State awards UCLA stem cell researchers $10.4M to develop new therapies for disease
California's state stem cell agency has awarded grants totaling $10.4 million to four researchers at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA to translate basic science into new and more effective therapies to regenerate bone, target deadly brain cancers and treat corneal disorders that result in blindness.
The Early Translational II grants, awarded Oct. 21 by the California Institute for Regenerative Medicine (CIRM), went to Dr. Bruno Peault and Dr. Chia Soo, professors of orthopedic surgery ($5,391,560); Dr. Noriyuki Kasahara, a professor of digestive diseases ($3,370,607); and Dr. Sophie Deng, an assistant professor of ophthalmology ($1,654,058).
These awards are the second in what CIRM officials expect to be a 12- to 18-month award cycle for the translational research grants. The UCLA Broad Stem Cell Research Center considers the research funded by these awards critical to its mission to translate basic discoveries into clinical treatments. The funded projects are expected to either result in a candidate drug or cell therapy or to make significant strides toward a drug candidate, which can then be developed for submission to the Food and Drug Administration for testing in clinical trials.
In all, CIRM approved funding for 19 early translational grants totaling more than $67 million.
To date, scientists with the UCLA Broad Stem Cell Center have received 39 CIRM grants totaling more than $133 million.
Dr. Bruno Peault and Dr. Chia Soo: Regenerating bone
Peault and Soo plan to use fat stem cells obtained through liposuction to form and regenerate bone, research that may result in a treatment that could help patients with back problems requiring spine fusion, bone fractures, herniated disks and, potentially, osteoporosis. Their work, if successful, could provide an alternative to traditional bone grafting.
Their study uses a novel combination of antibodies and cell sorting to prospectively isolate more purified stem cell populations from fat. The stem cells, called perivascular stem cells (PSC), are a breakthrough in stem cell technology because, unlike traditional fat-derived stem cells, PSC are not cultured for weeks before identification. The method allows patients to be treated much more quickly, yields more pure stem cell populations and decreases the risk of contamination. The PSC would be combined with a potent growth factor, NELL-1, that amplifies the ability of PSC to form bone, and the mixture would then be implanted into patients to form bone.
Ideally, the fat would be taken by liposuction from the patient needing bone regeneration in order to avoid the rejection that could result if the fat was taken from someone else. Peault and Soo hope to show that the rapidly isolated PSC can form bone better than conventional, culture-derived fat stem cells.
Dr. Noriyuki Kasahara: Brain cancers
In an effort to develop a new and more effective therapy to treat deadly glioblastomas, Kasahara seeks to use a replication-competent retrovirus that will only infect rapidly dividing cancer cells, transforming the tumor cells themselves into therapeutic virus–producing cells.
Modified viruses can be used to infect cancer tumor cells and make anti-tumor proteins. Most researchers use viruses that are replication-incompetent; such a virus can infect and modify the tumor cell it enters but cannot replicate itself to infect malignant cells surrounding the original infected cell. These viruses are considered safe because no additional virus, which potentially could get out of control, is generated inside the tumor. However, such therapies have shown only limited benefit, presumably because too many tumor cells remain uninfected.
Newer approaches focus on the use of replication-competent viruses, which transform the tumor cell itself into a virus-producing cell that attacks malignant cells and leaves normal brain cells alone.
Generally, a therapeutic virus is injected directly into a tumor, and the virus is unable to target malignant cells that have diffused to other areas of the brain. Kasahara proposes using a type of adult stem cell called a mesenchymal stem cell as a delivery system for the replication-competent retrovirus. These stem cells have been shown to have natural tumor-homing abilities and can migrate to diffuse tumor cells, as well as penetrate into the interior of the primary tumor. Kasahara hopes to engineer these stem cells into "aircraft carriers" that release tumor-selective viruses that can spread "suicide" genes from one cancer cell to another.
Dr. Sophie Deng: Corneal disorders
Deng hopes to regenerate functional human corneal epithelial progenitor cells to treat a blinding corneal disorder known limbal stem cell deficiency (LSCD).
Corneal diseases are the second leading cause of treatable blindness in the world and leave more than 3.2 million people blind worldwide. LSCD has been recognized as a major cause, either primary or secondary, of significant visual loss and blindness in many common corneal disorders, such as chemical/thermal burns, keratopathy related to contact lens wear, and severe infection and inflammation.
Deng hopes to develop new cell-engineering methods that can efficiently expand and regenerate patient-specific limbal stem cells using a contamination-free system to generate enough cells for transplantation.
The first goal is to establish the contamination-free culture system by replacing the mouse feeder cells traditionally used to expand and regenerate limbal stem cells with a human feeder system. Deng then hopes to further optimize the expansion efficiency of her system by modulating the Wnt and Notch cell-signaling pathways, which regulate the proliferation and differentiation of corneal epithelial cells.
In parallel, she hopes to reprogram human skin epithelial stem cells into corneal epithelial cells using a similar approach. The ability and safety of these regenerated human corneal epithelial stem cells to reconstruct the ocular surface of the eye will be tested in a LSCD animal model.
The success of all three projects will provide the basis for investigational new drug applications to the FDA and the initiation of human clinical trials.
The Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research: UCLA's stem cell center was launched in 2005 with a UCLA commitment of $20 million over five years. A $20 million gift from the Eli and Edythe Broad Foundation in 2007 resulted in the renaming of the center. With more than 200 members, the Broad Stem Cell Research Center is committed to a multidisciplinary, integrated collaboration among scientific, academic and medical disciplines for the purpose of understanding adult and human embryonic stem cells. The center supports innovation, excellence and the highest ethical standards focused on stem cell research with the intent of facilitating basic scientific inquiry directed toward future clinical applications to treat disease. The center is a collaboration of the David Geffen School of Medicine at UCLA, UCLA's Jonsson Cancer Center, the UCLA Henry Samueli School of Engineering and Applied Science and the UCLA College of Letters and Science.