Stem cell based treatment strategy for Age-related Macular Degeneration (AMD)

Retinal degeneration represents a group of blinding diseases that are increasingly impacting the health and well being of
Californians. It is estimated that by 2020, over 450,000 Californians will suffer from vision loss or blindness due to the age-related
macular degeneration (AMD), the most common cause of retinal degeneration diseases in the elderly. AMD is a progressive
ocular disease of the part of the retina, called the macula, which enables people to read, visualize faces, and drive. The disease
initially causes distortion in central vision, and eventually leads to legal blindness.
A layer of cells at the back of the eye called the retinal pigment epithelium (RPE), provide support, protection, and nutrition to
the light sensitive cells of the retina; the photoreceptors which consist of rods and cones . The dysfunction and/or loss of these
RPE cells play a critical role in the loss of the PR?s and hence the blindness in AMD. Effective treatment could be achieved by
proper replacement of damaged RPE and retinal cells with healthy ones. More specifically, the regenerated and restored RPE
layer would prevent the irreversible loss of the PR?s. However, the lack of a feasible approach to restore the RPE cells has
prevented the realization of a potential therapy.
Recent advances in knowledge and technology of human embryonic stem (hES) cells brings new hope for the development of
cell replacement treatment. hES cells are capable of unlimited self-replication and production of different cell types. RPE cells
derived from hES cells are a potentially unlimited and robust source for regenerating RPE.
We hypothesize that the dysfunction and/or loss of RPE can be overcome by regenerating and restoring the RPE through the
transplantation of functionally polarized RPE monolayers derived from hES cells. Such RPE cells derived from hES can then be
transplanted into the eye, using minimally invasive surgical procedures saving the PR from dying.
Our group is composed of unique multidisciplinary members who collectively have more than two decades of experience in
efforts to restore sight to the blind as well as retinal cell transplantation and stem cell research. Our plan for this grant is to use
our expertise and infrastructure to show to the FDA the success of our preclinical tests using hES derived RPE cells in order to get
approval to conduct a clinical trial in patients at risk of vision loss due to AMD.
Limit Public

The project objective is to develop a cellular therapy for AMD using retinal pigment epithelium (RPE) derived from human
embryonic stem cells (hESC). AMD is a leading cause of irreversible vision loss, and the late, dry form is associated with RPE loss.
The RPE monolayer is integral for maintenance of healthy photoreceptors (PR), and together with the PR provides the
transducing interface for visual perception. We hypothesize that lost RPE can be restored through transplantation of functionally
polarized RPE cell monolayers derived from hESC.
We have derived RPE from hESC?s and shown disease modifying activity in animal models. Building on these results, we will use
in-vivo imaging and post-mortem histology in our GLP animal trial to show safety (i.e., no infection/retinal detachment rates;
treatable intraocular inflammation). Long-term animal studies will be conducted to exclude tumor formation. Also efficacy (i.e.,
PR and RP function) will be measured by behavioral and/or functional-electrophysiological testing in the rat and pig models.
Agreements are in place to utilize FDA approved hESC (Geron Inc) and cGMP hESC (Shef 1; from our partner P.I.). We will implant
hESC-derived RPE differentiated into a polarized monolayer under cGMP conditions (City of Hope) on FDA-approved cGMP
synthetic substrates. The hESC-derived RPE monolayers will be implanted through the use of well-established minimally
invasive, 45 minute surgical procedure. After implantation of hESC-derived RPE, we will repeat above tests on a monthly interval
allowing us to assess safety and efficacy. GLP animal experiments and histology will be done at Comparative Biosciences, Inc. If
immunosuppression is required, we will implant an FDA approved intraocular steroid delivery platform. With the success of
these GLP preclinical studies along with a comprehensive plan for Phase 1 clinical trial in at risk AMD patients, we will be able to
submit an IND submission that has a very high likelihood of being successfully reviewed by the FDA.