ocular care 27
Retina
CLINICAL TRIAL STATUS
At the time of this publication, there were 30 institutions and companies actively engaged in research
involving stem cells in the United States, South America,
Europe, Iran, South Korea, Taiwan, Japan, and China to
treat a variety of primarily retinal conditions. It should be
noted that Advanced Cell Technology’s clinical trials for
both Stargardt disease and dry AMD, at several eye institutes in the United States and Europe, have shown positive results in human patients as reported in The Lancet.1
More than 200 patients worldwide have received stem
cell/cell therapy treatments to date.
In its phase 1/2 clinical trials for Stargardt disease
and dry AMD, Advanced Cell Technology has recently
reported no safety problems and the observation of evidence of engraftment of the transplanted ESC-derived
retinal pigment epithelial cells and visual acuity gain in
patients treated during the 18 months since the trials
were first initiated.2
CONCLUSION
As stated by Stephen Rose, PhD, chief research officer
at The Foundation Fighting Blindness, in his Eye on the
Cure blog,3 “Of course, it would be nice if all the parts of
our bodies, including our retinas, came with extended
warranties so you could just swap them out when they
go bad. But now that I think about it, that’s what stem
cells might do for us someday.” n
Irv Arons is a retired consultant to the
ophthalmic industry, and he writes a blog, Irv
Arons’ Journal, focused on new technologies,
including stem cells and gene therapy, for treating retinal diseases. His blog can be found at
http://tinyurl.com/ijablog. Mr. Arons may be reached at
[email protected]
1. Schwartz SD, Hubschman JP, Heilwell G, et al. Embryonic stem cell trials for macular degeneration: a preliminary
report. Lancet. 2012;379(9817):713-720.
2. Advanced Cell Technology Achieves Clinical Milestone [press release]. Marlborough, MA. January 8, 2013.
3. Rose S. There’s More than One Way to Correct a Genetic Defect. April 11, 2012. Available at: http://www.blindness.org/blog/index.php/2012/04/page/2/. Accessed January 17, 2013.
Suggested Reading:
1. Arons I. A primer on the use of stem cells in ophthalmology. September 14, 2010. Irv Arons’ Journal. Available at
http://irvaronsjournal.blogspot.com/2010/09/primer-on-use-of-stem-cells-in.html. Accessed January 17, 2013.
2. Schwartz SD, Hubschman JP, Heilwell G, et al. A primer on the use of stem cells in ophthalmology. Embryonic
stem cell trials for macular degeneration: a preliminary report. January 23, 2012. http://download.thelancet.com/
flatcontentassets/pdfs/S0140673612600282.pdf. Accessed January 21, 2013.
Contact Us
Send us your thoughts via e-mail
to [email protected].
28 Advanced ocular care march 2013