MJ, Aramant RB, Jones MK, Ferguson D, Bryda E,
Keirstead HS. A new immunodeficient
pigmented retinal degenerate rat strain to study transplantation of
human cells without immunosuppression. Graefe’s
Arch Clin Exp Ophthalmol, 252:1079-1092, 2014. Reference
This study crossed NIH immunodeficient rats that have no T-cells with
transgenic rats with a mutant rhodopsin (S334ter-3). The resulting rat
strain can be used to test the effect of human tissue/cell on retinal
degeneration without having to use immunosuppression.
MJ, Jones BW, Aramant RB, Yang PB, Keirstead
HS, Marc RE. Computational molecular phenotyping of retinal sheet
transplants to rats with retinal degeneration. Eur
J. Neurosci, 35:1692–1704, 2012. (Figure 9A selected for cover
of EJN's Virtual Issue: Disorders of the
Nervous System). Reference
This study used a state-of-the-art
analysis method, of cell types in transplant and host, computational
molecular phenotyping. The data indicated that horizontal cells and amacrine cells are involved in a novel circuit
between transplant and host, generating alternative signal pathways
between transplant and degenerating host
PB, Seiler MJ, Aramant RB, Yan F, Mahoney MJ, Kitzes
LM, Keirstead HS. Trophic Factors GDNF and
BDNF Improve Function of Retinal Sheet Transplants. Exp Eye Res 91: 727-738, 2010. Reference
compared the effects of the trophic factors BDNF and GDNF on the
functional outcome of fetal retinal sheet transplants, and demonstrated
that visual restoration is better with laminated transplants.
Transplantation of non-retinal neural progenitor tissue (cortex) had no
MJ, Rao B, Aramant RB, Yu L, Wang Q, Kitayama
E, Pham S, Yan F, Chen Z, Keirstead HS. Three-dimensional
Optical Coherence Tomography Imaging of Retinal Sheet Implants in Live
Rats. J. Neurosci. Methods, 188: 250–257, 2010. Reference
This study showed
in vivo imaging of retinal sheet transplants in live rats by serial
scans of Fourier-Domain 3D ocular coherence tomography (OCT). The
laminar structure of transplants, placement of the transplants in
relation to the optic disk and surgical defects could be correctly
detected by OCT with an accuracy of 83-98%. Histology of transplants was
correlated with OCT results.
MJ, Aramant RB, Thomas BB, Peng Q, Sadda SR, Keirstead HS. Visual restoration and transplant
connectivity in degenerate rats implanted with retinal progenitor
sheets. Eur J. Neurosci,
This was the first indisputable
demonstration by confocal and electron microscopy of synapse formation
between transplant and host; and a correlation with the visual
MJ, Thomas BB, Chen Z, Wu R, Sadda SR, Aramant RB. Retinal
transplants restore visual responses: trans-synaptic tracing from
visually responsive sites labels transplant neurons. Eur J. Neurosci,
This experiment proved that the
connectivity of the transplant with the host was responsible for the
ND, Aramant RB, Petry HM, Green PT, Pidwell DJ, Seiler
MJ. Vision Improvement in Retinal Degeneration Patients by
Implantation of Retina Together with Retinal Pigment Epithelium. Am J Ophthalmol,
This paper presents the positive
results of the Phase II clinical study spanning from one to over six
years in ten patients: four macular degeneration and six retinitis pigmentosa patients.
MJ, Thomas BB, Chen Z, Arai S, Chadalavada S,
Mahoney M, Sadda SR, Aramant RB. BDNF-Treated
Retinal Progenitor Sheets Transplanted to Degenerate Rats - Improved
Restoration of Visual Function.
Exp Eye Res. 86(1): 92-104, 2008. Reference
transplantation, the transplant was coated with a growth factor (BDNF).
This factor was released slowly in the host and increased the visual
function of the transplanted rats with over 20%.
BB, Arai S, Ikai Y, Qiu
G, Chen Z, Aramant RB, Sadda SR, Seiler MJ.Retinal Transplants Evaluated By
Optical Coherence Tomography in Photoreceptor Degenerate Rats. J Neurosci Methods, 151: 186-193, 2006. Reference
This study used optical coherence
tomography (OCT) for screening of retinal transplants in the live rat
eye. In 62% of transplanted rats, OCT revealed the presence of a subretinal graft. OCT imaging data correlated mostly
with transplant morphology.
MJ, Sagdullaev BT, Woch
G, Thomas BB, Aramant RB. Transsynaptic
virus tracing from host brain to subretinal
transplants. Eur J Neurosci,
A tracer was injected into the
visual center in the brain, migrated through the optic nerve to the host
retina, and labeled cells in the transplant indicating that the
transplant had synaptic connections with the brain.
BB, Seiler MJ, Sadda SR, Coffey PJ, Aramant
RB. Optokinetic test to evaluate visual acuity of each eye
independently. J Neurosci Meth, 138:7-13, 2004.
This experiment is
called optokinetic test and showed that eyesight was saved in
transplanted rats with retinal degeneration.
ND, Aramant RB, Seiler MJ, Petry HM, Pidwell D. Vision change after sheet transplant
of fetal retina with retinal pigment epithelium to a patient with
Retinitis Pigmentosa. Arch Ophthalmol,
122: 1159-1165, 2004.
paper describes visual improvement in one retinitis pigmentosa
BB, Seiler MJ, Sadda SR, Aramant RB. Superior
colliculus responses to light preserved by transplantation in a slow
degeneration rat model.
Exp Eye Res, 79(1): 29-39, 2004. Reference
These two papers used newly created
experimental rats that have been genetically manipulated. A human “sick”
gene has been introduced in the photoreceptors so that the rats develop
blindness like in human retinitis pigmentosa
demonstrated that eyesight has been saved and restored in both rat
It was also proven that no rescue of host photoreceptors took place so
the improvement was caused by the transplants. The two rat strains
differ in that one strain develops blindness much faster than the other.
BT, Aramant RB, Seiler MJ, Woch G, McCall MA. Retinal
transplantation-induced recovery of retinotectal
visual function in a rodent model of retinitis pigmentosa.
Invest Ophthalmol Vis Sci,
RB, Seiler MJ. Transplanted sheets of human retina and retinal
pigment epithelium develop normally in nude rats. Exp Eye Res,
This was a very important preclinical
Could human retinal pigment epithelium be
transplanted together with neuronal retina (containing photoreceptors),
and survive long term? – The answer was yes.
This could be
achieved in albino nude rats with no functional immune system that would
not reject the foreign human transplant. The RPE could stay as a
monolayer after 10 months and show a normal interaction with the
transplanted photoreceptors. This set the important stage to introduce
this approach (to transplant both sheets together) to human clinical
ND, Seiler MJ, Aramant RB, Petry HM, Pidwell DJ. Transplantation of intact sheets of
fetal neural retina with its RPE in retinitis pigmentosa
patients. Am J Ophthalmol, 133(4):544-550, 2002.
This paper was
I clinical trial
which demonstrated the safety of transplanting sheets of fetal retina
together with its RPE to patients with Retinitis Pigmentosa.
G, Aramant RB, Seiler MJ, Sagdullaev BT,
McCall MA. Retinal transplants restore visual responses in rats with
photoreceptor degeneration. Invest
Ophthalmol Vis Sci,
42 (7): 1669-76, 2001.
This is the first paper that showed
restoration of vision in a blind rat by transplanting both
retinal pigment epithelium and photoreceptors. Transplanted rat eyes
were illuminated and the electrical responses were recorded in the
visual center of the brain. Only responses from the transplanted eye
could be recorded.
To start testing the
function of the transplants’ effect on the host, it was a challenge to
develop the testing model of choice and the setup of instruments to measure
light responses in the superior colliculus (SC) in the brain. The
outcome was the demonstration that the light sensitivity could be
restored in the RCS rat co-transplanted with RPE and neuronal
retina. We demonstrated that there was no rescue of host
MJ, Liu OL, Cooper NGF, Callahan TL, Petry HM,
Aramant RB. Selective photoreceptor damage in albino rats using
continuous blue light – a protocol useful for retinal degeneration and
transplantation research. Graefe’s Arch Clin
We managed to create a needed new
experimental animal model with a damaged retina to test the transplants.
In albino rats, 2-3
days of continuous moderate blue light selectively destroyed most of the
photoreceptors and spared the RPE. There was a time window of 3-4 weeks
after light damage to perform the transplantation before the RPE
degenerated. An interesting aspect of our results was that the
transplant saved the RPE from degeneration and the RPE apparently had a
normal interaction with transplant photoreceptors and host choroid even
after 9‑10 months (as shown in the 1998 paper).
MJ, Aramant RB, Ball SL. Photoreceptor function of retinal
transplants implicated by light-dark shift of S-antigen and rod transducin. Vision
Res., 39:2589-2596, 1999.
This paper showed that the transplanted
photoreceptors can transform light into electrical signals,
the ultimate function of normal photoreceptors.
There are some models
of retinal degeneration in which the histology of photoreceptors can
look perfectly normal, but the shift of phototransduction
proteins cannot be seen. This is a sign that the photoreceptors are not
functional. The shift of phototransduction
proteins is a very sensitive test that clearly shows that our transplant photoreceptors can
function like normal photoreceptors.
RB, Seiler MJ, Ball SL. Successful cotransplantation
of intact sheets of fetal retina with retinal pigment epithelium. Invest Ophthalmol
Vis Sci, 40:1557-1564, 1999. Reference
We know that most patients with
retinal diseases need both new retinal pigment epithelium (RPE) and
we developed the surgery procedure to transplant a fresh sheet of
RPE together with photoreceptors. The RCS rat was the most
suitable model. It was one of the most difficult technical and
encouraging achievements so far in our research.
MJ, Aramant RB. Intact sheets of fetal retina transplanted to restore
damaged rat retinas. Invest.
Ophthalmol. Vis. Sci.,
This paper shows enormously
encouraging results – that the transplants can repair an area of a
damaged retina and develop cell types in layers that appear to be
functional like normal retinal cells.
Observe the good
integration that can be seen between transplant and host. Sometimes, it
can be impossible to define the interface even in electron microscope.
RB, Seiler MJ. Organized embryonic retinal transplants to normal
or light-damaged rats. Soc.
This was the first demonstration
that a retinal sheet transplant could develop to resemble a normal
R, Seiler M. Fiber and synaptic connections between embryonic
retinal transplants and host retina. Experimental Neurology,
The contact points between nerve
cells are called synapses. Synapses are a prerequisite for nerve
cells to talk with each other, e.g. between transplant cells and host
established that transplant processes can make all types of synapses with
the host retina.
Transplant was in a host injury site inside of retina. This study
gave hope that transplants placed in the subretinal
space (in the true target area) might also have the potential to
establish synaptic connections with the host retina.
MJ, Aramant RB. Cell replacement and visual restoration by retinal
sheet transplants. Progress
in Retinal and Eye Res,
This important paper is our most
recent extensive overview of 25 years of research, covering most of the
field of retinal transplantation.
MJ, Aramant RB, Keirstead HS. Retinal
Transplants: Hope to Preserve and Restore Vision Optics and Photonics News,
19(4): 37-42, 2008.
RB, Radtke N.D., Seiler MJ. Recent results
in retinal transplantation give hope for restoring vision. In
Retinal Degenerations: Genetics, Progression, and Therapeutics, eds. J. Tombran-Tink and C. Barnstable, Humana Press, Totowa,
MJ, Aramant RB. Transplantation of neuroblastic
progenitor cells as a sheet preserves and restores retinal function.
Ophthalmology, 20:31-42, 2005 Reference
RB, Seiler MJ. Progress in retinal sheet transplantation. Progress in Retinal and Eye
Research 23(5): 475-494, 2004. Reference
RB, Seiler MJ. Retinal transplantation – advantages of intact fetal
Progress in Retinal and Eye Research 21:57-73, 2002. Reference