Saudi researchers identify gene associated with juvenile ALS

Researchers from the Kingdom of Saudi Arabia have identified a mutation on the SIGMAR1 gene associated with the development of juvenile amyotrophic lateral sclerosis (ALS). Study findings published 12 August 2011 in Annals of Neurology, a journal of the American Neurological Association and the Child Neurology Society, show the gene variant affects Sigma-1 receptors which are involved in motor neuron function and disease development.

ALS, also referred to as Lou Gehrig’s disease, is a progressive neurodegenerative disorder that attacks brain and spinal cord nerve cells (neurons) responsible for controlling voluntary muscle movement. The degeneration of upper and lower motor neurons gradually weakens the muscles they control, leading to paralysis and eventual death from respiratory failure.

Studies report an annual incidence of 1- 3 per 100,000 individuals, with 90% of cases not having a family history of the disease (sporadic ALS). In the remaining 10% of cases there is more than one affected family member (familial ALS). Juvenile ALS – characterised by age of onset below 25 years – is a rare and sporadic disorder, making it difficult to determine incidence rates. One of the more prominent juvenile ALS patients is renowned physicist, Professor Stephen Hawking, who was diagnosed at the age of 21.

Previous research found that mutation of the superoxide dismutase 1 (SOD1) gene accounts for 20% of familial and 5% of sporadic ALS cases; gene mutations of ALS2 and SETX have been reported in juvenile ALS cases. The present study led by Dr Amr Al-Saif from the King Faisal Specialist Hospital and Research Center in Riyadh, KSA performed genetic testing on four patients from an ALS family who were diagnosed with juvenile ALS to investigate mutations suspected in disease development.

Researchers performed gene mapping on the DNA of study participants and used direct sequencing to detect the genetic variant. The team identified a shared homozygosity region in affected individuals and gene sequencing of SIGMAR1 revealed a mutation affecting the encoded protein, Sigma-1 receptor. Those cells with the mutant protein were less resistant to programmed cell death (apoptosis) induced by stress to the endoplasmic reticulum.

“Prior evidence has established that Sigma-1 receptors have neuroprotective properties and animal models with this gene inactivated have displayed motor deficiency,” explains Dr Al-Saif. “Our findings emphasise the important role of Sigma-1 receptors in motor neuron function and disease. Further exploration is warranted to uncover potential therapeutic targets for ALS.”


Researchers show direct conversion of non-heart cell into heart cell

For the past decade, researchers have tried to reprogram the identity of all kinds of cell types. Heart cells are one of the most sought-after cells in regenerative medicine because researchers anticipate that they may help to repair injured hearts by replacing lost tissue.

Now, researchers at the Perelman School of Medicine at the University of Pennsylvania are the first to demonstrate the direct conversion of a non-heart cell type into a heart cell by RNA transfer.

Working on the idea that the signature of a cell is defined messenger RNAs (mRNAs), which contain the chemical blueprint for how to make a protein, the investigators changed two different cell types, an astrocyte (a star-shaped brain cell) and a fibroblast (a skin cell), into a heart cell, using mRNAs.

James Eberwine, PhD, the Elmer Holmes Bobst Professor of Pharmacology, Tae Kyung Kim, PhD, post-doctoral fellow, and colleagues report their findings in the Proceedings of the National Academy of Sciences.

“What’s new about this approach for heart-cell generation is that we directly converted one cell type to another using RNA, without an intermediate step,” explained Eberwine.

The scientists put an excess of heart cell mRNAs into either astrocytes or fibroblasts using lipid-mediated transfection, and the host cell does the rest. These RNA populations (through translation or by modulation of the expression of other RNAs) direct DNA in the host nucleus to change the cell’s RNA populations to that of the destination cell type (heart cell, or tCardiomyocyte), which in turn changes the phenotype of the host cell into the destination cell.

The method the group used, called Transcriptome Induced Phenotype Remodeling, or TIPeR, is distinct from the induced pluripotent stem cell (iPS) approach used by many labs in that host cells do not have to be dedifferentiated to a pluripotent state and then redifferentiated with growth factors to the destination cell type.

TIPeR is more similar to prior nuclear transfer work in which the nucleus of one cell is transferred into another cell where upon the transferred nucleus then directs the cell to change its phenotype based upon the RNAs that are made. The tCardiomyocyte work follows directly from earlier work from the Eberwine lab, where neurons were converted into tAstrocytes using the TIPeR process.

While TIPeR-generated tCardiomyocytes are of significant use in fundamental science it is easy to envision their potential use to screen for heart cell therapeutics, say the study authors. What’s more, creation of tCardiomyoctes from patients would permit personalised screening for efficacy of drug treatments; screening of new drugs; and potentially as a cellular therapeutic. doi:10.1073/pnas.1101223108

New more efficient way discovered to generate induced pluripotent stem cells

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).

The researchers used fibroblast cells, which are easily obtained from skin biopsies, and could be used to generate patientspecific 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 patientspecific 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 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.

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. doi:10.1016/j.stem.2011.03.001

First patients receive stem cells to test therapy for macular degeneration

The first patients are undergoing dosing as part of a two phase (1 & 2) clinical trial for Stargardt’s macular dystrophy and dry age-related macular degeneration (dry AMD) using retinal pigment epithelial (RPE) cells derived from human embryonic stem cells (hESCs).

“The dosing of the first patients represents an important milestone for ACT and opens the doors to a potentially significant new therapeutic approach to treating the many forms of macular degeneration,” said Gary Rabin, interim chairman and chief executive officer of ACT (Advanced Cell Technology), the biotech company behind the development of these regenerative cells.

“One patient in each clinical trial, the Stargardt's trial and the dry AMD trial, has undergone surgical transplantation of a relatively small dose (50,000 cells) of fullydifferentiated retinal pigment epithelial (RPE) cells derived from human embryonic stem cells. Early indications are that the patients tolerated the surgical procedures well. The primary objective of these Phase 1/2 studies is to assess the safety and tolerability of these stem cell-derived transplants,” explained Steven Schwartz, MD, Ahmanson Professor of Ophthalmology at the David Geffen School of Medicine at UCLA and retina division chief at UCLA’s Jules Stein Eye Institute. Dr Schwartz is the studies’ principal investigator.

Dry AMD, the most common form of macular degeneration, Stargardt’s and other forms of atrophy-related macular degeneration are usually untreatable.

Safe and effective therapies are greatly needed for the treatment of these common forms of blindness. Disease progression of both Stargardt’s and dry AMD includes thinning of the layer of RPE cells in the patient's macula, the central portion of the retina and the anatomic location of central vision. With RPE cell death comes the loss of macular photoreceptors and loss of central vision. Currently both conditions are untreatable and often lead to legal blindness over a multi-year course. ACT’s Stargardt’s and dry AMD therapies treat these conditions by transplanting RPE cells in the patient’s eyes before the RPE population is lost.

Robert Lanza, MD, chief scientific officer of ACT, remarked: “13 years after the discovery of human embryonic stem cells – the great promise of these cells is finally being put to the test. The initiation of these two clinical trials marks an important turning point for the field. While we will continue writing research papers and carrying out more research, it's time to start moving these exciting new stem cell therapies out of the laboratory and into the clinic. Tens of thousands of people continue to die every day from diseases that could potentially be treated using stem cells.”

Scientists to study how genes regulate platelet function

Johns Hopkins scientists have launched a pioneering 5-year research programme to create, for the first time, human platelet cells from stem cells in order to study inherited blood clotting abnormalities ranging from clots that cause heart attacks and stroke to bleeding disorders.

One goal of the research is to increase understanding of how genes regulate the function of platelets. The researchers will also investigate how genetic variations can affect a person’s responsiveness to aspirin and other medications that are designed to prevent clotting, in order to find new ways to prevent and treat abnormal clotting.

The other key aspect of the research will be to develop the technical capacity to produce large numbers of blood platelets from a single individual’s blood sample.

“We will work to develop a completely new approach to generating blood cells for people who are desperately in need of chronic infusions,” says Lewis Becker, MD, professor of medicine and cardiologist at the Johns Hopkins University School of Medicine, who is the co-principal investigator of the study, called Functional Genomics of Platelet Aggregation Using iPS and Derived Megakaryocites.

Tailored treatment based on genomic information closer with eMERGE

In the United States, researchers in the Electronic Medical Records and Genomics (eMERGE) network will receive US$25 million over the next four years to demonstrate that patients’ genomic information linked to disease characteristics and symptoms in their electronic medical records can be used to improve their care. The grants are from the US National Human Genome Research Institute (NHGRI), part of the US National Institutes of Health (NIH).

“Our goal is to connect genomic information to high quality data in electronic medical records during the clinical care of patients. This will help us identify the genetic contributions to disease,” said NHGRI Director Eric D. Green, MD, PhD. “We can then equip healthcare workers everywhere with the information and tools that they need to apply genomic knowledge to patient care.”

The first phase of eMERGE, which wrapped up in July this year, demonstrated that data about disease characteristics in electronic medical records and patient's genetic information can be used in large genetic studies. So far, the eMERGE network has identified genetic variants associated with dementia, cataracts, highdensity lipoprotein (HDL) cholesterol, peripheral arterial disease, white blood cell count, type 2 diabetes and cardiac conduction defects.

In the next phase, investigators will identify genetic variants associated with 40 more disease characteristics and symptoms, using genome-wide association studies across the entire eMERGE network. DNA from about 32,000 participants will be analyzed in each study.

eMERGE researchers will then use the genomic information in clinical care. With patient consent, researchers may use information about genetic variants involved in drug response to adjust patient medications. In addition, eMERGE researchers who discover patients harboring genetic variants associated with diseases such as diabetes or cardiovascular disease will intervene to prevent, diagnose and/or treat such diseases.

The eMERGE network will share its data through the database of Genotypes and Phenotypes (dbGAP). The database of Genotypes and Phenotypes (dbGaP)

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