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Scandling J.D.,Stanford University | Busque S.,Stanford University | Dejbakhsh-Jones S.,Stanford University | Benike C.,Stanford University | And 7 more authors.
American Journal of Transplantation | Year: 2012

Sixteen patients conditioned with total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) were given kidney transplants and an injection of CD34+ hematopoietic progenitor cells and T cells from HLA-matched donors in a tolerance induction protocol. Blood cell monitoring included changes in chimerism, balance of T-cell subsets and responses to donor alloantigens. Fifteen patients developed multilineage chimerism without graft-versus-host disease (GVHD), and eight with chimerism for at least 6 months were withdrawn from antirejection medications for 1-3 years (mean, 28 months) without subsequent rejection episodes. Four chimeric patients have just completed or are in the midst of drug withdrawal, and four patients were not withdrawn due to return of underlying disease or rejection episodes. Blood cells from all patients showed early high ratios of CD4+CD25+ regulatory T cells and NKT cells versus conventional naive CD4+ T cells, and those off drugs showed specific unresponsiveness to donor alloantigens. In conclusion, TLI and ATG promoted the development of persistent chimerism and tolerance in a cohort of patients given kidney transplants and hematopoietic donor cell infusions. All 16 patients had excellent graft function at the last observation point with or without maintenance drugs. In a cohort of 16 patients given kidney and hematopoietic cell transplants enrolled in a tolerance induction protocol, 11 have been withdrawn from immunosuppressive drugs with observations for up to 3 years thereafter without evidence of acute or chronic rejection. See editorial by Bradley on page 1073. © 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.

Salazar D.L.,University of California at Irvine | Salazar D.L.,Ludwig Institute for Cancer Research | Uchida N.,StemCells | Hamers F.P.T.,Rehabilitation Hospital Tolbrug | And 2 more authors.
PLoS ONE | Year: 2010

Background: Traumatic spinal cord injury (SCI) results in partial or complete paralysis and is characterized by a loss of neurons and oligodendrocytes, axonal injury, and demyelination/dysmyelination of spared axons. Approximately 1,250,000 individuals have chronic SCI in the U.S.; therefore treatment in the chronic stages is highly clinically relevant. Human neural stem cells (hCNS-SCns) were prospectively isolated based on fluorescence-activated cell sorting for a CD133 + and CD24 -/lo population from fetal brain, grown as neurospheres, and lineage restricted to generate neurons, oligodendrocytes and astrocytes. hCNS-SCns have recently been transplanted sub-acutely following spinal cord injury and found to promote improved locomotor recovery. We tested the ability of hCNS-SCns transplanted 30 days post SCI to survive, differentiate, migrate, and promote improved locomotor recovery. Methods and Findings: hCNS-SCns were transplanted into immunodeficient NOD-scid mice 30 days post spinal cord contusion injury. hCNS-SCns transplanted mice demonstrated significantly improved locomotor recovery compared to vehicle controls using open field locomotor testing and CatWalk gait analysis. Transplanted hCNS-SCns exhibited long-term engraftment, migration, limited proliferation, and differentiation predominantly to oligodendrocytes and neurons. Astrocytic differentiation was rare and mice did not exhibit mechanical allodynia. Furthermore, differentiated hCNS-SCns integrated with the host as demonstrated by co-localization of human cytoplasm with discrete staining for the paranodal marker contactin-associated protein. Conclusions: The results suggest that hCNS-SCns are capable of surviving, differentiating, and promoting improved locomotor recovery when transplanted into an early chronic injury microenvironment. These data suggest that hCNS-SCns transplantation has efficacy in an early chronic SCI setting and thus expands the ''window of opportunity'' for intervention. © 2010 Salazar et al.

Piltti K.M.,University of California at Irvine | Salazar D.L.,University of California at Irvine | Salazar D.L.,Ludwig Institute for Cancer Research | Uchida N.,StemCells | And 2 more authors.
Stem Cells Translational Medicine | Year: 2013

The spinal cord injury (SCI) microenvironment undergoes dynamic changes over time, which could potentially affect survival or differentiation of cells in early versus delayed transplantation study designs. Accordingly, assessment of safety parameters, including cell survival, migration, fate, sensory fiber sprouting, and behavioral measures of pain sensitivity in animals receiving transplants during the chronic postinjury period is required for establishing a potential therapeutic window. The goal of the study was assessment of safety parameters for delayed transplantation of human central nervous system-derived neural stem cells (hCNS-SCns) by comparing hCNS-SCns transplantation in the subacute period, 9 days postinjury (DPI), versus the chronic period, 60 DPI, in contusion-injured athymic nude rats. Although the number of surviving human cells after chronic transplantation was lower, no changes in cell migration weredetectedbetweenthe 9 and 60 DPI cohorts; however, the data suggest chronic transplantationmay have enhanced the generation of mature oligodendrocytes. The timing of transplantation did not induce changes in allodynia or hyperalgesia measures. Together, these data support the safety of hCNS-SCns transplantation in the chronic period post-SCI. © AlphaMed Press 2013.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 305.20K | Year: 2008

DESCRIPTION (provided by applicant): We propose to carry out foundational studies to characterize the Hepatitis C infectivity of candidate human liver cell transplant products. In order to achieve these studies, we propose to a) assess the HCV infectivity of different fetal and adult liver cell populations, and 2) determine whether shRNA directed against HCV infectivity determinants, such as CD81, can be expressed stably in liver cell populations. PUBLIC HEALTH RELEVANCE: Liver disease is a leading source o f mortality in the US. Although liver transplantation is an option for some of patients suffering from liver disease, the scarceness of donor livers makes it difficult for patients to undergo the transplant, and many die waiting for a suitable organ. The t ransplantation of hepatocytes, rather than whole livers may circumvent many of the limitations of the orthotopic liver transplants. Additionally, almost all of the patients receiving a liver transplant for HCV-associated end-stage liver disease (ESLD) expe rience re-infection of their graft. Unfortunately, effective anti-HCV therapy for many patients remains elusive. A cell therapy may provide a safe alternative that could be available to more patients. The production of HCV-resistant liver cells will ensure that, upon transplantation, these cells provide the patient not only with the basic liver functions, but also provide an HCV-free liver cell reservoir. In the best case scenario, the liver cells that will be isolated from the healthy organ will be expanda ble, and HCV-resistant. As the first step in creating these biologically active and transplantable cells, StemCells, Inc. has isolated a population of cells, the human liver engraftable cells (hLECs), that have progenitor/stem cell properties. We propose t o use these cells as the starting material, and, in conjunction with shRNA silencing technology, accomplish proof-of-principle studies that will lead to the creation of a transplantable, biologically active, HCV-resistant liver cell product.

News Article | February 3, 2015
Site: www.xconomy.com

Home remodeling shows are a reality TV staple. But no Park Avenue mansion or country estate can top the nearly $1 billion price tag of the house C. Randal Mills is trying to renovate on the fly in California. Mills, who goes by Randy, is the president of the State of California’s stem cell agency, which just turned 10 years old. A former biotech executive, he’s been on the job at CIRM for seven months, pushing what he calls “CIRM 2.0″: an overhaul to fulfill the agency’s unfinished business of bringing regenerative medicine therapies to patients. (CIRM stands for “California Institute for Regenerative Medicine.”) For some time, the agency has mulled ways to extend its life beyond the original $3 billion in bond money Californians voted for in 2004. Ideas of public-private partnerships, rich benefactors, or perhaps going back to the public have been floated. Turns out the answer, for now, is CIRM must first get its own house in order. The renovation plan could be fully in place by mid-year, if the agency’s board approves. Some of it Mills has discussed in detail, which we’ll delve into later, and some of it remains vague. With board meetings open and available online, it’s a reality show that skews more C-SPAN than Housewives. But it’s crucial for Californians of all stripes—taxpayers and patients, health providers and researchers alike—because CIRM has spent more than $2 billion on new buildings, job training, and R&D, yet only a handful of the projects it has funded have led to therapies now being tested in humans. That’s to be expected; turning radical new science into medical products is a long slog. But critics say CIRM’s original backers (real estate developer Bob Klein and the Proposition 71 campaign—one could call CIRM “The House That Klein Built”) underplayed that caveat to voting taxpayers a decade ago. Perhaps the media and public weren’t going to tune into it, anyway. But expectations are expectations. “CIRM-funded labs have produced genuine achievements,” wrote Los Angeles Times columnist Michael Hiltzik last summer. “But the specific cures promised by the Proposition 71 campaign haven’t materialized, which doesn’t surprise anyone steeped in the realities of the scientific method.” CIRM must also show it can fund industry without shooting itself in the foot. Awards to companies have been sparse, about 10 percent of the $2.1 billion total. One of the few firms to receive CIRM cash so far is StemCells Inc. of Newark, CA. CIRM awarded StemCells $19 million in 2012 to help with its experimental Alzheimer’s treatment, despite initial rejections from CIRM reviewers and a questionable tangle of close ties with folks like Stanford University researcher Irv Weissmann—a frequent recipient of CIRM grants and a StemCells founder and board member. The arrangement became an embarrassment in 2014 when Mills’s predecessor Alan Trounson, who oversaw the StemCells grant, immediately took a StemCells board seat upon leaving CIRM. In December, CIRM pulled the plug on its funding, but StemCells had already received nearly $10 million it won’t have to pay back. After Trounson’s ill-advised move—which reportedly took CIRM officials by surprise—the agency revised its conflict-of-interest policy, although it maintained that Trounson’s action broke no previous rules. It was the second big adjustment CIRM had made in three years. In late 2012, the U.S. Institute of Medicine, at CIRM’s behest, wrote a long report on the agency’s practices, pro and con, which spurred several changes, some related to conflict-of-interest problems and perceptions. Back in 2004, California voters said yes to $3 billion in bonds to fund the research agency, knowing that interest payments would swell the final bill to $6 billion. It was an expensive thumb-to-the-nose at President George W. Bush, whose executive rules—since overturned by President Obama—had cut off federal funding for nearly all embryonic stem cell research. California, the thought went, would skirt federal bans, build new buildings, attract bright minds, create new jobs, and ultimately share the financial and moral rewards of cures for all kinds of diseases. (Economic impact reports are notoriously squishy, but for what it’s worth, one commissioned by CIRM said in 2012 that from 2006 to 2014 the agency would generate 38,000 full time jobs and $205 million in state tax revenues.) But now it’s renovation time. Mills’s first task was to add a fresh coat of exterior paint, rebranding “CIRM 2.0″ as an efficient, business-friendly entity. According to the new rhetoric, CIRM is less a grant-making government agency than a “discerning investor” that’s going to be “as creative and innovative” as possible in getting treatments approved, Mills says. “We have no mission above accelerating stem cell therapies to patients.” That language is tuned to catch the ears of the biopharma industry, which CIRM needs to convince to take its money and move regenerative medicine products through the clinic. Mills ran Osiris Therapeutics (NASDAQ: OSIR), of Columbia, MD, for a decade and brought a stem-cell-based treatment to market for kids with graft-versus-host disease. He knows the language of business, as does chairman John Thomas, who cofounded a private equity firm in Santa Monica, CA. They are indeed promising big changes. The biggest, perhaps, is an overhaul of the grant application process, shaving it from as much as two years down to four months, and holding review meetings on the phone instead of flying reviewers to California and paying for hotel rooms. (Mills was one of those reviewers for five years.) Before, application windows would open every 12 to 18 months “like a game of whack-a-mole, and you had to apply whether or not you were ready,” says Mills. Now, scientists and companies can apply for grants at any time, and if their proposals aren’t up to snuff, they can amend them and resubmit them quickly. The first test of the new structure is already underway; the board has approved $50 million for clinical-stage projects, and there could be approvals by May. The rolling submissions will theoretically attract for-profit groups that previously didn’t want to get caught in the bureaucracy. “If we’re going to be in the drug development business, the continuum has to be predictable,” says Mills. Businesses will technically receive loans, not grants, but they will only pay CIRM back … Next Page »

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