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
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
“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
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.
First patients receive stem cells to test therapy for macular
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
“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
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
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
The eMERGE network will share its data through the database of Genotypes
and Phenotypes (dbGAP). The database of Genotypes and Phenotypes (dbGaP)