Download CORNEAL ENDOTHELIAL STEM CELL

CORNEAL ENDOTHELIAL
STEM CELL
HEALTH TECHNOLOGY ASSESSMENT SECTION
MEDICAL DEVELOPMENT DIVISION
MINISTRY OF HEALTH
MALAYSIA
i
023/09
DISCLAIMER
Technology review is a brief report, prepared on an urgent basis, which draws on
restricted reviews from analysis of pertinent literature, on expert opinion and / or
regulatory status where appropriate. It is not subjected to an external review process.
While effort has been made to do so, this document may not fully reflect all scientific
research available. Additionally, other relevant scientific findings may have been
reported since completion of this review.
Please contact: [email protected], if you would like further information.
Health Technology Assessment Section (MaHTAS)
Medical Development Division
Ministry of Health Malaysia
Level 4, Block E1, Precinct 1
Government Office Complex
62590 Putrajaya.
Tel: 603 88831246
Fax: 603 8883 1230
Available at the following website: http://www.moh.gov.my
ii
Prepared by: Puan Noormah Darus
Principal Assistant Director
Health Technology Assessment Section (MaHTAS)
Medical Development Division
Ministry of Health Malaysia
Dr Izzuna Mudla bt Mohamed Ghazali
Principal Assistant Director
Health Technology Assessment Section (MaHTAS)
Medical Development Division
Ministry of Health Malaysia
Reviewed by: Datin Dr. Rugayah Bakri
Deputy Director
Health Technology Assessment Section (MaHTAS)
Medical Development Division
Ministry of Health Malaysia
DISCLOSURE
The author/ authors of this report have no competing interest in this subject and the
preparation of this report is totally funded by the Ministry of Health, Malaysia.
iii
EXECUTIVE SUMMARY
1.
Introduction
The main causes of corneal failure worldwide are trachoma, vitamin A deficiency, herpes
simplex and other types of infectious keratitis. The most frequent causes of corneal
transplantation in Malaysia from the National Transplant Registry are keratoconus (17%),
corneal scar (15%), pseudophakic bullous keratopathy (13%) and other non-pseudophakic
bullous keratopathy (11%). These diseases destroy the optical function of the cornea by
scarring and opacification, with or without stromal melting and thinning that cause surface
topographic irregularity. When corneal grafting is carried out in these conditions it is
necessary to replace either the diseased superficial stromal layers or the fully thickness of the
cornea to restore normal corneal clarity and optical function.
Bullous Keratopathy (BK) in early stages is manageable medically; however advanced
disease warrants either total corneal transplantation or partial thickness transplantation of the
deeper layers of the cornea for which a donor-cadaver cornea is necessary. Bullous
keratopathy is caused by oedema of the cornea, resulting from failure of the corneal to
maintain the normally dehydrated state of the cornea. Most frequently it is due to Fuch‟s
corneal endothelial dystrophy or corneal endothelial trauma.
For such cases a penetrating keratoplasty (full thickness corneal transplantation) with of a
viable donor endothelial cell layer has historically been the only effective treatment. In the
majority of corneal grafts, topical steroids alone are sufficient to control postoperative
inflammation and act as prophylaxis against, or if necessary as treatment for, immune
rejection. Nevertheless, in high dose or with prolonged use, their chief local side-effects are
cataract formation, and steroid-induced glaucoma. Both, of course, lead to progressive visual
degradation and introduce additional complications when assessing the quality of the
outcome of the transplantation procedure.
The human corneal endothelium is essentially nonregenerative in vivo. Because endothelial
cell loss due to dystrophy, trauma, or surgical intervention is followed by a compensatory
enlargement of the remaining endothelial cells, the eventual outcome is often irreversible
corneal endothelial dysfunction. Penetrating keratoplasty for corneal endothelial dysfunction
is not risk free, and alternative methods for replacing the endothelium without corneal
trephination and sutures have been developed, which include posterior lamellar keratoplasty,
deep lamellar endothelial keratoplasty, and Descemet‟s stripping endothelial keratoplasty.
Irrespective of the selected keratoplasty procedure, fresh donor corneas are necessary to treat
corneal endothelial dysfunction, and because their availability is limited, the replacement of
endothelial cells with cultivated corneal endothelial cells (CECs) constitutes an important
alternative treatment method for corneal endothelial dysfunction.
This review was requested by Senior Private Secretary, Minister of Health Office, following
a request to start an initiative of a Niche-in Centre for Regenerative Medicine (NCRM) to
start a human corneal endothelial stem cells bank equipped with corneal diagnosis and
treatment clinic. The company proposes 2 options: (1) to set up a fully fledged facility for
diagnosis and treatment of corneal diseases worth a cGMP laboratory and clinical trials done
in Malaysia. Total cost of project is approximately USD 17 Million including technology
transfer fee of USD 10 Million. After 5 years the institute will be handed over to the
government, (2) to collaborate with local institution of research or hospitals whereby the
company will transfer the technology to the local institute who will provide the infrastructure
and other facilities. The technology transfer fee will be the same as above which is USD 10
1
Million. The company stated that treatment for all Malaysians could be subsidized whereas
foreigners will have to pay the full fee.
Objective
To assess the effectiveness, safety and cost-effectiveness of the advanced cell based
treatment technologies using corneal endothelial stem cell technology.
Results and conclusion
Based on the above review, there was no retrievable evidence to support the effectiveness,
safety and cost-effectiveness of the advanced cell based treatment technologies using corneal
endothelial stem cell technology. Evidence did indicate that this technology is under
experimental stage.
Organizational concerns that need to be addressed are policies with regards to national
standards for stem cell transplantation and guidelines for stem cell research and therapy
developed by Ministry of Health Malaysia which must be adhered to by practitioners and
scientists to ensure patients safety. Another important issue is the qualification and skills of
staff personnel that are competent, trained, qualified and experienced to maintain the corneal
endothelial stem cell laboratory and conduct the research.
Recommendation
Clinical trials are warranted to support the effectiveness, safety and cost-effectiveness of this
technology before it can be recommended for use in hospitals.
Establishment of a CES bank in Malaysia is not recommended for commercial purpose as
this technology is under experimental stage. Economic evaluation and financial risk
assessment are advocated before embarking on this initiative even if it is for research
purpose.
Methods
Literatures were searched through electronic databases specifically PubMed/Medline,
Cochrane, INAHTA and also in general databases. The search strategy used the terms, which
are either singly or in various combinations: " corneal endothelial stem cell technology",
“limbo-keratoplasty”, "donor epithelial cell", “CESBANK”, “corneal epithelial disease‟,
unilateral corneal epithelial disease”, “bilateral corneal epithelial disease”, safety,
effectiveness and cost effectiveness either singly or in combination with the limits to humans
and English. In addition websites for existing HTA agency, society websites and crossreferencing of the articles retrieved were also carried out accordingly to the topic.
A critical appraisal of the retrieved papers was performed and the evidence level was graded
according to the US/Canadian Preventive Services Task Force.
2
CORNEAL ENDOTHELIAL STEM CELL
1.
INTRODUCTION
1.1 Indications for Grafting
The main causes of corneal failure worldwide are trachoma, vitamin A deficiency, herpes
simplex and other types of infectious keratitis. The most frequent causes of corneal
transplantation in Malaysia from the National Transplant Registry are keratoconus (17%),
corneal scar (15%), pseudophakic bullous keratopathy (13%) and other non-pseudophakic
bullous keratopathy (11%). 1
These diseases destroy the optical function of the cornea by scarring and opacification, with
or without stromal melting and thinning that cause surface topographic irregularity. When
corneal grafting is carried out in these conditions it is necessary to replace either the diseased
superficial stromal layers or the fully thickness of the cornea to restore normal corneal clarity
and optical function.
Bullous Keratopathy (BK) in early stages is manageable medically; however advanced
disease warrants either total corneal transplantation or partial thickness transplantation for
which a donor-cadaver cornea is necessary. Bullous keratopathy is caused by oedema of the
cornea, resulting from failure of the corneal to maintain the normally dehydrated state of the
cornea. Most frequently it is due to Fuch‟s corneal endothelial dystrophy or corneal
endothelial trauma. Fuch‟s corneal endothelial dystrophy causes bilateral, progressive
endothelial cell loss, sometimes leading to symptomatic bullous keratopathy by age 50 to 60.
Corneal endothelial trauma can occur during intraocular surgery (e.g. cataract removal) or
after placement of a poorly designed or malpositioned intraocular lens implant leading to
bulous keratopathy. Bulous keratopathy after cataract removal is called pseudophakic (i.e. if
an intraocular lens implant is present) or aphakic bullous keratoplathy (i.e. if no intraocular
lens implant is present).
1.2
Refractive Errors after Keratoplasty
The restoration of corneal transparency, although a wonderful achievement, is not
synonymous with restoration of vision, as many clinicians have become painfully aware.
Keratoplasty may often leave considerable refractive error in the eye. The refractive property
of the cornea, and the possibility of manipulation of the kerato-refractive status of the eye,
has been the subject of research. In penetrating keratoplasty, achieving a satisfactory optical
outcome remains a challenge. Clinicians continue to be frustrated in achieving the desired
optical outcome by primary intention. Part of the problem is the slowness and weakness of
the corneal wound healing process. Although per- and postoperative adjustment of suture
tension can improve short-term optical performance, the situation can only really be judged
finally when all sutures have been removed, and often there will be considerable residual
astigmatism.
For such cases a penetrating keratoplasty (full thickness corneal transplantation) with a viable
donor endothelial cell layer has historically been the only effective treatment. In the absence
of a clear differentiation of the types of corneal pathology being treated, penetrating
keratoplasty became the standard treatment for all types of corneal disease. In the majority of
corneal grafts, topical steroids alone are sufficient to control postoperative inflammation and
act as prophylaxis against, or if necessary as treatment for, immune rejection. Nevertheless,
in high dose or with prolonged use, their chief local side-effects are cataract formation, and
3
steroid-induced glaucoma. Both, of course, lead to progressive visual degradation and
introduce additional complications when assessing the quality of the outcome of the
transplantation procedure. 2, 3
The human corneal endothelium is essentially nonregenerative in vivo. Because endothelial
cell loss due to dystrophy, trauma, or surgical intervention is followed by a compensatory
enlargement of the remaining endothelial cells, the eventual outcome is often irreversible
corneal endothelial dysfunction. Penetrating keratoplasty for corneal endothelial dysfunction
is not risk free, and alternative methods for replacing the endothelium without corneal
trephination and sutures have been developed, which include posterior lamellar keratoplasty,
deep lamellar endothelial keratoplasty, and Descemet‟s stripping endothelial keratoplasty.
Irrespective of the selected keratoplasty procedure, fresh donor corneas are necessary to treat
corneal endothelial dysfunction, and because their availability is limited, the replacement of
endothelial cells with cultivated corneal endothelial cells (CECs) constitutes an important
alternative treatment method for corneal endothelial dysfunction.
1.3
Eye Banking
Alongside the changes in surgical technique came introduction of eye banking and
developments in tissue handling and storage. Historically, donor globes were harvested up to
24 hours post-mortem and the whole eye was then kept in a moist chamber at 4°C for a
further 24 to 48 hours, before the corneal button for transplantation was excised for
immediate transplantation. In 1974, McCarey and Kaufman in the U.S. demonstrated that
by excising the cornea from the globe and placing it in a tissue culture medium at 4°C, that
the endothelium could remain viable for several days 4. Their „MK medium‟ which contained
TC199, Earle's salts, HEPES buffer and gentamicin remained the standard corneal
preservation medium for some 15 years. This was subsequently superseded by other
commercial preparations, such as KSol and Optisol, containing osmotic agents to limit
corneal tissue swelling, and offering extended preservation times of a week or ten days 5. In
the quest for longer term storage, much work has explored the possibility of cryopreservation
of the cornea. The first successful graft using cryopreserved tissue was reported by Eastcott
et al. in 1954. A different approach to extending corneal tissue preservation times is that of
organ culture at 34°– 37°C. By placing corneas in organ culture, tissue can be preserved for
four to six weeks, and the risk of transmission of infective endophthalmitis is probably
reduced in comparison to 4°C storage. However the organ culture system is labour intensive,
and whilst it has become the favoured storage method for European eye banks, 4°C storage is
still used by most banks in the U.S.
1.4
Eye Bank Associations
The massive increase in cataract surgery in the latter half of the 20th century brought with it
a tide of complications. Surgical damage to the corneal endothelium can lead to corneal
failure manifest as aphakic and pseudophakic bullous keratopathy, and these became the
prime indications for keratoplasty in some the institutions. The development of eye banks
and eye bank organizations such as the American and European Eye Bank Associations has
done much to improve standards and quality of tissue provided for keratoplasty, and to
encourage positive public attitudes towards tissue and organ donation.
This review was requested by Senior Private Secretary, Minister of Health Office, following
a request to start an initiative of a Niche-in Centre for Regenerative Medicine (NCRM) to
start a human corneal endothelial stem cells bank equipped with corneal diagnosis and
treatment clinic. The company proposes 2 options: (1) to set up a fully fledged facility for
4
diagnosis and treatment of corneal diseases with a cGMP laboratory and clinical trials done
in Malaysia. Total cost of project is approximately USD 17 Million including technology
transfer fee of USD 10 Million. After 5 years the institute will be handed over to the
government, (2) to collaborate with local institution of research or hospitals whereby the
company will transfer the technology to the local institute who will provide the infrastructure
and other facilities. The technology transfer fee will be the same as above which is USD 10
Million. The company stated that treatment for all Malaysians could be subsidized whereas
foreigners will have to pay the full fee.
2.
OBJECTIVE
To assess the effectiveness, safety and cost-effectiveness of the advanced cell based
treatment technologies using corneal endothelial stem cell technology.
3.
TECHNICAL FEATURES
Schematic diagram of the
Human Eye showing the cornea.
3.1
Figure 2A:
Diagram of layers of the cornea
Figure 2B:
Diagram of layers of the cornea
Culturing Corneal Endothelial Cells
The human corneal endothelium is essentially nonregenerative in vivo. Because endothelial
cell loss due to dystrophy, trauma, or surgical intervention is followed by a compensatory
enlargement of the remaining endothelial cells, the outcome is often irreversible corneal
endothelial dysfunction. Penetrating keratoplasty for corneal endothelial dysfunction is not
risk free, and alternative methods for replacing the endothelium without corneal trephination
and sutures have been developed, which include posterior lamellar keratoplasty, deep
lamellar endothelial keratoplasty, and Descemet‟s stripping endothelial keratoplasty.
Irrespective of the selected keratoplasty procedure, fresh donor corneas are necessary to treat
corneal endothelial dysfunction, and because their availability is limited, the replacement of
endothelial cells with cultivated corneal endothelial cells (CECs) constitutes an important
alternative treatment method for corneal endothelial dysfunction.
Previously, Gospodarowics et al. 6 transplanted cultivated bovine CECs into feline eyes.
Insler and Lopez 7 replaced CECs in eye bank donor corneas with cultivated human neonatal
CECs and transplanted the corneas into rhesus monkeys. However, as these studies involved
xenogeneic transplantation, the ultimate applicability of their results to the treatment of
human corneal endothelial dysfunction is limited and the need for an allogeneic
transplantation model remains.
5
Techniques for growing human CECs in culture have been reported, and attempts have been
made to develop transplantation models of cultivated human CEC sheets using carriers such
as collagen sheets, amniotic membrane, or no carrier matrix. In these studies, the transplant
recipient was the rabbit, an animal in which the corneal endothelium retains highproliferation ability throughout most of its life, and in which residual peripheral CECs
proliferate rapidly after injury and regenerate a clear cornea. The eventual establishment of
cultivated CEC transplants into the clinical realm requires in vivo confirmation of their longterm efficacy. 7,8,9
The present invention relates to a laminate of cultured human corneal endothelial cells
(HCECs) layer comprised of a transparent type I collagen sheet and a cultured layer of
HCECs provided on this sheet. The transparent type I collagen sheet constituting the laminate
of the present invention is a material that can maintain its transparency under physiological
conditions (neutral pH). Here, the term "transparency" means transparency of a degree that
does not cause problems with vision when the laminate of the present invention is implanted.
The thickness of the transparent type I collagen sheet is not specifically limited; when
implantation is considered, a thickness ranging from 5 to 500 micrometers suffices. When
implanting only the vicinity of the corneal endothelium, a thickness ranging from 5 to 50
micrometers is suitable.
Any transparent type I collagen sheet made from a starting material of soluble collagen
satisfying the following conditions may be employed: (1) alkali-soluble collagens (collagens
with an isoelectric point of about pH 4, such as chemically modified collagens); (2) collagens
with an isoelectric point of about pH 9, such as acid-soluble collagens and enzyme-soluble
collagens, to which a substance inhibiting the formation of fiber (for example, glucose,
sucrose, and arginine) has been admixed. The transparent type I collagen sheet can be formed
by causing a collagen solution to flow onto a casting mold such as an acrylic sheet and
drying. The casting mold may be flat or concave.
The transparent type I collagen sheet may be in the form of a solution or a molded collagen
sheet that has been crosslinked. Crosslinking may be conducted by a physical crosslinking
method such as irradiation with UV or gamma rays, or a chemical crosslinking method
employing a condensing agent such as a water-soluble carbodiimide. A collagen sheet of
desired thickness may be obtained by varying the crosslinking method, concentration of
condensing agent, processing time, reaction temperature, and the like.
The laminate of the present invention may have a layer of adhesive factor or bioadhesive on
the opposite side from the cultured layer of HCECs on the transparent type I collagen sheet.
Having a layer of adhesive factor or bioadhesive on the opposite side from the cultured layer
of HCECs on the transparent type I collagen sheet promotes adhesion of the laminate of the
present invention to the corneal stroma during implant. The adhesive factor and bioadhesive
need only be compounds that do not affect the organism once the laminate of the present
invention has been implanted into the eye. Examples of bioadhesives are fibrin pastes;
examples of adhesive factors are human plasma fibronectin and laminin. 10
3.2
Other Techniques
3.2.1 Epithelial Transplantation
The fine optical fuction of the cornea is dependent not only on the stromal contour but on the
health of the corneal epithelium and its overlying tear film. When there is corneal epithelial
failure, the surface of the cornea becomes conjuctivised, vascularised, and irregular. In 1977,
Thoft described conjunctival transplantation for ocular surface disease, and in the 1980s
6
devised an operation that he named „keratoepithelioplasty‟. In this procedure, thin lenticules
of superficial donor stroma with their overlying corneal epithelium were transplanted to
restore normal epithelial cover on the recipient cornea.
Limbal stem cells located in the basal limbal area are involved in renewal of the corneal
epithelium. Limbal epithelial stem cells (LESC) deficiency can occur as a result of primary
or acquired insults. 11, 12 Deficiency can arise following injuries including chemical or
thermal burns and through diseases such as aniridia and Stevens Johnson syndrome. As a
result of LESC deficiency conjunctivalisation, neovascularisation, chronic inflammation,
recurrent erosions, ulceration and stromal scarring can occur causing painful vision loss. 4, 5
Long term restoration of visual function requires renewal of the corneal epithelium; through
replacement of the stem cell population. Limbal stem cells can be transplanted by using
autografts in cases of unilateral disease or allografts from relatives or cadaver eyes for
bilateral disease. 13, 14 Each procedure carries a risk of complication such as damage to
healthy eye by removal of autologous tissue for transplantation or side effects from long-term
immunosuppressant with allogenic tissue.
Allografts of corneal epithelial stem cells require major systemic immunosuppression thus
has a more problematical risk/benefit ratio for the treatment of a non-life threatening
condition. Recently, cultured limbal stem cells have been used; a small biopsy specimen
from a healthy limbus can be expanded ex vivo and then grafted to an eye with stem cell
deficiency. 13 Future studies will focus on the potential use of adult pluripotent stem cells for
ocular surface reconstruction and also strategies for promoting a state of tolerance in allograft
limbal transplantation. 12, 15
There are two established techniques for the advanced treatments for corneal epithelial
diseases. For unilateral (one side) corneal epithelial disease, one successfully used
therapeutic strategy for ocular surface reconstruction is the transplantation of autologous
epithelial cell sheets engineered from limbal epithelial cells expanded in vitro using
appropriate delivery systems, such as amniotic membrane. 15, 16 This approach, however,
usually requires a limbal biopsy from the contralateral healthy unaffected eye and is therefore
not applicable in patients with bilateral total limbal stem cell deficiency. In these cases,
allogeneic limbal epithelium, harvested either from living related donors or from cadaveric
donor eyes, may be used for transplantation in combination with prolonged systemic
immunosuppressive therapy. This approach has a very low success rate (of approximately
30% or less) long term, as compared with autologous cell. The human amniotic membrane
being a biological protein may also induce inflammatory reaction and immunosuppressants
are not always well tolerated by patients.
For bilateral (both side eyes) epithelial disease, oral mucosal epithelium has attracted much
attention as an autologous epithelial stem cell source. The patients‟s own buccal mucosa
could be taken and grown using 3T3 cells (animal feeder layers). Tissue-engineered
epithelial-cell sheets were fabricated ex vivo by culturing harvested cells for two weeks on
temperature-responsive cell-culture surfaces with 3T3 feeder cells that had been treated with
mitomycin C. After conjunctival fibrovascular tissue had been surgically removed from the
ocular surface, sheets of cultured autologous cells that had been harvested with a simple
reduced-temperature treatment were transplanted directly to the denuded corneal surfaces
(one eye of each patient) without sutures. The transplantation of cultivated oral mucosal
epithelial cell sheets has provided favorable early results in patients with bilateral stem cell
deciency 17, 18. Long-term outcomes were, however, less satisfactory, mostly due to a
relatively high rate of peripheral corneal neovascularization. 9
7
Recently it has been demonstrated that other stem cell populations including human
embryonic stem cells 19 and hair follicle stem cells 20 can be driven towards a corneal
epithelial-like phenotype. These exciting data may lead to alternative therapeutic strategies in
the future for patients blinded by ocular surface disease cause by failure of LESC function.
4.
METHODOLOGY
4.1 Search Methods
Literatures were searched through electronic databases specifically PubMed/Medline,
Cochrane, INAHTA and also in general databases. The search strategy used the terms, which
are either singly or in various combinations: " corneal endothelial stem cell technology",
“limbo-keratoplasty”, "donor epithelial cell", “CESBANK”, “corneal epithelial disease‟,
unilateral corneal epithelial disease”, “bilateral corneal epithelial disease”, safety,
effectiveness and cost effectiveness either singly or in combination with the limits to humans
and English. In addition websites for existing HTA agency, society websites and crossreferencing of the articles retrieved were also carried out accordingly to the topic.
4.2
Selection of studies
Any primary and secondary papers pertaining to “corneal endothelial stem cell technology ",
will be included in this technology review. Those which full text could not be obtained were
excluded. A critical appraisal of the retrieved relevant papers was performed and the
evidence level was graded according to the US/Canadian Preventive Services Task Force
(Appendix 1).
5
RESULTS AND DISCUSSION – CORNEAL ENDOTHELIAL STEM CELL
TECHNOLOGY
5.1
Effectiveness
There was no retrievable evidence addressing effectiveness of the advanced cell based
treatment technologies using corneal endothelial stem cell technology. Most of the studies
retrieved were laboratory experiments and experiments using animals as representative
models.
5.2
Safety
There was no retrievable evidence addressing safety of the advanced cell based treatment
technologies using corneal endothelial stem cell technology.
While no specific guidelines are available with reference to this technology, generic codes
for manufacturing and clinical practice do exist on a national level along with associated
national and international guidance documents. International guidance for scientists,
surgeons, regulators, ethics committee is essential to ensure that potential health risks are
managed globally in a consistent and uniform manner. 8
5.3
Cost-effectiveness
There was no retrievable evidence addressing cost-effectiveness of the advanced cell based
treatment technologies using corneal endothelial stem cell technology.
8
5.4
Organizational Concerns
Ministry of Health Malaysia has developed policies with regards to national standards for
stem cell transplantation and guidelines for stem cell research and therapy. It is stipulated
that practitioners and scientists must adhere to the guidelines to ensure patients safety.
i.
Laboratory Standards
In the field of medical products manufacturers and suppliers have to comply with the
quality system requirements like Good manufacturing Practices (GMP), current Good
manufacturing Practices ( cGMP), Good laboratory Practices (GLP) and current Good
laboratory Practices (cGLP).
With respect to products processed by tissue banks, several organizations such as the
European Association of Tissue Banks (EATB) and American Association of Tissue
Banks (AATB) have general standards as a form of Good Tissue Practices (GTP)
which should be followed.
The research institute should have at least a Grade B (ISO Class 5) clean room type of
laboratories. Clean room facilities are important in avoiding microbial contamination
of the product, but equally and perhaps even more important in implementing GMP
will be the development of validated SOPs for the entire process, establishment of
quality control methodology and release criteria of the cells produced. This will be
challenging given the lack of European Medicines Agency-licensed cell therapy
products in Europe and the fact that in the USA the FDA has not yet approved any
human cell therapy product for sale. It should also be emphasized that implementing
GMP will not necessarily ensure that the produced cells are of the highest possible
quality or are the most efficient cells for a certain application. However, the benefit of
GMP lies in the fact that the cells are produced in a reproducible manner and meet
preset specifications that will ensure the safety of the patient.
ii.
Training
Laboratory staff training, continuing education and continued competency for the
performance of all operations and procedures should be ensured and documented.
iii.
Qualified Personnel to maintain the laboratory
Another important element to be addressed is the qualification and skills of staff
personnel that are competent, trained, qualified and experienced to maintain the
corneal endothelial stem cell laboratory and conduct the research.
6
CONCLUSION
Based on the above review, there was no retrievable evidence to support the effectiveness,
safety and cost-effectiveness of the advanced cell based treatment technologies using corneal
endothelial stem cell technology. Evidence did indicate that this technology is under
experimental stage.
9
7
RECOMMENDATION
Clinical trials are warranted to support the effectiveness, safety and cost-effectiveness of this
technology before it can be recommended for use in hospitals.
Establishment of a CES bank in Malaysia is not recommended for commercial purpose as
this technology is under experimental stage. Economic evaluation and financial risk
assessment are advocated before embarking on this initiative even if it is for research
purpose.
10
8.
REFERENCES
1. http://www.mst.org.my/ntrSite/publications_4thReport2007.htm
2. Rostron CK. The History of Corneal Transplantation. In: Hakim NS, Papalois VE (Eds).
History of organ and cell transplantation. Imperial College Press, London 2003.
3. Smith GTH, Taylor HR. Epidemiology of corneal blindness in developing countries.
Refract Corneal. 1991;7:436-439.
4. McCarey BE, Kaufman HE. Improved corneal storage. Invest Ophthalmol. 1974;3:165173.
5. Kaufman HE, Beuerman RW, Steinemann TL et al. Optisol corneal storage medium,
Arch Ophthalmol. 1991:109; 864-868.
6. Gospodarowicz D, Greenburg G, Alvarado J. Transplantation of cultured bovine corneal
endothelial cells to species with nonregenerative endothelium: the cat as an experimental
model. Arch Ophthalmol. 1979;97:2163–2169.
7. Insler MS, Lopez JG. Heterologous transplantation versus enhancement of human corneal
endothelium. Cornea. 1991;10:136 –148.
8. Schwab IR, Johnson NT, Harkin DG. Inherent Risks Associated With Manufacture of
Bioengineered Ocular Surface Tissue. Arch Ophthalmol. 2006;124:1734-1740.
9. Sitalakshmi G, Sudha B, Madhavan HN et al. Ex Vivo Cultivation of Corneal Limbal
Epithelial Cells in a Thermoreversible Polymer (Mebiol Gel) and Their Transplantation in
Rabbits: An Animal Model. Tissue Engineering: Part A. 2009;15(2): 407-415.
10. Yamagami S, Chuo-Ku K, Amano S et al. Laminate Of Human Corneal Endothelial Cell
Culture Layer And Method Of Constructing The Same European Patent Application
Ep1726639. Freepatentsonline. Retrieved on 13 October 2009 at
http://www.freepatentsonline.com/EP1726639.html
11. Chen JJ, Tseng SC. Abnormal corneal epithelial wound healing in partial-thickness
removal of limbal epithelium. Invest Ophthalmol Vis Sci. 1991;32:2219–2233.
12. Dua HS, Azuara-Blanco A. Limbal stem cells of the corneal epithelium. Surv Ophthalmol.
2000;44:415-425.
13. Kenyon, K.R. Tseng, S.C. (1989). Limbal autograft transplantation for ocular surface
disorders. Ophthalmology 96, 709–722
11
14. Ramaesh T, Collinson, JM, Ramaesh, K et al. Corneal abnormalities in Pax6 +/- small eye
mice mimic human aniridia-related keratopathy. Invest Ophthalmol Vis Sci.
2003;44:1871–1878.
15. Holland EJ, Djalilian AR, Schwartz GS. Management of aniridic keratopathy with
keratolimbal allograft: a limbal stem cell transplantation technique. Ophthalmology.
2003;110:125-130.
16. Shortt AJ, Secker GA, Notara MD et al. Transplantation of exvivo cultured limbal
epithelial stem cells:A review of techniques and clinical results. Surv Ophthalmol
2007;52:483–502.
17. Nakamura T, Kinoshita S. Ocular surface reconstruction using cultivated mucosal
epithelial stem cells. Cornea. 2003;22(7suppl):S75–S80.
18. Inatomi T, Nakamura T, Koizumi N et al. Mid term results on ocular surface
reconstruction using cultivated autologous oralmucosal epithelial transplantation. Am J
Ophthalmol 2006; 141:267–275.
19. Ahmad S, Stewart R, Yung S et al. Differentiation of human embryonic stem cells into
corneal epithelial like cells by in vitro replication of the corneal epithelial stem cell niche.
Stem Cells. 2007; 25:1145–1155.
12