Yona Levites, Ph.D.
Department of Neuroscience
Center for Translational Research in Neurodegenerative Disease (CTRND)
1275 Center Drive
PO Box 100159
Gainesville, FL 32610-0159
|Faculty of Medicine & Unit of Biotechnology
Technion, Haifa, Israel
|Mayo Clinic, Neurodegeneration Research Center
Key Words: Immunotherapy; Adeno-associated virus; Amyloid; Alzheimer’s disease; Spinal cord neurodegeneration; Neuronal death
Our research involves generation of single-chain variable fragments (antibody fragments) that recognize potentially toxic proteins or protein species and administrating them to Neurodegenerative diseases animal models via Adeno-Associated virus mediated gene transfer. We developed anti- amyloid single-chain fragments directed specifically against fibrillar Amyloid beta. Currently we have single chain fragments against amyloid, phosporylated Tau, alpha-synuclein and can test them in Alzheimer’s and Parkinson’s disease transgenic mice.
Another path of research that we are pursuing is testing a new strategy to develop animal models that more closely resemble Alzheimer’s disease processes in the human brain. we will test the utility of a novel mechanism to deliver individual beta-amyloid protein fragments as well as other non-Abeta amyloidogenic peptides to rodent brain and determine whether these models develop a brain pathology that closely resembles Alzheimer’s.
Lastly, we are developing various routs of gene delivery using AAV. We have observed and demonstrated that transduced cell types and biodistribution of AAV depend on the viral serotype and timing of injection. We examine novel serotypes and develop efficient methods of delivery into the CNS and spinal cord.
Research Focus & Aims:
Adeno-associated viruses (AAV) have been extensively used for targeted gene expression in numerous organs across species. We utilize an innovative approach of AAV mediated gene delivery and expression in the rodent brain in order to test prevention and treatment paradigms as well as develop new models of amyloidosis and neurodegeneration. Somatic brain transgenesis allows time and cost effective validation of a various array of mediators of CNS function.
- Development of immunotherapeutic tools for treatment and prevention in AD models.
- Numerous strategies to prevent Abeta aggregation and accumulation are being evaluated as ways to treat or prevent AD. Recently we and other have shown data supporting the hypotheses that targeting Abeta assemblies may be a better target for AD immunotherapy. We hypothesized that single chain variable fragments (scFv) that recognize generic amyloid will effectively attenuate pathology in Alzheimer’s Disease mouse model. Our goal is to develop a high affinity binding agent (scFv, as well as full length antibody) that will bind amyloid and prevent amyloid toxicity in animal models and, potentially, in clinic.
- The mechanisms underlying the abnormal phosphorylation and accumulation of Tau protein in AD remain unclear, but one of the possibilities is that it might be due to its conformational changes. Our objective is to generate and characterize stable intracellular anti-Ptau scFvs (intrabodies), and determine their effect on the pathological accumulation of tau in neurons, as well on neurofibrillary tangle formation and neuron loss, using AAV mediated trunsduction to the brain of tau-transgenic mice.
- Development of novel models of neurodegenerative diseases.
Another path of research we are pursuing is development of animal models that more closely than the existing ones resemble Alzheimer’s disease processes in the human brain. We deliver individual beta-amyloid protein fragments, non-Abeta amyloidogenic peptides as well as other proteins suggested to either directly or indirectly interact with APP to rodent brain and determine whether these models develop a brain pathology similar to Alzheimer’s.
- AAV gene delivery.
Additionally, we have been attempting to deliver genes into subpopulations of cells as well as distinct regions in CNS and spinal cord. We test various routes of delivery, promoters and various AAV serotypes.