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Publications

 

We have published a string of encouraging results in respected scientific journals, supporting our claims and validating our approach.

Each article has been evaluated by professional knowledgeable reviewers before they have been accepted for publication.

 

 

In 1998 we published our first breakthrough paper:

 

Seiler MJ, Aramant RB. Intact sheets of fetal retina transplanted to restore damaged rat retinas.  Invest. Ophthalmol. Vis. Sci., 39:2121-2131,1998.

This study showed enormously encouraging results:– 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. 

Complete remedy approach :  Sheets of Retina and RPE together

Aramant 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.
We know that most patients with retinal diseases need both new retinal pigment epithelium (RPE) and photoreceptors. Therefore, we developed the surgery procedure to transplant a fresh sheet of RPE together with photoreceptors.  It was one of the most difficult technical and encouraging achievements so far in our research. Since then nobody else has been able to copy it.

Aramant RB, Seiler MJ. Transplanted sheets of human retina and retinal pigment epithelium develop normally in nude rats. Exp Eye Res, 75(2):115-125, 2002.
In a "nude" rat that does not reject foreign tissue we implanted a double sheet of retina and RPE (retinal pigment epithelium) that contain a maximum healing potential. After 9 months both sheets had  developed layering. A complete fusion with the rat host and transplanted human sheet RPE. The host was albino so the pigment in the RPE must be from the human transplanted sheet. The RPE had developed a membrane  (Bruch's  membrane) towards the blood vessel layer of the rat.

Transplant Photoreceptors show ultimate function.

Seiler 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, an extraordinarily sensitive mechanism and the ultimate function of normal healthy photoreceptors

  Patient study

Radtke 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, 146:172-182, 2008.
This Phase II clinical study covered one to over six years in 10 patients: This paper presents visual improvement in 4 macular degeneration and 3 retinitis pigmentosa patients and one patient remained the same. 

Extensive Overview in Retinal Transplantation

   This paper shows 25 years of our research, covering most of the retinal transplantation field.
Seiler MJ, Aramant RB. Cell replacement and visual restoration by retinal sheet transplants. Progress in Retinal and Eye Res, 31:661-687, 2012.

Transplanted retinal cells that take part in the process of restoring vision extend many dark stained processes into the blind host retina.

Vision recovery and connectivity after transplantation to immunodeficient retinal degenerate rats

Seiler MJ, Lin R, McLelland BT, Mathur A, Lin B, Sigman J, De Guzman A, Kitzes LM, Aramant RB, Thomas BB. Vision Recovery and Connectivity by Fetal Retinal Sheet Transplantation in an Immunodeficient Retinal Degenerate Rat Model. Invest. Ophthalmol Vis Sci, 58:614-630, 2017. DOI 10.1167/iovs.15-19028
   This study showed visual recovery, development and integration of rat fetal retinal sheet transplants in a new immunodeficient rat model of retinal degeneration.

This figure shows live imaging of retinal sheet transplants in the rat eye over time, and the  histological results at the end of the experiment.  - A laminated transplant is shown in panels A,C,E,G,I,K, and M. The images in M and N show red staining of photoreceptors.

Modified after Fig. 3 of Seiler et al. Vision Recovery and Connectivity by Fetal Retinal Sheet Transplantation in an Immunodeficient Retinal Degenerate Rat Model, IOVS 2017;58:614-–630. DOI:10.1167/iovs.15-19028; licensed under the Creative Commons Attribution License.


Additional Selected Publications

Aramant R, Seiler M.  Fiber and synaptic connections between embryonic retinal transplants and host retina. Experimental Neurology,133:1-12, 1995.
 This paper established that transplants in a host retina injury site can send in processes and make all types of synapses with the host. This gave hope that transplants placed in the true target area might establish synaptic connections with the host retina.
 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 cells.

Seiler 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 Exp Ophthalmol, 238:599-607, 2000
We created 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)

Woch 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 a visual center of the brain. Visual responses could only be elicited from the transplanted eyes.  In addition, we demonstrated that there was no rescue of host photoreceptors.

Review paper:
Aramant RB, Seiler MJ. Retinal transplantation -– advantages of intact fetal sheets. Progress in Retinal and Eye Research 21:57-73,  2002.

Patient paper:
Radtke 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 the Phase I clinical trial which demonstrated the safety and feasibility of transplanting sheets of fetal retina together with its RPE to patients with Retinitis Pigmentosa

 

Sagdullaev 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, 44(4):1686-1695, 2003.

Thomas 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.
This experiment used newly created rats that had been genetically manipulated. A human “sick” gene had been introduced in the photoreceptors so that the rats develop blindness like in human retinitis pigmentosa patients. It was demonstrated that eyesight had been saved and improved in this damaged rat retina.
It was also proven that no rescue of host photoreceptors took place so the improvement was caused by the transplant photoreceptors.

Review paper:
Aramant RB, Seiler MJ. Progress in retinal sheet transplantation. Progress in Retinal and Eye Research 23(5): 475-494, 2004

Thomas 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.

Patient study:
Radtke 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
This clinical paper describes visual improvement in one retinitis pigmentosa patient.

Seiler MJ, Sagdullaev BT, Woch G, Thomas BB, Aramant RB. Transsynaptic virus tracing from host brain to subretinal transplants. Eur J Neurosci, 21:161-172, 2005
A tracer was injected into a 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.

Review paper:
Seiler MJ, Aramant RB.Transplantation of neuroblastic progenitor cells as a sheet preserves and restores retinal function. Seminars in Ophthalmology, 20:31-42, 2005

Review paper:
Aramant 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. BarnstableHumana Press, pp 363-381 Totowa, NJ,. 2006

Thomas 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.
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.

Seiler MJ, Thomas BB, Chen Z, Wu R, Sadda SR, Aramant RB. Retinal transplants restore visual responses: Trans-synaptic tracing from visually responsive sites in brain labels transplant neurons. Eur J. Neurosci, 28:208-220,2008.
This experiment proved that the connectivity of the transplant with the host was responsible for the visual improvement.

Seiler 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
Before 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%.

Review paper:
Seiler MJ, Aramant RB, Keirstead HS. Retinal Transplants: Hope to Preserve and Restore Vision. Optics and Photonics News, 19(4): 37-42, 2008

Seiler 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, 31(3):508-520, 2010
This was the first indisputable demonstration by confocal and electron microscopy that synapse formation between transplant and host was a key factor of the visual improvement

Yang 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.
Factors like BDNF and GDNF can promote cell survival and extension of nerve processes. This study demonstrated that the effect of BDNF and GDNF improves visual restoration of host with laminated sheet transplants.

Seiler 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.
This new instrument called "Fourier-Domain 3D ocular coherence tomography (OCT)" can penetrate living tissue with harmless infrared waves. The laminar transplants, placement of the transplants in relation to the optic disk and surgical defects could be correctly detected. The true structure could later be correlated with OCT results.

Seiler 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). This study used a state-of-the-art method, to identify different cell types which were involved in the communication between transplant and host.

Seiler 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
This study genetically created rats with an eye disease resembling human retinitis pigmentosa with no rejection of transplanted human cells. The resulting rat strain can be used to test human tissue and cells without rejection. An extraordinary advantage not to need immunosuppressive drugs that cause negative side effects.