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Tissue-Engineered Solutions for
Cell Replacement Therapy in
Age-Related Macular Degeneration
BIOE689Y Fall 2017
Dr. Martha Wang
Mostafa Lotfi, Niloofar Massahi, Shannon Schreiner (Team 4)
Physiology of the Eye
2
Physiology of the Eye
3
Physiology of the Eye
4
Adult Macular Degeneration (AMD)
• Adult Macular Degeneration (AMD)
• Leading cause of blindness in the elderly
• Affects 2 million Americans
• Progressive damage to the macula – central region of
the retina
• Retina: light receiving nerve layer in the back of the
eye
• Important for detail and central vision
5
Adult Macular Degeneration (AMD)
• Dry AMD
• Non-neovascular
• Wet AMD
• Neovascular
6
Current Treatments
• Dry AMD
• Bolus injection
• hESC-RPE implant
• Wet AMD
• Anti-VEGF
• Anti-PDGF
• Macular translocation
• RPE transplant
7
Current Treatments
• hESC-RPE Derived
• iPSC-RPE Derived
• Photoreceptor Replacement
8
Project Aims
• Global hypothesis:
The delivery of a monolayer of hESC-RPE to the ocular subretinal space via a porous,
biodegradable, ultra-thin parylene scaffold, impregnated with an anti-VEGF therapeutic,
will repair existing RPE damage while simultaneously preventing future neovascularization.
• Specifically:
1. Parylene-C film is an amenable scaffold for hESC-RPE while demonstrating biocompatibility with hESC-RPE,
choroidal, and retinal tissues
2. Scaffold degradation rates can be controlled by the physical dimensions of the implant
3. Neovascularization will be suppressed by the delivery of an anti-VEGF therapeutic to the local tissues via the
implant
• Aims proposed:
1. Investigate implant toxicity i.e. genotoxicity, carcinogenicity, blood response, and cytotoxicity. Reproductive
toxicity will not be investigated as AMD patients are past their reproductive window. Implant will also be
investigated for any adverse mechanical effects that may result from its subretinal placement.
2. Investigate implant degradation rates by varying the radial dimension, thickness, porosity, and pore size of the
implant.
3. Investigate bevacizumab and ranibizumab for in vivo suppression of neovascularization of choroidal layer
9
Research Design & Aims – In Silico
10
Research Design & Aims – In Vitro
Phase II A
11
Research Design & Aims – In Vitro
Phase II B
12
Research Design & Aims – In Vivo
Phase III
13
Research Design & Aims – Anti-VEGF
Anti-VEGF Suppression of Choroidal Neovascularization
14
Tissue-Engineered? ?Solutions? ?for
Cell? ?Replacement? ?Therapy? ?in
Age-Related? ?Macular? ?Degeneration
BIOE689Y? ?Fall? ?2017
Dr.? ?Martha? ?Wang
Mostafa? ?Lotfi,? ?Niloofar? ?Massahi,? ?Shannon? ?Schreiner? ?(Team? ?4)
Fischell? ?Department? ?of? ?Bioengineering
“We? ?pledge? ?on? ?our? ?honor? ?that? ?we? ?have? ?not? ?given? ?or? ?received? ?any
unauthorized? ?assistance? ?in? ?this? ?assignment”
Abstract
According? ?to? ?the? ?World? ?Health? ?Organization,? ?adult? ?macular? ?degeneration? ?(AMD)? ?ranks? ?third? ?among
global? ?causes? ?of? ?visual? ?impairment? ?with? ?a? ?blindness? ?prevalence? ?of? ?8.7%.? ?AMD? ?is? ?the? ?primary? ?cause? ?of
visual? ?deficiency? ?in? ?industrialized? ?countries?? ?and? ?affects? ?2? ?million? ?Americans.(Nazari? ?et? ?al.)? ?As? ?RPE
tissue? ?does? ?not? ?have? ?regenerative? ?capacity? ?and? ?the? ?root? ?cause? ?of? ?AMD? ?is? ?unknown? ?at? ?this? ?time,
research? ?is? ?focused? ?on? ?treatment? ?strategies? ?which? ?include? ?the? ?use? ?of? ?human? ?embryonic? ?stem? ?cell
derived? ?retinal? ?pigmented? ?epithelium? ?(hESC-RPE).? ? ?This? ?proposal? ?seeks? ?to? ?deliver? ?a? ?monolayer? ?of
hESC-RPE? ?to? ?the? ?ocular? ?subretinal? ?space? ?via? ?porous,? ?biodegradable,? ?ultra-thin? ?parylene? ?scaffold,
impregnated? ?with? ?an? ?anti-VEGF? ?therapeutic,? ?to? ?repair? ?existing? ?RPE? ?damage? ?while? ?simultaneously
preventing? ?future? ?neovascularization.? ? ?Implant? ?viability? ?will? ?be? ?evaluated? ?based? ?on? ?cytotoxicity,
including? ?any? ?adverse? ?mechanical? ?effects? ?that? ?may? ?result? ?from? ?its? ?subretinal? ?placement,? ?implant
degradation? ?rates,? ?and? ?suppression? ?of? ?neovascularization? ?of? ?the? ?choroidal? ?layer? ?through? ?two? ?potential
anti-VEGF? ?drugs,? ?bevacizumab? ?and? ?ranibizumab.
Clinical? ?Need
There are two types of adult macular degeneration (AMD): dry (non-neovascular) and wet
(neovascular). Both forms of AMD are characterized by discoloration of the retinal pigment epithelium
(RPE), a buildup of cellular debris known as a drusen formation, followed by a thickening of Bruch’s
membrane.(Birch and Liang) Early stage indicators and risk factors for the two types of AMD are
similar,? ?but? ?late? ?stage? ?development? ?and? ?presentation? ?are? ?distinct.
Dry AMD is characterized by
drusen formations in the back of
the eye.(Birch and Liang) Drusen
formations in patients with AMD,
although present in normal eyes
as well, have entered a vicious
cycle and accumulated to form
larger, more rigid aggregates.
(Sarks, Sarks, and Killingsworth)
In
these
regions,
drusen
eventually fade away and are
replaced by a patch of dead RPE termed geographic atrophy (GA).(Nazari et al.) The primary
challenge in the treatment of dry AMD is a lack of knowledge of its root cause and although a variety
of risk factors have been identified, currently there is no consensus regarding the specific cause of
AMD.(Nazari? ?et? ?al.)
Wet AMD is characterized by the formation of blood vessels below the retina.(Kaarniranta et al.) The
barrier function of the new vessels is compromised and results in leakage of plasma to form
edematous regions under the retina or into the eye.(Kaarniranta et al.) It is known that inappropriate
regulation of vascular endothelial growth factor (VEGF) is responsible for the growth of these new
vessels.(Nazari et al.)?1 Management of VEGF is a strategy for slowing down the progression of wet
AMD? ?but? ?does? ?not? ?stop? ?the? ?inevitable? ?result.
1
Current? ?Strategies? ?for? ?Treatment
Dry? ?AMD? ?Treatment
At this time, there are no clinical treatment options for dry AMD as the root cause is unknown
(Rickman, C.B., LaVail, M.M., Anderson, R.E., Grimm, C., Hollyfield, J., Ash) however, there are a
variety of cell therapy treatments being investigated. Current research is focused on the use of RPE
implants obtained from either human embryonic or induced pluripotent stem cells by either bolus
injection of RPE cell suspension or via prefabricated RPE stem cell sheets implanted into the
subretinal space.(Olmos et al., 2015) According to Vugler et al, in vitro experiments demonstrated
hESC-RPE could form a monolayer of regular, polarised cells which demonstrated apical and basal
regions and expressed markers of both developing and mature RPE.(Vugler et al.) Additionally,
characteristics of RPE cells cultured on collagen membranes have been shown to develop similar
differentiation? ?indicators? ?to? ? ?RPE? ?cells? ?in? ?vivo.(White? ?and? ?Olabisi)
Experimental evidence indicates hESC-RPE has a survival period of 12 months in
immunocompromised laboratory models and a polarized monolayer of hESC-RPE had a higher
survival rate than suspensions without a teratoma or ectopic development.(Diniz et al.) This suggests
the probability of a positive association of hESC-RPE in human retinal subjects as well. Due to the
possibility of implant rejection, immune response needs to be considered, and immunosuppressant
medications required for these therapies.(Olmos et al.) Experimental evidence has also indicated
favorable survival rates, and functionality of hESC derived RPE in the form of monolayer on polymer
substrates (rCPCB-RPE1 cells?/?pluripotent stem cells) in cultured cells in rats.(Thomas et al.; Tian et
al.;? ?Thumann? ?et? ?al.)
Wet? ?AMD? ?Treatment
Since it has been shown that VEGF regulation is important in the progression of wet AMD,
pharmaceutical companies have begun producing anti-VEGF treatment options. Examples of these
anti-VEGF drugs are Pegaptanib (ss nucleic acid), Ranibizumab (monoclonal antibody), and
Aflibercept (recombinant fusion protein).(Avery et al.) Stated briefly, all of these treatments work by
binding or blocking VEGF-A or a combination of VEGF isomers.(Nazari et al.) All 3 are FDA approved
for use in the treatment of wet AMD and require monthly or semi-monthly injections of the agent into
the eye.(Avery et al.) The motivation behind these treatments is, if the rate of angiogenesis can be
decreased, patients will have a better prognosis; however, this strategy requires early diagnosis. In
the same vein as the treatments above, a cursory search of ClinicalTrials.gov revealed there are
many co-treatment trials where anti-VEGF therapies have been paired with anti-platelet derived
growth? ?factor? ?(anti-PDGF)? ?which? ?is? ?important? ?in? ?the? ?formation? ?of? ?blood? ?vessels.
2
Macular translocation and RPE transplantation surgery have also been options for patients suffering
from AMD.(Steven D Schwartz et al.) Both of these surgical interventions demonstrate healthy RPE
tissue can have vision restorative capabilities which have been demonstrated to last at least 5
years.(Oshima et al.) However, these surgical options can be technically challenging and may result
in? ?vitreoretinopathy? ?or? ?torsion.? ?(Nazari? ?et? ?al.)
Current? ?Investigated? ?Tissue? ?Engineering? ?Strategies? ?for? ?Treatment
hESC-RPE? ?derived
Transplantation of human embryonic stem cell – derived retinal pigment epithelium (hESC-RPE) has
been demonstrated as an effective and promising strategy in the treatment of AMD. In a study
published in 2016, Schwartz, et al. produced results that indicated it was possible to implant
hESC-RPE in patients suffering from dry AMD resulting in restoration of function of both
photoreceptors and visual function.(Steven D. Schwartz et al.) ?These conclusions were based
primarily on the tolerance and safety of the hESC-RPE cells and secondarily on the efficacy of the
transplanted? ?cells.
In this study, 18 patients (9 dry AMD, 9 STGD [Stargardt Disease]) were injected sub-retinally with a
target dose of resuspended hESC-RPE. Each group of 9 patients was further subdivided into 3
cohorts, each receiving a differing number of hESC-RPE cells: 50,000, 100,000, or 150,000. The
patients were then given a 6 week regimen of immunosuppressants including tacrolimus and
mycophenolate mofetil; after the first 6 weeks had elapsed, the tacrolimus was discontinued and
mycophenolate mofetil was continued to be administered for an additional 6 weeks. Following the
procedure, all patients were serially observed for overall changes in health as well as changes in
visual capabilities. To deem the procedure as safe, patients were physically examined, had their vitals
taken and underwent electrocardiograms, hematological and serological testing as well as cancer
screening. Although no patient in the study suffered an intraocular or systemic event as a result of the
hESC cells, a number of patients were observed to have adverse effects as a result of the
immunosuppressants? ?administered.
To examine the visual outcomes, the patients were examined for best-corrected visual acuity (BCVA),
visual fields, slit-lamp biomicroscopy, ophthalmoscopy, OCT, fluorescein angiography,
autofluorescence, fundus photography and electroretinography. Thirteen out of 18 patients exhibited
an increase in subretinal pigmentation and at the 6 month mark, 9 out of the 18 eyes demonstrated
stable? ?or? ?better? ?visual? ?performance? ?on? ?a? ?visual? ?acuity? ?test.
While these results are promising, the use of hESCs is not without risk or controversy. Although
hESCs are not sourced from an abortion their use remains contentious. Additionally, the use of
hESCs? ?can? ?result? ?in? ?the? ?formation? ?of? ?a? ?teratoma,? ?unwanted? ?differentiation,? ?and? ?immunologic? ?rejection.
iPSC-RPE? ?derived
In 2006, Yamanaka et. al. showed that by overexpressing 4
factors (OCT3/4, Sox2, c-Myc, Klf-4) fibroblasts can be induced
into an embryonic-like pluripotent state.(Takahashi and
Yamanaka) ?These cells were called induced pluripotent stem
cells (iPSC) and are another renewable source of stem cells that
can be differentiated into a variety of tissues. Also, because
these cells can be generated from readily available fibroblasts,
this method opens up the potential for creating autologous
transplant where a patient’s own cells can be reverted to the
iPSC state, differentiated, and then implanted back into the
patient.
There have been two primary methods of utilizing
iPSC-derived RPE (iPSC-RPE) in a cure for AMD. Both
3
involve the transplantation of iPSC- RPE in the eye at locations where later stage macular
degeneration has caused the loss of the RPE layer. The first method is the transplantation of a
suspension of RPE cells at the back of the eye.(Westenskow et al.) The second method is the
transplantation of a monolayer of iPSC-RPE on a scaffold at the back of the eye. Both methods have
drawbacks? ?and? ?design? ?challenges.
In the injection of iPSC-RPE suspension, the cells are cultured, differentiated, loaded into syringe, and
injected into the eye. There are a few similar culturing methods available in the literature, the details of
which are beyond the scope of this paper however, it is necessary to note that in culturing iPSCs the
purity of the final cellular product is an omnipresent hurdle regardless of the cell type being produced.
In both methods, the integration of the cells into the eye is a concern that needs to be addressed. In
the suspension-injection method, integration is optimized by placing the cells at a very specific
location in the back of the eye. Unfortunately, this requires expert surgical skills and misplacement is
common.(Westenskow? ?et? ?al.)
In the iPSC-RPE monolayer placement method, a single layer of cultured RPE is grown on a scaffold
and placed in the back of the eye.(Bird et al.) Many of the challenges in the injection method are
applicable here as well. Purity is a concern, placement can be a hassle, and this method has the
added challenge of a scaffold. This method has many advantages over the bolus approach which
include: a rigid scaffold for easier placement of the cells in the desired location and the ability to
analyze? ?the? ?cells? ?in? ?their? ?macro-structural? ?formation? ?(as? ?a? ?monolayer? ?sheet).
Photoreceptor? ?replacement
There are several transplant strategies that meet the requirement for a successful photoreceptor
replacement therapy however, in all cases, donor cells must be able to migrate to the recipient retina
and differentiate into a functional and connected photoreceptors.(Westenskow et al.) Whole retinal
sheets from embryonic and neonatal retinae have the ability to differentiate. In a study completed by
Radtke et al, scientists saw an improvement in vision in 7 out of 10 AMD patients after receiving fetal
retinal sheet transplants.(Pearson) Transplantation of brain derived neural stem cells into the neural
retina is another possibility that researchers have investigated. However, these integrated cells do not
show intrinsic characteristics of mature retinal neurons.(Iyer et al.) ?To overcome this issue stem cells
from embryonic retinas can be used as they are able to differentiate into glial cells and cells
expressing specific photoreceptors.(Pearson) However, they are not able to integrate into the laminar
structure of retina. Successful transplantation also depends on the developmental stage of the donor
cell. This was seen in the study completed by MacLaren et al. where postnatal donor cells were
transplanted into the recipients at the exact developmental stage. The cells migrated and matured into
normal? ?photoreceptors.(Qiu? ?et? ?al.)
One of the challenges faced after transplanting photoreceptors is their ability to improve vision. A
study completed by Pearson et al suggests that there is a direct correlation between the number of
integrated cells and the amount of vision restored.(MacLaren et al.) The researchers also used gene
replacement therapy to show that 120,000 functioning photoreceptors are needed to produce scotopic
electroretinogram? ?response.(Pearson? ?et? ?al.)
The described strategies for photoreceptor replacement are derived from postnatal retina which
occurs in the second trimester in humans and therefore supply is limited. Researchers are
investigating reproducible sources of photoreceptor precursors. Embryonic stem cells derived from
the inner cell mass of a preimplantation blastocyst have also shown great promise in their ability to
generate retinal cells. In a study published by Eiraku et al, researchers were able to develop a 3D
culture in which the ESCs mimicked retina morphology.(Eiraku et al.) The reprogramming of nuclei of
somatic cells, to the pluripotent state, can bypass the problems associated with the use of human
embryos. These induced pluripotent stem cells should have similar capability as ESCs; in a study
published by Lamba et al, investigators showed that the iPSCs can generate photoreceptor like cells
but? ?can? ?have? ?some? ?resistant? ?to? ?retinal? ?differentiation.(Lamba? ?et? ?al.)
The realistic prospect of photoreceptor transplantation presents an important landmark in therapies for
patients? ?suffering? ?from? ?AMD? ?as? ?these? ?cells? ?are? ?able? ?to? ?integrate? ?into? ?recipient? ?retina? ?and? ?restore? ?vision.
4
Project? ?Aims
Age related macular degeneration, which stems from a loss or damage to the Retinal Pigmented
Epithelium (RPE), is the leading cause of visual disability in the western world.(Idelson et al.; Oshima
et al.) ?RPE tissue is characterized by a monolayer of hexagonal cells, which are filled with pigment,
and is located between the highly vascularized choroidal layer of the eye and the neuroepithelium,
which contains rod and cone photoreceptors.(Maminishkis et al.) ?These hexagonal cells have well
defined apical and basolateral regions as well as tight junctions between cells which help to form a
blood-retinal barrier.(Peyman, Spitznas, and Straatsma) ?The RPE’s main functions are: phagocytosis
of rod and cone outer segment fragments, shed from their distal ends; uptake, processing, transport,
and release of vitamin A (retinol); regulation of net ion and water movement in the apical to basal
direction; absorption of stray light, thus improving visual images; and to aid in the attachment of the
retina to the choroidal layer.(Idelson et al.) ?Derived from the neuroectoderm, RPE, once
differentiated, does not self-renew and must remain functional for the lifetime of …
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