I received my M.D. degree from the Hebrew University - Hadassah Medical School, and completed my residency in Obstetrics and Gynecology at the Hadassah Medical Center. Currently, I am a full Professor of Obstetrics and Gynecology, and since 2012 serve as Chairman of the Department of Obstetrics and Gynecology at Hadassah.
I joined the The Goldyne Savad Institute of Gene Therapy at Hadassah in 2000 after receiving my PhD degree in developmental biology from Monash University, Australia. Since 2003 I serve as the director of the Sidney and Judy Swartz Human Embryonic Stem Cell Research Center at The Goldyne Savad Institute.
In 2006 I founded Cell Cure Neurosciences Ltd. I serve as the Chief Scientific Officer (CSO) of the company.
The major focus of my research is human embryonic stem cells (hESCs). hESCs are pluripotent cells derived from early surplus human embryos (5-6 days after fertilization). These embryos were created for infertility treatment purposes through in vitro fertilization (IVF) procedures and donated to research. hESCs are unique since they can self-renew infinitely in culture and also have a remarkable potential to develop into all cells and tissues of the human body.
This project is performed in collaboration with Prof. Eyal Banin, Director of Center for retinal diseases at Hadassah and with Cell Cure Neurosciences Ltd.
The aim of the project is to develop various types of retinal cells from hESCs for transplantation and regeneration in blinding diseases. One of these projects is focused on Age Related Macular Degeneration (AMD). AMD is the leading cause of blindness in people over the age of 60. In dry-AMD, there is progressive loss of the layer of Retinal Pigment Epithelial (RPE) cells. This loss leads to degeneration of the nearby photoreceptors, which causes severe vision loss or even legal blindness.
Transplantation of hESC-derived RPE cells and regeneration of the RPE layer may halt disease progression.
We developed a highly efficient methodology for directing the differentiation of hESCs towards RPE fate under defined conditions. The hESC-derived RPE cells rescued retinal structure and function after transplantation to a rat model of retinal degeneration (Idelson et al. Cell Stem Cell, 2009).
Next, we produced clinical-grade RPE batches for clinical use and obtained FDA and Israeli MOH approval for a clinical trial. We are currently performing a Phase I/IIa clinical trial to analyze the safety and tolerability of the clinical-grade hESC-derived RPE cells in patients with advanced dry AMD. Findings on imaging suggest engraftment and persistence of the transplanted cells in the sub-retinal space.
Figure 1. Derivation of RPE cells from hESCs
hESC colonies of undifferentiated cells are induced to differentiate by transfer and culture in suspension as floating clusters (Spherical Bodies (SBs)) in the presence of differentiation inducing factors. Pigmented areas appear within the SBs. Following selection of the pigmented areas and plating, a monolayer of polygonal shape pigmented cells expressing markers of RPE cells develop.
Modeling Amyotrophic lateral sclerosis (ALS) by human iPSCs derived from ALS patients-
This project is performed in collaboration with Prof. Eva Feldman from Michigan University.
ALS is a progressive neurodegenerative disease that affects motor neurons (MNs) in the brain and the spinal cord. A Hexanucleotide repeat (HR) expansion in the first intron of C9orf72 is the most common cause of ALS accounting for approximately 34% of familial ALS and 6% of sporadic ALS cases.
The goal of this study is to elucidate the potential role of astrocytes in the pathogenesis of C9orf72 ALS, towards the development of novel therapies.
We derived induced pluripotent stem cell (iPSC) lines from fibroblasts of patients with a mutation in the gene C9orf72 and from matched healthy controls. We developed a highly efficient protocol to derive pure cultures of spinal cord astrocytes from human iPSCs. This protocol was used to develop iPSC-derived C9orf72 mutated and control human astrocytes as an in vitro model for our study.
We are currently characterizing the mutated astrocytes, and studying their effects on motor neurons.
Figure 2. hiPSC-derived astrocytes
Immunoflorescence staining of hiPSC-derived astrocytes from healthy (left panel) and C9orf72 mutated (right panel) donors, expressing GFAP (Green). The nuclei of the cells are demonstrated in blue.
Human ESC-derived oligodendrocytes as a model for cerebral palsy (CP)
Periventricular leukomalacia (PVL) is a perinatal brain injury involving the brain’s white matter. Hypoxia-ischemia of the brain and intrauterine infection has both been implicated as causes of perinatal white matter damage. PVL often results in lifelong brain damage, and cerebral palsy (CP).
The greatest period of risk for PVL is during mid-to-late gestation (23-32 weeks), when the cerebral white matter is immature, and myelin sheaths are not yet actively synthesized. Myelin is generated in the brain by oligodendrocyte cells. Within PVL lesions there is acute loss of early differentiating oligodendrocytes, the pre-oligodendrocytes that may lead to loss of mature, myelin-producing oligodendrocytes, and impaired cerebral myelination.
Our study aims to use hESC-derived oligodendrocytes, for in-vitro modeling of human PVL. We developed a protocol that allows efficient derivation of oligodendrocytes from hESCs. With this protocol, we achieved a culture of human pre-oligodendrocytes. We are currently using this platform to model PVL and study its pathogenesis.
Figure 3. hESC-derived mature oligodendrocytes
Immunoflorescence staining of hESC-derived mature oligodendrocytes expressing the myelin basic protein (MBP-green).
Pluripotent stem cells – a potentially unlimited donor source of oocytes and sperm cells
Egg and sperm donations are required in cases of female or male infertility due to gamete-deficiency of genetic origin, aggressive treatments for cancer and advanced female reproductive age.
The aim of the project is to develop protocols for the derivation of oocytes and sperm cells from hESCs or from induced pluripotent stem (iPS) cells, which are reprogrammed from somatic cells. Deriving iPS cells from a patient's somatic cells may allow the development of sperm cells or oocytes from these iPS cells for the patient.
The study focuses on elucidating the mechanisms underlying germ cell differentiation aiming to clarify the causes of infertility related to lack of sperm cells and eggs. In the future, our results might enable the use of hESC and iPSC-derived sperm cells and eggs for regenerative medicine treatments for infertility.
Figure 4. hESC-derived PGCs
Immunoflorescence staining of hESC-derived PGCs expressing the specific PGC markers PRDM1 (Red) and NANOS3 (Green). The nuclei of the cells are demonstrated in blue in the right panels.
Left to Right:
Upper row: Sharona Even- Ram ,Yaniv Gil, Benjamin Reubinoff, Shelly Tannenbaum, Yael Berman Zaken, Miriam Haimov, Nili Ilouz, Masha Gornshtein, Hanita Khaner, Israel Ben-Dor, Michal Gropp.
Lower row: Etti Ben-Shushan, Yulia Magergut, Deby Steiner, Orna Singer, Ofra Zidon Benmenahem.