ACT Files European Clinical Trial Application For Phase 1/2 Study Using Embryonic Stem Cells To Treat Macular Degeneration

Advanced Cell Technology, Inc. ("ACT"; OTCBB: ACTC), a leader in the field of regenerative medicine, announced today that it has filed a clinical trial application (CTA) with the European Medicines and Healthcare products Regulatory Agency (MHRA) seeking clearance to initiate its Phase 1/2 clinical trial using retinal pigment epithelial (RPE) cells derived from human embryonic stem cells (hESCs) to treat patients with Stargardt's Macular Dystrophy (SMD).

"With this filing, our initiatives in Europe are really starting to gain momentum," said Gary Rabin, interim chairman and CEO of ACT. "Through data from this proposed trial, and the two trials we are preparing to commence in the United States, we are eagerly anticipating beginning to assess the capabilities of our RPE cells to repair and regenerate the retina. As in the US, we also intend to file in Europe for clinical trials involving Dry Age-Related Macular Degeneration (Dry AMD) and other degenerative diseases of the retina, concurrently targeting the two largest pharmaceutical markets in the world."

The proposed clinical trial will be a prospective, open-label study that is designed to determine the safety and tolerability of the RPE cells following sub-retinal transplantation to patients with advanced SMD, similar to the FDA-cleared U.S. trial which is set to commence in the first half of this year. During the CTA review process, which requires a minimum of 60 days, the reviewers decide if an applicant is permitted to proceed with its proposed clinical trial. Additional information may be requested from the applicant, which could extend the review period.

"We are very excited about this European filing, because our preclinical data from various animal models with hESC-derived RPE cells have been tremendously encouraging," said Robert Lanza, M.D., chief scientific officer at ACT. "In rats we have seen 100 percent improvement in visual performance over untreated animals without any adverse effects. Near-normal function was also achieved in a mouse model of Stargardt's disease."

In 2010, the US Food and Drug Administration (FDA) granted Orphan Drug designation for ACT's RPE cells for treating SMD, and earlier this year the company received a positive opinion from the Committee for Orphan Medicinal Products (COMP) of the European Medicines Agency (EMA) towards designation of this product as an orphan medicinal product for the treatment of Stargardt's disease. ACT anticipates adoption of the EMA's recommendation by the European Commission in coming weeks.

About Stargardt's Macular Dystrophy and Degenerative Diseases of the Retina

Stargardt's Macular Dystrophy (SMD) is one of the most common forms of macular degeneration in the world. SMD causes progressive vision loss, usually starting in children between 10 to 20 years of age. Eventually, blindness results from photoreceptor loss associated with degeneration in the pigmented layer of the retina, called the retinal pigment epithelium or RPE cell layer.

Degenerative diseases of the retina are among the most common causes of untreatable blindness in the world. As many as thirty million people in the United States and Europe suffer from macular degeneration, which represents a $25-30 billion worldwide market that has yet to be effectively addressed. Approximately 10% of people ages 66 to 74 will have symptoms of macular degeneration, the vast majority the "dry" form of AMD which is currently untreatable. The prevalence increases to 30% in patients 75 to 85 years of age.

Source: Advanced Cell Technology, Inc

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Study Of Umbilical Cord Blood-Derived Stem Cells For Lupus Therapy

Main Category: Lupus
Also Included In: Stem Cell Research
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Human umbilical cord blood-derived mensenchymal stem cells (uMSCs) have been found to offer benefits for treating lupus nephritis (LN) when transplanted into mouse models of systemic lupus erythematosus (SLE). SLE is an autoimmune disease with "myriad immune system aberrations" characterized by diverse clinical conditions, including LN, a leading cause of morbidity and mortality for patients with SLE.

The beneficial results were reported in a study by Taiwanese researchers published in the current issue of Cell Transplantation (20:2), freely available on-line here.

According to corresponding author Dr. Oscar K. Lee of the National Yang-Ming University School of Medicine, MSCs have been shown to possess immune-modulatory capabilities and can alleviate immune responses by inhibiting inflammation as well as the function of mature and immature immune system T cells. Seeking to explore the therapeutic effects of uMSCs in treating LN, their study transplanted umbilical cord blood-derived stem cells into mice modeled with systemic immune diseases closely resembling SLE in humans.

"We found that uMSC transplantation markedly delayed the deterioration of renal function, reduced certain antibody levels, alleviated changes in renal pathology and the development of proteinuria - the presence of excess protein serum in the urine and a sign of renal damage," said Dr. Lee.

The positive difference in survival rate for mice treated at two months of age compared with mice treated at six months of age, led the researchers to conclude that early uMSC transplantation may be most efficacious. The researchers also deduced that their findings favored the use of allogenic (other-donated) rather than autologous (self-donated) MSCs for SLE treatment, which would make sense with an autoimmune disorder.

"The therapeutic effects demonstrated in this pre-clinical study support further exploration of the possibility of using uMSCs from mismatched donors in LN treatment," concluded Dr. Lee.

"The ability of uMSCs to reduce inflammation means that they are likely to be of use in the treatment of autoimmune disorders and this study supports that reasoning and, in this case, also advocates the use of non-self cells," said Dr. David Eve, associate editor of Cell Transplantation and an instructor at the University of South Florida Center of Excellence for Aging and Brain Repair.

Citation:
Chang, J-W.; Hung , S-P.; Wu, H-H.; Wu, W-M.; Yang, A-H.; Tsai, H-L.; Yang, L-Y.; Lee, O. K. Therapeutic Effects of Umbilical Cord Blood-Derived Mesenchymal Stem Cell Transplantation in Experimental Lupus Nephritis. Cell Transplant. 20(2):245-257; 2011.

Source:
David Eve
Cell Transplantation Center of Excellence for Aging and Brain Repair

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To Reprogram Stem Cells Penn Study Eliminates The Use Of Transcription Factors And Increases Efficiency 100-Fold

Researchers at the University of Pennsylvania School of Medicine have devised a totally new and far more efficient way of generating induced pluripotent stem cells (iPSCs), immature cells that are able to develop into several different types of cells or tissues in the body. The researchers used fibroblast cells, which are easily obtained from skin biopsies, and could be used to generate patient-specific iPSCs for drug screening and tissue regeneration.

iPSCs are typically generated from adult non-reproductive cells by expressing four different genes called transcription factors. The generation of iPSCs was first reported in 2006 by Shinya Yamanaka, and multiple groups have since reported the ability to generate these cells using some variations on the same four transcription factors.

The promise of this line of research is to one day efficiently generate patient-specific stem cells in order to study human disease as well as create a cellular "storehouse" to regenerate a person's own cells, for example heart or liver cells. Despite this promise, generation of iPSCs is hampered by low efficiency, especially when using human cells.

"It's a game changer," says Edward Morrisey, PhD, professor in the Departments of Medicine and Cell and Developmental Biology and Scientific Director at the Penn Institute for Regenerative Medicine. "This is the first time we've been able to make induced pluripotent stem cells without the four transcription factors and increase the efficiency by 100-fold." Morrisey led the study published this week in Cell Stem Cell.

"Generating induced pluripotent stem cells efficiently is paramount for their potential therapeutic use," noted James Kiley, PhD, director of the National Heart, Lung, and Blood Institute's Division of Lung Diseases. "This novel study is an important step forward in that direction and it will also advance research on stem cell biology in general."

Before this procedure, which uses microRNAs instead of the four key transcription factor genes, for every 100,000 adult cells re-programmed, researchers were able to get a small handful of iPSCs, usually less than 20. Using the microRNA-mediated method, they have been able to generate approximately 10,000 induced pluripotent stem cells from every 100,000 adult human cells that they start with. MicroRNAs (miRNAs) are short RNA molecules that bind to complementary sequences on messenger RNAs to silence gene expression.

The Morrisey lab discovered this new approach through studies focusing on the role of microRNAs in lung development. This lab was working on a microRNA cluster called miR302/367, which plays an important role in lung endoderm progenitor development. This same microRNA cluster was reported to be expressed at high levels in embryonic stem cells, and iPSCs and microRNAs have been shown to alter cell phenotypes.

The investigators performed a simple experiment and expressed the microRNAs in mouse fibroblasts and were surprised to observe colonies that looked just like iPSCs. "We were very surprised that this worked the very first time we did the experiment," says Morrisey. "We were also surprised that it worked much more efficiently than the transcription factor approach pioneered by Dr. Yamanaka."

Since microRNAs act as repressors of protein expression, it seems likely that they repress the repressors of the four transcription factors and other factors important for maintaining the pluripotent-stem-cell state. However, exactly how the miRNAs work differently compared to the transcription factors in creating iPSCs will require further investigation.

The iPSCs generated by the microRNA method in the Morrisey lab are able to generate most, if not all, tissues in the developing mouse, including germ cells, eggs and sperm. The group is currently working with several collaborators to redifferentiate these iPSCs into cardiomyocytes, hematopoietic cells, and liver hepatocytes.

"We think this method will be very valuable in generating iPSCs from patient samples in a high-throughput manner" says Morrisey. microRNAs can also be introduced into cells using synthetically generated versions of miRNAs called mimics or precursors. These mimics can be easily introduced into cells at high levels, which should allow for a non-genetic method for efficiently generating iPSCs.

"The upshot is that we hope to be able to produce synthetic microRNAs to transform adult cells into induced pluripotent stem cells, which could eventually then be redifferentiated into other cell types, for example, liver, heart muscle or nerve cells" says Morrisey.

Other authors of the study include Frederick Anokye-Danso, Chinmay M. Trivedi, and Jonathan A. Epstein, all from Penn. These studies were funded by the National Heart, Lung and Blood Institute Progenitor Cell Biology Consortium and Division of Lung Disease and the American Heart Association Jon DeHaan Myogenesis Center Award.

Source:
Karen Kreeger
University of Pennsylvania School of Medicine

 

Brain Cells Recreated From Skin Cells To Study Schizophrenia Safely

Main Category: Schizophrenia
Also Included In: Autism;  Bipolar;  Stem Cell Research
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A team of scientists at Penn State University, the Salk Institute for Biological Studies, and other institutions have developed a method for recreating a schizophrenic patient's own brain cells, which then can be studied safely and effectively in a Petri dish. The method brings researchers a step closer to understanding the biological underpinnings of schizophrenia. The method also is expected to be used to study other mysterious diseases such as autism and bipolar disorder, and the researchers hope that it will open the door to personalized medicine - customized treatments for individual sufferers of a disease based on genetic and cellular information. The study will be published in a future edition of the journal Nature and will be posted on the journal's advance online website on 13 April 2011.

Gong Chen, an associate professor of biology at Penn State and one of the study's authors, explained that the team first took samples of skin cells from schizophrenic patients. Then, using molecular-biology techniques, they reprogrammed these original skin cells to become unspecialized or undifferentiated stem cells called induced pluripotent stem cells (iPSCs). "A pluripotent stem cell is a kind of blank slate," Chen explained. "During development, such stem cells differentiate into many diverse, specialized cell types, such as a muscle cell, a brain cell, or a blood cell."

After generating iPSCs from skin cells, the authors cultured them to become brain cells, or neurons. They then compared the neurons derived from schizophrenic patients to the neurons created from the iPSCs of healthy individuals. They found that the neurons generated from schizophrenic patients were, in fact, distinct: compared with healthy neurons, they made fewer connections with each other. Kristen Brennand, a Salk researcher and one of the study's authors, then administered a number of frequently prescribed antipsychotic medications to test the drugs' ability to improve how neurons communicate with neighboring cells. "Now, for the very first time, we have a model system that allows us to study how antipsychotic drugs work in live, genetically identical neurons from patients with known clinical outcomes, and we can start correlating pharmacological effects with symptoms," Brennand said.

Chen, who contributed to the study by using electrophysiology techniques to test the function of the iPSC-derived neurons, described the new method as "patient specific," offering a step toward personalized medicine for sufferers of schizophrenia and potentially other diseases. "What's so exciting about this approach is that we can examine patient-derived neurons that are perhaps equivalent to a particular patient's own neural cells," Chen said. "Obviously, we don't want to remove someone's brain cells to experiment on, so recreating the patient's brain cells in a Petri dish is the next best thing for research purposes. Using this method, we can figure out how a particular drug will affect that particular patient's brain cells, without needing the patient to try the drug, and potentially, to suffer the side effects. The patient can be his or her own guinea pig for the design of his or her own treatment, without having to be experimented on directly."

Lead author Fred Gage, a professor at Salk's Laboratory of Genetics and holder of the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Diseases, explained that schizophrenia exemplifies many of the research challenges posed by complex psychiatric disorders. "This model not only affords us the opportunity to look at live neurons from schizophrenia patients and healthy individuals to understand more about the disease mechanism, but also it allows us to screen for drugs that may be effective in reversing it," Gage said.

Schizophrenia, which is defined by a combination of paranoid delusions, auditory hallucinations, and diminished cognitive function, afflicts one percent of the population worldwide, corresponding to nearly three million people in the United States alone. Genetic evidence indicates that many different combinations of genetic lesions - some of them affecting the susceptibility to environmental influences - may lead to a variety of signs and symptoms collectively labeled schizophrenia.

"Nobody knows how much the environment contributes to the disease," said Brennand. "By growing neurons in a dish, we can take the environment out of the equation and start focusing on the underlying biological problems." In another part of the study, Brennand used a modified rabies virus, developed by Salk professors Edward Callaway and John Young, to highlight the connections between neurons. The viral tracer made it apparent that the schizophrenic neurons connected less frequently with each other and had fewer projections growing out from their cell bodies. In addition, gene-expression profiles identified almost 600 genes whose activity was misregulated in these neurons; 25 percent of those genes had been implicated in schizophrenia before.

Gage added that, for many years, mental illness has been thought of as a strictly social or environmental disease. "Many people believed that if affected individuals just worked through their problems, they could overcome them," he said. "But we are showing real biological dysfunctions in neurons that are independent of the environment."

Notes:

In addition to Gage, Brennand, and Chen, other researchers who contributed to the study include Anthony Simone, Jessica Jou, Chelsea Gelboin-Burkhart, Ngoc Tran, Sarah Sangar, Yan Li, Yanglin Mu and Diana Yu in the Gage Laboratory; Shane McCarthy at the Cold Spring Harbor Laboratory in New York; and Jonathan Sebat at the University of California at San Diego.

The work was funded, in part, by the California Institute for Regenerative Medicine, the Lookout Foundation, the Mathers Foundation, and the Helmsley Foundation.

Source:
Barbara Kennedy
Penn State

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