Breaking News
March 24, 2019 - Combined immunosuppression may be effective, safe in treating older patients with Crohn’s disease
March 24, 2019 - GSK sells health drinks arm, buys US cancer treatment firm
March 24, 2019 - Bacteria and innate immune factors in birth canal, cervix may be key to predicting preterm births
March 24, 2019 - IgG antibodies play unexpected role in atherosclerosis
March 24, 2019 - Sounds and vibrations are quite similar for the brain, finds new study
March 24, 2019 - Practices for Reducing COPD Hospital Readmissions Explored
March 24, 2019 - Could an eye doctor diagnose Alzheimer’s before you have symptoms?
March 24, 2019 - Enzyme inhibitor stops inflammation and neurodevelopmental disorders in mouse models
March 24, 2019 - Walk, Dance, Clean: Even a Little Activity Helps You Live Longer
March 24, 2019 - Americans used less eye care in 2014 versus 2008
March 24, 2019 - Study finds link between depression in 20s linked to memory loss in 50s
March 24, 2019 - New tool helps physiotherapy students to master complex fine motor skills
March 24, 2019 - The AMR Centre secures £2.3m funding boost
March 24, 2019 - Study examines effects of taking ondansetron during first trimester of pregnancy
March 24, 2019 - Researchers identify a more effective treatment for cancer
March 24, 2019 - Open-source solution for multiparametric optical mapping of the heart’s electrical activity
March 24, 2019 - New nanotechnology approach shows promise in treating triple negative breast cancer
March 24, 2019 - Trevena Announces Publication of APOLLO-1 Results in The Journal of Pain Research Highlighting Oliceridine’s Potential for Management of Moderate-to-Severe Acute Pain
March 24, 2019 - Maternal deaths following C-section 50 times higher in Africa compared to high-income countries
March 24, 2019 - Apple watch could detect irregular heart beat says study
March 24, 2019 - Queen Mary University of London’s BCI boosts radionuclide imaging capabilities with MILabs VECTor technology
March 24, 2019 - Girls should be encouraged to gain more ball skills, shows study
March 24, 2019 - Acute doses of synthetic cannabinoid can impair critical thinking and memory
March 24, 2019 - Presence of bacteria in urine does not always point to infection, shows study
March 24, 2019 - Scientists identify a new role for nerve-supporting cells
March 24, 2019 - Hidden differences between pathology of CTE and Alzheimer’s disease discovered
March 24, 2019 - Knowing causative genes of osteoporosis may open door to more effective treatments
March 24, 2019 - Toilet-seat based cardiovascular monitoring system getting ready to begin commercialization
March 24, 2019 - New model for intensive care identifies factors that send ill patients to ICU
March 24, 2019 - Recommendations Issued for HSCT in Multiple Myeloma
March 24, 2019 - Deep brain stimulation provides sustained relief for severe depression
March 24, 2019 - “Statistical significance” may soon be a thing of past?
March 24, 2019 - Researchers track effects of epigenetic marks carried by sperm chromosomes
March 24, 2019 - AHA News: Family Adopts Three Children With Three Different Heart Conditions
March 24, 2019 - Research into opioid painkillers could provide clues for safer drug development
March 23, 2019 - Lung cancer survivor recounts her lifetime struggles
March 23, 2019 - Radial and femoral approach for PCI achieve similar results in terms of survival
March 23, 2019 - Study sheds light on the optimal timing of coronary angiography in NSTEMI patients
March 23, 2019 - Excess hormones could cause a condition that can lead to blindness in women, study finds
March 23, 2019 - Dramatic shifts in first-time opioid prescriptions bring hope, concern
March 23, 2019 - Antidepressant drugs may not work when neurons are out of shape
March 23, 2019 - TTUHSC El Paso to establish endowed chair in neurology through a major grant
March 23, 2019 - New device approved by FDA for treating patients with moderate-to-severe heart failure
March 23, 2019 - People with peripheral artery disease have lower Omega-3 Index, shows research
March 23, 2019 - Trigger warnings have minimal impact on how people respond to content, shows research
March 23, 2019 - Gilead Announces Data From Two Studies Supporting Further Development of GS-6207, a Novel, Investigational HIV-1 Capsid Inhibitor as a Component of Future Long-Acting HIV Therapies
March 23, 2019 - Selfish genetic elements amplify inflammation and age-related diseases
March 23, 2019 - Study provides new understanding of how the brain recovers from damage caused by stroke
March 23, 2019 - CRISPR/Cas libraries could revolutionize drug discovery
March 23, 2019 - Allergic reaction during pregnancy may alter sexual-development in offspring’s brain
March 23, 2019 - Seeing through a robot’s eyes helps those with profound motor impairments
March 23, 2019 - Recent research shows that ease of breastfeeding after C-section differs culturally
March 23, 2019 - Newly discovered parameters offer more control over efficient release of drugs
March 23, 2019 - ‘De-tabooing’ of abortion- Women would like more support from health care community
March 23, 2019 - Anti-TB drugs can increase susceptibility to Mtb reinfection
March 23, 2019 - New survey indicates need of attention to neglected tropical diseases
March 23, 2019 - Innovative in vitro method to develop easy-to-swallow medicine for children and older people
March 23, 2019 - Sugary drinks could raise risk of early deaths finds study
March 23, 2019 - Lian wins ENGINE grant for stem-cell-based therapy to treat Type 1 diabetes
March 23, 2019 - Overall, Physicians Are Happy and Enjoy Their Lives
March 23, 2019 - Researchers discover how blood vessels protect the brain during inflammation
March 23, 2019 - CDC study shows modest improvement in optimal hospital breastfeeding policy
March 23, 2019 - Family-based prevention program to reduce alcohol use among older teens
March 23, 2019 - Remote monitoring of implanted defibrillators in heart failure patients prevents hospitalizations
March 23, 2019 - Appropriate doffing of personal protective equipment may reduce healthcare worker contamination
March 23, 2019 - Window screens can suppress mosquito populations, reduce malaria in Tanzania
March 23, 2019 - Researchers discover new biomarker for postoperative liver dysfunction
March 23, 2019 - Pregnancy history may be linked to cognitive function in older women, finds study
March 23, 2019 - Study shows ticagrelor is equally safe and effective as clopidogrel after heart attack
March 23, 2019 - FDA Approves First Drug for Postpartum Depression, Zulresso (brexanolone)
March 23, 2019 - New guidelines outline new treatment management for psoriasis
March 23, 2019 - Thermally abused cooking oil may promote progression of breast cancer
March 23, 2019 - High-fructose corn syrup fuels growth of colon tumors in mice
March 23, 2019 - Partnership aims at establishing best practices to promote diversity in clinical trials
March 23, 2019 - New study examines presence of microbes in tap water from residences, office buildings
March 23, 2019 - Early life trauma may affect brain structure, contribute to major depressive disorder
March 23, 2019 - NIH starts clinical trial of drug to treat cravings associated with opioid use disorder
March 23, 2019 - Cervix bacteria, immune factors could be a warning signal of premature birth, reports new research
March 23, 2019 - Worst-ever emergency care performance figures underscore the need to focus on staffing
March 23, 2019 - The Current issue of “The view from here” is concerned with Cancer
Gene therapy shown to remove core component of Parkinson’s disease

Gene therapy shown to remove core component of Parkinson’s disease

image_pdfDownload PDFimage_print
Photomicrograph of regions of substantia nigra in a Parkinson’s patient showing Lewy bodies and Lewy neurites in various magnifications. Top panels show a 60-times magnification of the alpha synuclein intraneuronal inclusions aggregated to form Lewy bodies. The bottom panels are 20 × magnification images that show strand-like Lewy neurites and rounded Lewy bodies of various sizes. Neuromelanin laden cells of the substantia nigra are visible in the background. Stains used: mouse monoclonal alpha-synuclein antibody; counterstained with Mayer’s haematoxylin. Crdit: Suraj Rajan

An international team led by Rush researcher Jeffrey Kordower, Ph.D., has moved a step closer to developing a treatment to clear brain cells of a protein that is an integral cause of Parkinson’s disease. The team published the findings of their study in the Aug. 22 issue of Nature Parkinson’s Disease.

Parkinson’s disease is a chronic, progressive movement disorder that affects the body’s ability to control movement. The condition is a result of damage to brain cells that produce dopamine, a chemical that relays messages to the parts of the brain that control movement, resulting in trembling, stiffness, slow movement and poor balance and coordination.

Working with rats induced with a simulation of Parkinson’s disease, Kordower’s team showed that a genetically engineered fragment of an antibody—called a nanobody—cleared away toxic clumps of the protein alpha-synuclein after the team injected the nanobody into the rats’ brains.

The hope is that once this therapy is introduced, it will continue to keep brain cells clear of the alpha-synuclein for the rest of the person’s life, said Kordower, a professor in Rush Medical College’s Department of Neurological Sciences, where he also is director of the Section of Neurobiology.

Fixing cells from within

Alpha-synuclein, abbreviated as α-syn, occurs naturally in the brain and elsewhere in the body. In neurological disorders, however, the protein clusters in misfolded (abnormally clumped together) and disordered forms. In Parkinson’s disease—known as PD for short—malformed α-syn accumulates in distinctive formations called Lewy bodies, which is considered an integral part of PD.

“We’re looking for ways to reduce alpha-synuclein levels, accumulation and toxicity resulting from the spread of alpha-synuclein around the nervous system,” Kordower said.

The treatment his team is testing is part of a rapidly evolving approach that deploys therapeutic nanobodies to invade cells as part of genetically-altered viruses. In this study, once inside the cell, the nanobody appears to have stopped the clumping of the dysfunctional α-syn that leads to a loss of nerve cells and, eventually, full-blown PD. Stopping the clumping should prevent the progression of the disease.

This study is the first to use nanobodies for PD. Some previous research has shown promise with clearing α-syn in areas outside the cells, but Kordower believes an intracellular approach could be even more effective, because the amount of α-syn within cells is more plentiful than the amount outside them. “If you reduce intracellular levels, chances are that the a-synuclein won’t get extracellular, so it won’t spread,” Kordower elaborated.

Letting PESTs inside

His team created an “overexpression” (overabundance) of α-syn in the test rats’ brains. They then tested two types of the gene therapy, each on a different group of rats, and used saline in a control group, to see if the nanobodies could clear away the clutter inside those cells. The nanobodies were custom-made for the study by the University of North Carolina Vector Core.

One of the treatments, VH14*PEST, clearly worked best. It improved dopamine levels and reduced motor-function symptoms significantly better than the saline given the control group. VH14*PEST measurably improved the symptoms by one measure, the stepping test, and somewhat by another measure called the cylinder test.

VH14*PEST accomplished these results by reducing the levels of an amino acid in α-syn called Serine-129 that had undergone a chemical reaction called phosphorylation (the addition of a phosphate). Amino acids are the building blocks of proteins, and Serine-129 is a normal component of α-syn, but phosphorylated Serine-129 causes the deformities in α-syn that are seen in PD.

“The decrease in serine 129 phospho synuclein demonstrates the success of the nanobodies in reducing pathological alpha synuclein in the brain,” Kordower said.

The second nanobody the team tried, NbSyn87*PEST, was effective, but less so overall, and had side effects like increased inflammation. PEST refers to a sequence of the amino acids proline, aspartate or glutamate, serine and threonine, which targets proteasomes – combinations of proteins that work to break down unneeded or damaged proteins. This PEST sequence has been found to be an effective intervention against disordered proteins such as the excessive α-syn found in Parkinson’s.

‘Humanizing’ a PEST

Given the promising results of the VH14*PEST treatment, Kordower and his team plan to pursue it further. First, though, the group has to fully “humanize” the compound it used in the rat model. That is, they have to make it safe for people.

“Then we have to repeat these studies, in rats, with the humanized version to make sure it is as effective as the ones we’ve been testing,” which were compatible with a rodent’s physiology, Kodower explained. Only then can the team consider using the therapy in clinical trials in humans.

Down the road, this nanobody treatment could have implications for other parts of the brain as well, including the cortex, where misfolded α-syn may cause dementia, Kordower added.


Explore further:
Study identifies chaperone protein implicated in Parkinson’s disease

More information:
Diptaman Chatterjee et al. Proteasome-targeted nanobodies alleviate pathology and functional decline in an α-synuclein-based Parkinson’s disease model, npj Parkinson’s Disease (2018). DOI: 10.1038/s41531-018-0062-4

Provided by:
Rush University Medical Center

Tagged with:

About author

Related Articles