Breaking News
November 16, 2018 - High school students less likely to select milk, fruit for lunch when fruit juice is available
November 16, 2018 - Football coaches with great emotional competence are more successful
November 16, 2018 - Researchers awarded $10 million grant to address root causes of asthma in Puerto Rico
November 16, 2018 - Health Tip: Manage Morning Sickness
November 16, 2018 - Immunotherapy combination and chemotherapy show encouraging results in Phase II acute myeloid leukemia study
November 16, 2018 - ACC Latin America Conference brings experts to discuss latest cardiovascular science
November 16, 2018 - Pooled analysis of Intersect ENT’s steroid releasing implants in patients after frontal sinus surgery to be published
November 16, 2018 - Expectations about pain intensity can become self-fulfilling prophecies
November 16, 2018 - NIH awards $3.4 million to UC researchers to study gastrointestinal lymphatic system
November 16, 2018 - Scientist Dr David Taylor of MR Solutions is a finalist in the BMW i UK Tech Founder Awards
November 16, 2018 - Earlier treatment could help reverse autistic-like behavior in tuberous sclerosis
November 16, 2018 - Vegetables and salad may include bacteria that are resistant to antibiotics
November 16, 2018 - Endocrine Society chooses four Diabetes Caucus leaders as winners of Diabetes Champion Award
November 16, 2018 - Brain and muscle cells found within kidney organoids
November 16, 2018 - Person’s sex hormones may play key role in trauma survival, finds study
November 16, 2018 - PTEN Genetic Test: MedlinePlus Lab Test Information
November 16, 2018 - Toxic metal pollution linked with development of autism spectrum disorder
November 16, 2018 - Calcified nodules in the retina increase risk for progression to late stages of AMD
November 16, 2018 - ZEISS teams up with arivis AG to offer complete 3D imaging solutions
November 16, 2018 - Georgia State professor receives $1.2 million grant to study how the brain controls eating behavior
November 16, 2018 - Specific bacterial toxins reduce number of cells suppressing immune response
November 16, 2018 - Review by ID physician improves outcomes for outpatient parenteral antimicrobial therapy
November 16, 2018 - Conditions that produce signs similar to arthritis
November 16, 2018 - New artificial intelligence-based method predicts treatment effectiveness
November 16, 2018 - AHA: Dapagliflozin Noninferior to Placebo for MACE in T2DM
November 16, 2018 - Surgery remains best treatment for appendicitis, Stanford study finds
November 16, 2018 - Non-surgical fistula creation system Ellipsys becomes key focus of attention at CiDA
November 16, 2018 - Researchers find no link between ‘allergy friendly’ dogs and lower risk of asthma
November 16, 2018 - Researchers elucidate new rules of connectivity of neurons in the neocortex
November 16, 2018 - Treating children with ‘bubble baby disease’
November 16, 2018 - Nexus announces availability of Arsenic Trioxide Injection in the US
November 16, 2018 - Researchers find metabolite shuttle between cells in the liver that may combat tissue fibrosis
November 16, 2018 - AHA: PTSD Common Among Those Who Suffer Tear in the Aorta’s Wall
November 16, 2018 - Many RA patients’ pain related to central nervous system
November 16, 2018 - Changes in Himalayan gut microbiomes linked to diet
November 16, 2018 - Inhibition of prostaglandin E2 enhances ability to combat infectious colitis
November 16, 2018 - Chronic dry eye can slow reading rate and disrupt day to day tasks
November 16, 2018 - Researchers develop new drug molecule that inhibits inflammation
November 16, 2018 - Dementia symptoms peak in winter and spring, study finds
November 16, 2018 - Stanford tobacco researcher weighs in on JUUL
November 16, 2018 - Increasing omega-3 fatty acid intake during pregnancy reduces risk of premature birth, review finds
November 16, 2018 - Researchers find no link between infants waking up at night and later developmental problems
November 16, 2018 - Both parents and children agree about confidential medical services
November 16, 2018 - FDA warns against use of unapproved pain medications with implanted pumps
November 16, 2018 - Precision medicine-based approach to slow or reverse biologic drivers of Alzheimer’s disease
November 16, 2018 - Study provides new insight into norovirus outbreaks, may help guide efforts to develop vaccines
November 16, 2018 - Inexpensive, portable air purifier could help protect the heart from pollution
November 16, 2018 - New 15-minute scan could help diagnose brain damage in babies up to two years old
November 16, 2018 - Deep brain stimulation not effective for treating early Alzheimer’s
November 16, 2018 - Traditional chemotherapy superior to new alternative for oropharyngeal cancers | News Center
November 16, 2018 - What This Pond Protist Does With Its Genome Will Astound You
November 15, 2018 - Researchers develop tool that speeds up analysis and publication of biomedical data
November 15, 2018 - Scientists identify mechanism used by lung cancer cells to obtain glucose
November 15, 2018 - Abnormalities in development of the brain could be involved in onset of autism, finds new study
November 15, 2018 - Soy protein equally effective as animal protein in building muscle strength
November 15, 2018 - American Academy of Pediatrics, Nov. 2-6
November 15, 2018 - Dopamine drives early addiction to heroin
November 15, 2018 - Variance in gut microbiome in Himalayan populations linked to dietary lifestyle | News Center
November 15, 2018 - Reducing Cardiovascular Disease: The Amish Way
November 15, 2018 - King’s researchers launch charter to guide organizations to engage abuse survivors in research
November 15, 2018 - Enable Injections enters into development agreements with UCB and Apellis Pharmaceuticals
November 15, 2018 - TGen North collaborates with NARBHA Institute to advance human health
November 15, 2018 - Researchers discover molecular basis for therapeutic actions of an African folk medicine
November 15, 2018 - Human Cell Atlas study of early pregnancy shows how mother’s immune system is modified
November 15, 2018 - New guidelines for detecting and managing sarcopenia to be launched in the UK
November 15, 2018 - Researchers explore role of dietary composition on energy expenditure
November 15, 2018 - Elsevier launches Entellect™ Platform, unlocking value by creating AI-ready life sciences data
November 15, 2018 - Now that cannabis is legal in Canada, let’s use it to tackle the opioid crisis
November 15, 2018 - In the Spotlight: At the intersection of tech, health, and ethics
November 15, 2018 - Traditional Glaucoma Test Can Miss Severity of the Disease
November 15, 2018 - Researchers directly connect activities of genes with instinctive behavior in male cichlids
November 15, 2018 - Salk researchers report new methods to identify AD drug candidates with anti-aging properties
November 15, 2018 - St. Jude Hospital announces availability of largest collections of leukemia samples
November 15, 2018 - Attenua Announces First Patient Treated in Phase 2 Clinical Trial in Chronic Cough with Bradanicline
November 15, 2018 - Designing a novel cell-permeable peptide chimera to promote wound healing
November 15, 2018 - NEI investigators combine two imaging modalities to view the retina in unprecedented detail
November 15, 2018 - Determining how hearts develop to better understand congenital heart defects
November 15, 2018 - Maverick immune cells can act independently to identify and kill cancer cells, finds research
November 15, 2018 - Advanced AI and big data methods to tackle dementia
November 15, 2018 - Report reveals increase in pancreatic cancer death rates across Europe
First step toward CRISPR cure of Lou Gehrig’s disease

First step toward CRISPR cure of Lou Gehrig’s disease

image_pdfDownload PDFimage_print
The UC Berkeley team used an adeno-associated virus (AAV) to ferry genes for CRISPR-Cas9 into motor neurons to delay onset of symptoms of ALS in mice. Credit: David Schaffer graphic

University of California, Berkeley scientists have for the first time used CRISPR-Cas9 gene editing to disable a defective gene that causes amyotrophic lateral sclerosis, or Lou Gehrig’s disease, in mice, extending their lifespan by 25 percent.

The therapy delayed the onset of the muscle wasting that characterizes the disease, which results in progressive weakness and eventually proves fatal when the muscles that control breathing fail.

This step toward a CRISPR cure for human ALS will be reported Dec. 20 in the journal Science Advances.

The mice were genetically engineered to express a mutated human gene that in humans causes about 20 percent of all inherited forms of the disease and about 2 percent of all cases of ALS worldwide. Though the genetic cause is not known for all cases of ALS, all are accompanied by the premature death of motor neurons in the brain stem and spinal cord. The neurons allow the brain to control muscles, so loss of this connection means loss of muscle control.

“Being able to rescue motor neurons and motor neuron control over muscle function, especially the diaphragm, is critically important to being able to not only save patients, but also maintain their quality of life,” said senior author David Schaffer, a professor of chemical and biomolecular engineering and director of the Berkeley Stem Cell Center.

The devastating disease usually strikes people between the ages of 40 and 70. An estimated 20,000 Americans are afflicted, and there are no treatments to slow the muscle degeneration.

The UC Berkeley research team used a virus that Schaffer’s team engineered to seek out only motor neurons in the spinal cord and deliver a gene encoding the Cas9 protein into the nucleus. There, the gene was translated into the Cas9 protein, a molecular scissors that cut and disabled the mutant gene responsible for ALS.

In this case, Cas9 was programmed to knock out the mutated gene SOD1 (superoxide dismutase 1. The onset or start of the disease was delayed by almost five weeks, and mice treated by the gene therapy lived about a month longer than the typical four-month lifespan of mice with ALS. Healthy mice can live a couple of years.

The researchers found that, at death, the only surviving motor neuron cells in the mice were those that had been “infected” with the virus and contained Cas9 protein, said Thomas Gaj, a postdoctoral fellow who led the study, now at the University of Illinois at Urbana-Champaign.

“The treatment did not make the ALS mice normal and it is not yet a cure,” Schaffer cautioned. “But based upon what I think is a really strong proof of concept, CRISPR-Cas9 could be a therapeutic molecule for ALS. When we do additional optimization of the delivery to get CRISPR-Cas9 into an even higher percentage of cells, we think we are going to see even better increases in lifespan.”

One of several challenges is to eliminate the SOD1 mutation in other brain and spinal cord cells that support motor neurons. Schaffer’s team is designing a version of the virus – a highly modified adeno-associated virus, or AAV – that will deliver the Cas9 gene to two types of glial cells, astrocytes and oligodendrocytes, that appear to take out neighboring motor neurons, effectively a “bystander effect.”

“I tend to be really cautious, but in this case I would be quite optimistic that if we are able to eliminate SOD1 within not just the neurons but also the astrocytes and supporting glia, I think we are going to see really long extensions of lifespan,” he said.

Schaffer also is working on a self-destruct switch for the Cas9 protein, so that once it knocks out the SOD1 gene, the Cas9 can be eliminated from the cell so as not to accidentally modify other genes or trigger an immune reaction.

Schaffer has been working with the AAV virus for nearly 20 years, evolving it to target specific cells, like motor neurons, without infecting other types of cells. AAV is found in many if not all humans and primates, and appears to be benign.

“We have engineered new AAV vehicles that are capable of high-efficiency delivery to a number of cell and tissue targets in the body, and when CRISPR-Cas9 came along, we viewed it as a wonderful opportunity to put together this incredibly powerful cargo with the ability to carry that cargo to a number of cells and disease targets in vivo,” he said.

A modified AAV is likely to be approved soon by the Food and Drug Administration as a delivery vehicle for a gene therapy against a rare disease called Leber congenital amaurosis type 2, and other therapies delivered by AAV are in the pipeline, Schaffer said.

These therapies are currently based on natural versions of AAV, however, which are not optimized for high-efficiency delivery to most therapeutically important cell targets, so clinicians must either use massive doses or apply the AAV using an invasive surgery. Schaffer has developed technology to engineer viruses for targeted delivery to many cells and tissues following simple routes of administration, for example directly into tissue such as the eye and brain. This led him to cofound a company in 2014, 4D Molecular Therapeutics, to optimize AAV to target any tissue and carry a variety of gene therapies into cells.

“Researchers in the field really know we need better vectors that can target cells through a simple, logical route of administration, and can do so in a very, very efficient way,” he said. “Ours do.”


Explore further:
Researchers devise improved gene-editing process for Duchenne muscular dystrophy

More information:
T. Gaj el al., “In vivo genome editing improves motor function and extends survival in a mouse model of ALS,” Science Advances (2017). advances.sciencemag.org/content/3/12/eaar3952

Journal reference:
Science Advances

Provided by:
University of California – Berkeley

Tagged with:

About author

Related Articles