Research Roundup: Gene Therapy for Deafness, Autism Genes, Breakthroughs in Parkinson’s and ALS, and More

row of test tubes with dropper depositing pink liquid

There are plenty of great scientific research stories out this week. Here’s a look at just a few of them.

Gene Therapy Cures Deafness

Researchers with the Institut Pasteur and several other institutions restored the hearing in adult mice with a specific congenital form of deafness using gene therapy. Researchers with Institut Pasteur, University of Florida, University of California, San Francisco (UCSF), Columbia University Medical Center, College de France, Sorbonne University and the University of Clermont Auvergne published their research in the Proceedings of the National Academy of Sciences.

The mice had DFNB9 deafness. Individuals with this type of deafness are profoundly deaf. The gene coding for otoferlin does not function, and this protein is required for transmitting sound data at the auditory sensory cell synapses. They injected the gene into the cochlea of the mice, restoring auditory synapse function and hearing thresholds to a near-normal level.

The authors wrote, “Here, we used a mouse model of DFNB9, a human deafness form accounting for 2-8 percent of all cases of congenital genetic deafness. We show that local gene therapy in the mutant mice not only prevents deafness when administered to immature hearing organs, but also durably restores hearing when administered at a mature stage, raising hopes for future gene therapy trials in DFNB9 patients.”

Autism Risk Gene Variants Identified

Although autism has been around for a very long time, it was first diagnosed as such in 1938. Numerous factors have been associated with autism, and genetics plays a significant role. Researchers with the Danish iPSYCH project and Broad Institute identified the first common genetic risk variants for autism. They published the findings in the journal Nature Genetics.

“When we look at autism, there is a heredity factor of up to 80 percent, so genes have a great deal of impact overall,” stated Mark Daily from the Broad Institute and Institute for Molecular Medicine Finland, one of the leading scientists in the study. “Nevertheless, despite many years of work, identifying precisely which genes are involved has been challenging.”

The team compared the genome of 20,415 people with autism and 174,280 control subjects. They identified five different genetic variants that increase the risk of autism. All five play important roles for the development of the brain, especially of the cerebral cortex.

Potential New Treatment for Parkinson’s Disease

Researchers funded by Parkinson’s UK with support from The Cure Parkinson’s Trust and in association with the North Bristol NHS Trust conducted a clinical trial evaluating whether increasing levels of Glial Cell Line-Derived Neurotrophic Factor (GDNF) can regenerate the brain cells that are dying in Parkinson’s patients and reverse that condition. The results of the open-label extension study were published in the Journal of Parkinson’s Disease. The researchers were with the University of Bristol, North Bristol NHS Trust, Med Genesis Therapeutix, Renishaw, Cardiff University, and the University of British Columbia.

GDNF is a naturally-occurring growth factor. Six patients took part in the initial pilot study, then another 35 patients participated in a nine-month double-blind trial. Half were randomly assigned to receive infusions of GDNF once a month. The other half were infused with placebo. After the nine-month trial wrapped, an open-label extension trial was initiated, evaluating the effects and safety of continued exposure to GDNF for another 40 weeks. The delivery system involved a specially designed implant, which allowed high flow rate infusions to be given every four weeks and also allowed Convection Enhanced Delivery (CED) of the drug.

After nine months, patients receiving the placebo had no change. However, in the same period, the patients who received GDNF showed a 100-percent improvement in a key area of the brain affected by the disease. After 18 months, all patients who received GDNF showed moderate to large improvements in symptoms.

“The spatial and relative magnitude of the improvement in the brain scans is beyond anything seen previously in trials of surgically delivered growth-factor treatments for Parkinson’s,” stated Alan L. Whone, principal investigator with the University of Bristol. “This represents some of the most compelling evidence yet that we may have a means to possibly reawaken and restore the dopamine brain cells that are gradually destroyed in Parkinson’s.”

Understanding How Chromosome Size Affects Inheritance

DNA and proteins are organized into chromosomes inside cells. They come in varying sizes. Researchers with New York University recently identified a mechanism that determines how short chromosomes accurately secure genetic exchange. The research was published in the journal Nature Communications.

“Short chromosomes are at a higher risk for errors that can lead to genetic afflictions because of their innate short lengths and therefore have less material for genetic exchange,” stated Viji Subramanian, a post-doctoral researcher at NYU and the paper’s lead author. “However, these chromosomes acquire extra help to create a high density of genetic exchanges—but it hadn’t been understood as to how short chromosomes receive this assistance.”

Essentially, they found that large regions at the ends of both short and long chromosomes are primed for high density of genetic exchanges. These zones are called end-adjacent regions (EARs). A high density of genetic exchanges in EARs are conserved in several organisms, including humans and birds. The EARS are about the same size in all chromosomes. As a result, EARS only take up a small amount of a large chromosome, but a large amount of a small chromosome. It essentially gives all chromosomes an even playing field for genetic exchange regardless of chromosome size.

Machine Learning Leads to Better Childhood Arthritis Diagnoses

A team of researchers with the University of Toronto developed a machine learning algorithm that can more effectively diagnose childhood arthritis. This is particularly important because children sometimes grow out of the disease. More accurately diagnosing which type they have could spare some from treatments with drugs that may have serious side effects. The research was published in the journal PLOS Medicine.

About 300,000 children in the U.S. have been diagnosed with arthritis. “The final stage of treatment is very effective in some children, but also very expensive, and it’s not clear what the long-term effects are,” stated Quaid Morris, a professor of computational science at the University of Toronto. “When you are inhibiting the function of the immune system, this type of treatment can be associated with potential side-effects including increased risk of infection and others.”

The algorithm classified patients into seven distinct groups based on patterns of swollen or painful joints. It also accurately predicted which patients would go into remission quicker and which would go on to develop a more severe type of arthritis.

Rae Yeung, professor of Pediatrics, Immunology and Medical Science at the U of T, stated, “Knowing which children will benefit from which treatment at which time is really the cornerstone of personalized medicine and the question doctors and families want answered when children are first diagnosed.”

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Researchers “Bait” Abnormal Protein Implicated in ALS and Frontotemporal Dementia

A specific protein, TDP-43, when it “misbehaves,” is implicated in 97 percent of amyotrophic lateral sclerosis (ALS) cases and 45 percent of frontotemporal dementia cases. TDP-43 is also found in 80 percent of chronic traumatic encephalopathy and 60 percent of Alzheimer’s diseases. Researchers with the University of Pittsburgh have developed a method to “trap” TDP-43 so it doesn’t create toxic clumps that cause neurodegeneration. The research was published in the journal Neuron.

“The problem is the vast majority of patients with neurodegenerative disorders do not have specific mutations,” stated senior author Christopher Donnelly, assistant professor of neurobiology and science director of the LiveLikeLou Center for ALS Research at the University of Pittsburgh Brain Institute. “Instead of targeting the gene that causes disease in a subset of patients, we’re targeting the proteins that clump in nearly all of them. That’s never been done before.”

The researchers reproduced TDP-43 in cultured human cells, then developed a method that uses light pulses to “push” the proteins into clumps. They note this was so effective that they could watch the cells die as it happened. But they found it only worked when the TDP-43 RNA binding partners were missing. These lock with the TDP-43 protein and prevent it from forming clumps. Donnelly notes that it’s what protects normal cells against toxic TDP-43 buildup. They then created TDP-43-targeting oligonucleotides that mimic the action of the RNA binding partners, called “bait-oligonucleotides.”

This approach prevented the clumping. It’s a long way from Petri dishes to human beings, with many steps between, including animal studies. However, there is already one drug that uses a similar mechanism on the market for spinal muscular atrophy and two more currently in clinical trials for ALS.

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