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Alzheimer's Disease Research
Completed Award

Dr. Biju Chandu

Biju K. Chandu, Ph.D.

The University of Texas Health Science Center at San Antonio
San Antonio, TX, United States

Title: iPS-Derived Microglia-Based Gene Therapy for Alzheimer's
Non-Technical Title: A New Therapy Using Stem Cells to Halt or Reverse the Course of Alzheimer's Disease

Co-PI(s):
Senlin Li, M.D. (Mentor)
University of Texas Health Science Center
Robert A. Clark, M.D. (Mentor)
University of Texas Health Science Center
Mentor:
Multiple mentors, listed above.

Acknowledgements: This grant is made possible due to a generous bequest from the Estate of Frederick J. Pelda.
Duration: July 1, 2011 - June 30, 2014
Award Type: Research Fellowship
Award Amount: $100,000

Summary:

Extracting bone marrow cells requires surgery, which may be strenuous or impossible for older patients. To meet large-scale demand for bone marrow cells in clinical trials for the treatment of Alzheimer's disease, we will generate bone marrow cells from blood, which we in turn will genetically modify to secrete drugs once these cells migrate to the brain. This new approach is expected to contribute to the development of an important therapy for Alzheimer's.

Details:

Therapies using your own (self‐derived) bone marrow cells have promise for treating many different diseases, including Alzheimer's disease. This type of self‐recognizing stem cell therapy has an increased chance of success, because one can avoid the pesky problem of the immune system labeling the cells as foreign invaders and killing them before they have a chance to work. Dr. Biju Chandu and collaborators will be testing a new bone marrow cell treatment for Alzheimer's disease. First, they will isolate white blood cells that roam freely in the easily-accessible blood vessels. These cells will in turn be genetically modified to become bone marrow cells and re-purposed to release anti-Alzheimer's disease drugs. The modified cells are injected back in the blood stream, where they migrate to the parts of the brain that require treatment. After this new treatment is tested in cell culture and animals in this project, the researchers may then decide to move this technique into human clinical trials.

Progress Updates:

Bone marrow-based gene therapy is emerging as a promising tool for overcoming drug delivery problems associated with neurodegenerative diseases, as bone marrow cells are able to cross the blood-brain barrier. Once they enter the brain, bone marrow cells are recruited to sites of neurodegeneration wherever they occur in the central nervous system. At the site, bone marrow cells change into microglia, a kind of brain cell. Dr. Chandu’s team plans to artificially modify the bone marrow cells to contain the gene for neuroprotective drugs, so they begin to secrete the drug at these sites of neurodegeneration after they’ve changed into microglia.

Extracting bone marrow cells requires surgery, which may be strenuous or impossible for older patients. To meet large scale demand of bone marrow cells in the clinic for the treatment of Alzheimer's disease, the team will generate bone marrow cells from blood, which will in turn be genetically modified to secrete drugs once these cells migrate to the brain.

To make bone marrow cells from blood, Dr. Chandu’s team first collected blood and then isolated white blood cells. These white blood cells were cultured in dishes using specialized incubators for tissue culture. The cells were then "forced" to express certain stem cell-associated genes by a gene therapy technique. After 3-4 weeks, small numbers of the genetically-altered cells became similar to embryonic stem cell-like cells called induced pluripotent stem cells (iPSC). These iPSC will later be converted to bone marrow cells under specific cell culture conditions. The team was able to convert the blood cells to embryonic stem cell-like cells, but they didn’t survive, perhaps because the blood cells were not completely converted. Currently, Dr. Chandu’s team is fine-tuning the culture conditions for conversion to iPSC. Once successful, the team will continue their plan to deliver the drug-expressing cells into mice with Alzheimer’s disease.

Investigator Biography:

Dr. Biju Chandu is a postdoctoral fellow in the Department of Medicine at the University of Texas Health Science Center in San Antonio, Texas. He completed his doctoral studies in Neuroscience at the Department of Pharmaceutical Sciences, Nagpur University, India.  In 2004 he moved to the Neuroscience Program at Florida State University to do postdoctoral work with Prof. Debra Fadool. Some of his experiments with Prof. Fadool drew his attention to that fact that increasing the levels of certain neurotrophic factors might provide great benefit to people suffering from neurodegenerative diseases. To learn more about the impact neurotrophic factors might have on reversing the course of neurodegenerative diseases, he moved to the laboratory of Dr. Senlin Li at the University of Texas Health Science Center. At the Health Science Center Chandu has been collaborating with Dr. Li to develop and test neuroprotective therapeutics for neurodegenerative diseases. 

Currently, they use bone marrow-derived macrophages as a cellular vehicle to deliver neurotrophic factors to the degenerating neurons. The use of macrophages to deliver neurotrophic factors is particularly attractive, given that these cells are capable of crossing the blood-brain barrier, after which they differentiate into microglia and are preferentially recruited in large numbers to sites of neurodegeneration. They are also performing experiments to determine whether different kinds of neurotrophic factors have more and less beneficial effects.  Extracting bone marrow requires surgery, which may be strenuous or impossible for older patients. To address the issue, they have begun working on generating macrophages using induced pluripotent stem cell technology.