Dr. Tsang: Stem Cell Treatment Research and Its Possible Applicability to Achromatopsia

Edward S. Harkness Eye Institute Stephen Tsang, MD, PhD [email_address] Greater NY Center

Retinal Cell loss in Achromatopsia
Gene Therapy (Cells need to be present)
Cell-based therapies
Stem Cells
Other therapies: Retinal Prosthesis
[email_address]

No Gap 20/200, 24 yo 20/80, 15 yo

20/150, 35 yo

Optically Empty Gap 20/150, 48 yo 20/160, 23 yo

20/100, 21 yo

Results: SD-OCT
13/15 patients with disorganization/loss of IS/OS junction.
Diameter of IS/OS junction loss corresponded well with the inner margin of the hyperflourescent ring on FAF.
7/15 patients with optically empty gap in fovea
9/15 patients also exhibited a hyper-reflective and thickened external limiting membrane.

Cartoon from NY Times
Induced Pluripotent Stem (iPS) cells  retinal cells  the patient ’ s personalized cytokine profile W/O biopsy the RPE.
Retinal Cells from iPS cells: transplantation and it will not be rejected.
[email_address]

The human induced pluripotent stem (iPS) cells have been produced by reprogramming somatic cells (skin fibroblast) with a set of 4 transcription factors. The human iPS-cells show striking similarities in their morphological, gene expression, and functional characteristics to human ES-cells, and seem to have acquired the critical ES-cell characteristics of unlimited growth and potential to differentiate to all cell types of human body. Fibroblasts and iPS Cells. (A) Fibroblasts taken from patient skin. (B) Fibroblasts after treatment with OCT4, SOX2, KLF4, and cMYC. (C) iPS colonies after SB431542 and PD0325901 selection. (D) Detail of iPS colonies pictured in (C). Induced Pluripotent Stem Cells can be derived from a patient skin fibroblasts

Study Design Skin Biopsy Stem Cell Colonies Stem Cells Differentiation toward Retinal Cells Transplantation

Human Induced Pluripotent Stem (iPS) Cells Skin Fibroblasts Stem Cells Stem Cell Colonies Retinal Cells Yao Li, M.D.

Differentiation of Stem Cells into Photoreceptors Control Stem Cells [email_address]

ES cells can Differentiate into Photoreceptors Negative Control Pdeg -IRES-EGFP R1#49 Pol2-EGFP (Positive Control) [email_address]

Optically Empty Gap 20/150, 48 yo 20/160, 23 yo

Stem Cells

Pablo Picasso. Breakfast of a blind man . 1903.

Stem Cells

-/- Five Years old

-/- Sixteen Years old

Fundus photo of Rpe65 rd12 /Rpe65 rd12 Pang et al. 2005 [email_address] 3 M 5 M 7 M 15 M

Severely attenuated ERG of Rpe65 rd12 /Rpe65 rd12 1 M 8 M

Histology of Rpe65 rd12 /Rpe65 rd12 Pang et al. 2005 6 W 3 M 7 M 15 M

Methods
Normal retinal cells transplanted subretinally to one eye
The other eye is untouched or receives saline
ERGs are examined before and after surgery
Retinal histology is examined at selected times

Mouse Fetal Transplantation 10 days Post-transplantation 1 M Post-transplantation

ERG change after transplantation

N=1 N=1 N=1 N=2 N=2 N=10 N=10 N=13 N=13 Width of Outer Nuclei (rows of nuclei)

C2J-YFP Embryonic Stem (ES) cells [email_address]

Study Design PA6 cells (feeder cells) Embryonic stem cells Subretinal injection into postnatal 5 days old mice In vitro differentiation

[email_address]

Positive Control [email_address]

9.3--> 28 week

Transplant Survival Nan-Kai Wang, M.D.

ES Transplant Survival Control Transplant Transplant Nan-Kai Wang, M.D.

[email_address]

ERG Analysis

ERG Analysis 40 0 20 1 2 3 4 5 6 7 Months Post-transplantation Maximal Responses b-wave Enhancement (μV) ** * * p<0.05 ** p<0.01

Injection Technique 40 0 20 ES-RPE PBS Mit-C PA6 Mit-C ESC Injection Components (3 Months Post-Injection) Maximal Responses b-wave Enhancement (μV) ** * p<0.05 ** p<0.01

Conclusions
Stem cells have the potential to differentiate morphologically and functionally into retinal cells.
The use of stem cell-based therapy may represent a future option in treating certain forms of retinal degeneration.

Induced Pluripotent Stem (iPS) cells  retinal cells  the patient ’s personalized cytokine profile W/O biopsy the RPE.
RPE from iPS cells: transplantation and it will not be rejected.
39

Differentiation of Stem Cells into Photoreceptors
Control Stem Cells

Stem Cells
Other cell based therapies .
Retinal Prosthesis

Tao et al, 2002 IOVS In mice with retinal degeneration

In humans
2005
NEI at NIH
10 human volunteers with retinitis pigmentosa <20/400 vision
ECT plus recombinant RPE cells, producing CNTF, intra-ocular surgery, implanted, removed 6 months later
No adverse effects; device well-tolerated
Several patients improved vision one or more lines

Copyright ©2006 by the National Academy of Sciences Sieving, Paul A. et al. (2006) Proc. Natl. Acad. Sci. USA 103, 3896-3901 Fig. 1. Visual acuity (VA) changes of the study eyes and fellow control eyes of the 10 participants over the 6-month implant period. Grouped by lower-dose implants (Phase IA) and higher-dose implants (Phase IB)

Copyright ©2006 by the National Academy of Sciences Sieving, Paul A. et al. (2006) Proc. Natl. Acad. Sci. USA 103, 3896-3901 Fig. 2. Histology in longitudinal section of a CNTF device after removal at 6 months from the study eye of a Phase-IB participant

Stem Cells
Retinal Prosthesis

Second Sight: Retinal Prosthesis Trial Completes First Phase Of Testing Ft. Lauderdale, Fla., May 8 – Researchers from the Keck School of Medicine of the University of Southern California, its Doheny Retina Institute and Second Sight, LLC, are reporting on the initial results of their groundbreaking, FDA-approved feasibility trial of an intraocular retinal prosthesis that appears to be able to restore some degree of sight to the blind.

Human phase I trial
10 humans with NLP vision from RP
All tolerated the implant
2-3 attained vision of 20/200
Most could see more after surgery
Questions:
How long does it work?
Ideal candidate?
Sub retinal vs epiretinal?

Stem Cells
Retinal Prosthesis

The Mice
J. Tosi, MD
Nan Kai Wang , M.D.
Richard Davis, Ph.D.
Peter Gouras, M.D.
Jian Gong, M.D.
Takayuki Nagasaki, Ph.D.
Rando Allikmets, PhD.
Burroughs Wellcome Fund
Charles Culpepper Scholarship
Foundation Funding Blindness
Acknowledgements [email_address]

Dr. Tsang: Stem Cell Treatment Research and Its Possible Applicability to Achromatopsia

by AchromatopsiaConvention on Aug 13, 2011

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