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Ma et al. J Transl Genet Genom 2022;6:179-203 https://dx.doi.org/10.20517/jtgg.2021.48 Page 191

Stargardt disease, also named Stargardt’s macular degeneration (STGD), is one of the most prevalent
[161]
inherited juvenile macular dystrophies . The early onset of STGD results in a visual loss in the working
[162]
age population . Three genes have been found responsible for three types of STGD. ABCA4 (1p22.1),
ELOV4 (6q14.1), and PROM1 (4p15.32) are implicated in STGD1, STGD3, and STGD4, respectively.
STGD1 is an autosomal recessive inherited disease caused by an ABCA4 gene mutation. This gene encodes
the ATP-binding cassette transporters protein (ABCA4) expressed in the outer segment of photoreceptors.
ABCA4 transports retinylidene-phosphatidylethanolamine (N-retinylidene-PE) from the inside of disk to
the cytoplasmic side of the disk and avoids N-retinylidene-PE reacting with all-trans-retinal and forming di-
retinoid-pyridinium-ethanolamine (A2E), which is toxic to photoreceptors and RPE . STGD3 is an
[163]
autosomal dominant inherited disease caused by a mutation in ELOVL4. This gene encodes ELOVL fatty
acid elongase 4, which is involved in a catalyzing reaction of the long-chain fatty acids elongation cycle .
[164]
Mutated ELOVL4 causes the production of a truncated ELOVL4 protein lacking a motif for endoplasmic
reticulum retention. Dysfunction of ELOVL4 protein results in decreased synthesis of long-chain (C28-C36)
fatty acids. C28-C36 fatty acids are components of phosphatidylcholines which are distributed in
[165]
[166]
photoreceptor outer segments , bind to rhodopsin , and regulate activities of photo-transduction
proteins . The truncated ELOVL4 protein causes deficiency of C32-C36 acyl phosphatidylcholines,
[167]
[168]
alternation in photo-transduction proteins, and an increase in lipofuscin accumulation . STGD4 is an
autosomal dominant inherited disease caused by the mutation in PROM1 gene . Prominin 1, encoded by
[169]
PROM1, is located at the base of the photoreceptor outer segments and participates in disk membrane
formation. Mutated PROM1 causes overgrown and misoriented outer segment disk membranes, which
indicate defective disk morphogenesis . Similar to AMD, complete loss of photoreceptors, RPE, and
[170]
choriocapillaris is observed at the end stage of STGD.
The key functions of RPE cells are delivering nutrients and disposing waste for photoreceptors and
phagocytosis of outer segments of photoreceptors . The purpose of delivering RPE cells to the subretinal
[171]
space is to rescue the remaining photoreceptors. The subretinal space is an immune-privileged environment
suitable for cell-based therapy. Subretinal injection of cell suspension and the delivery of cell patches are
new replacement therapy processes . A clinical trial on stem cell transplantation for STGD and dry AMD
[172]
was first conducted to prove the safety and tolerability of human embryonic stem cell-derived RPE (hESC-
derived RPE) in 2012 . From then on, the innovation of cell transplantation focuses on sources of cells
[173]
and approaches of delivery. Because polarized RPE cells array in a monolayer in physical conditions,
researchers proposed that loading RPE cells on a bioengineered scaffold is an optimal method for delivery.
A synthetic biocompatible membrane for RPE loading made from different materials has been
innovated [174, 175] , and some tested in clinical studies [176,177] . In 2017, iPSC-RPE cell sheets were first
transplanted in one wet AMD patient . Although the visual acuity did not improve, the implanted graft
[178]
integrated well with the local neuroretina. Thus far, the safety of stem cell-based therapy has been proved,
while the efficacy requires further investigation. A recent review comprehensively summarizes the current
status of stem cell-based retinal regeneration .
[179]

CONCEPTUALIZED CELL THERAPY FOR MYOPIC MACULOPATHY
[180]
Cell therapy is substitutive therapy by regenerating dysfunctional tissues or cells with curative cells . It is a
novel method to treat diseases that were previously regarded as incurable. Here, we review the cells which
are theoretically available for cell therapy for pathologic myopia.

Autologous iPSC-RPE
Hypoplasia and loss of RPE are characteristics during the progression of myopic maculopathy. As with
other forms of macular degeneration, loss of RPE cells leads to apoptosis of photoreceptors in pathologic