Brief Biography

• Staff in the Division of Immunology/Allergy & Bone Marrow Transplantation
  The Hospital for Sick Children, Toronto, Canada. 2002.
• Fellowship in Allergy and Clinical Immunology
  The Hospital for Sick Children, Toronto, Canada. 1998-2001.
• Master in Paediatrics
  Sackler Faculty of Medicine, Tel-Aviv University. 1998
• Paediatric residency
  Hasharon Hospital and Schneider Children Medical Center, Israel. 1992 - 1998
• M.D. Hadassah Medical School, Hebrew University
  Jerusalem, Israel. 1988
• B.Sc. Hadassah Medical School, Hebrew University
  Jerusalem, Israel. 1983

Clinical Care Activities

• Diagnosis and treatment of patients suffering from primary immunodeficiency diseases, including patients with hypo-gammaglobulinemia, common variable immunodeficiency and DiGeorge syndrome
• Management of patients undergoing bone marrow transplantation for primary immunodeficiency or hematology/oncology diseases.
• Long term follow up and treatment of patients with primary immune deficiencies who received hematopoietic stem cell transplantation

Research Interests

• Studying the effect of various methods of hematopoietic stem cell transplantation on the outcome of patients with primary immune deficiency.
• Using murine models of immune deficiency, including mice in which the gene for Purine Nucleoside Phosphorylase was "knocked out" to better understand normal immune development.
• Investigating various immune and non-immune abnormalities associated with PNP deficiency.
• Studying the effect of supplementing missing enzymes by exogenous means. My research is focused on the ability of short peptides, called “Protein-Transduction Domain” to efficiently delivers PNP into the cells and across the blood-brain barrier of PNP-deficient mice.
• Evaluating the ability of Lenti-virus based vectors that contain PNP to integrate into murine hematopoietic stem cells derived from the PNP-deficient mice.

Research Activities

My research is related to the diagnosis and treatment of individuals that are born with a defect in their immune system. They are susceptible to significant infections which may be lethal. In severe cases, children could survive only if they were kept in a “bubble” or if they received new immune cells through a bone marrow transplant from a genetically identical brother or sister. Recently we showed that stem cell transplantation from other sources is also successful, although further improvement is required.

Utilizing the ability of viruses to enter cells and introduce genes into the human genome, researchers were able to replace some of the abnormal genes that cause defects in the immune system. Similarly, I am developing gene therapy for an immunodeficiency disease called purine nucleoside phosphorylase (PNP) deficiency. I am also studying factors that influence hematopoietic stem cells differentiation into T-lymphocytes which are crucial for successful cells or gene therapy in PNP deficiency, other forms of immune deficiency and several genetic diseases including those that affect the lungs, blood and malignancies.

Another field I am investigating is the ability to deliver missing proteins into human cells such as the thymus, liver and brain. My lab has shown that repeated injections of PNP enzyme attached to a protein transduction domain correct the abnormalities of PNP-deficient mice. We hope that this research may pave the way for delivering other enzymes, antibiotics and medications into cells and tissues that previously were difficult to access.

Future Research Interests

• Identify factors that affect hematopoietic and lymphoid development.
• Optimize conditions for successful gene therapy.
• Establish safe and efficient gene therapy in children.

External Funding

Canadian Gene Cure Foundation, 2004.
Gene therapy strategies in purine nucleoside phosphorylase deficiency- a murine model

Canadian Institutes of Health Research, 2004.
Correcting purine nucleoside phosphorylase (PNP) deficiency by intracellular delivery of human PNP combined with the HIV-TAT protein transduction domain.

Jeffrey Modell Immunodeficiency Foundation. 2006.
Gene therapy for inherited primary immune deficiency.

The Hospital for Sick Kids Foundation and the Institute of Human Development, Child and Youth Health (Canadian Institutes of Health Research) 2006.
Correcting purine nucleoside phosphorylase using lenti-virus mediated human PNP gene delivery into hematopoietic stem cell

Publications

Guggenheim R, Somech R, Grunebaum E, Atkinson A, Roifman CM: Bone marrow transplantation for cartilage-hair-hypoplasia. Bone marrow transplant 2006, Oct 16. PMID: 17041608

Al-Jenaidi F, Makitie O, Grunebaum E, Sochett E: Parathyroid gland dysfunction in 22q11.2 deletion syndrome. Hormone Research 2006: Oct 19;67(3):117-122. PMID: 17057408

Toro A, Grunebaum E: TAT-mediated intracellular delivery of purine nucleoside phosphorylase corrects its deficiency in mice. Journal of Clinical Investigation. 2006 Oct;116(10):2717-26.

Toro A Paiva M, Ackerley C, Grunebaum E: Intracellular delivery of purine nucleoside phosphorylase (PNP) fused to protein transduction domain corrects PNP deficiency in vitro. Cellular Immunology. 2006 Apr;240(2):107-15.

Grunebaum E, Sharfe N, Roifman CM: Human T cell immunodeficiency: when signal transduction goes wrong. Immunologic research 2006;35(1-2):117-26.

Grunebaum E, Mazzolari E, Porta F, Dallera D, Atkinson A, Reid B, Notarangelo LD, Roifman CM: Bone marrow transplant from matched unrelated donors in severe combined immune deficiency. JAMA 2006: 295: pp 508-518.

Carcao M, St Louis J, Poon MC, Grunebaum E, Lacroix S, Stain AM, Blanchette VS, Rivard GE: Rituximab for congenital haemophiliacs with inhibitors: a Canadian experience. Haemophilia 2006: 12: pp 7-18.

Zhang J, Quintal L, Atkinson A, Williams B, Grunebaum E, Roifman CM: Novel RAG1 mutation in a case of severe combined immunodeficiency. Pediatrics 2005: 116: pp 445.

Grunebaum E, Zhang Y, Roifman CM: Novel mutations and a "hot-spot" in purine nucleoside phosphorylase deficient patients. Nucleosides, Nucleotides and Nucleic acids 2004: 23: pp 1411-5.

Dror Y, Grunebaum E, Hitzler J, Narendran A, Ye C, Tellier R, Edwards V, Freedman MH, Roifman CM. Purine nucleoside phosphorylase deficiency associated with a dysplastic marrow morphology. Pediatr Res. Mar;55(3):472-7, 2004.