Neurotoxicity of chemotherapy drugs / triggers changes in ion channels on dorsal root ganglia and dorsal horn neurons

Contact: Meng Zhao eic@nrren.org 86-138-049-98773 Neural Regeneration Research

Chemotherapy is one of the primary treatments for cancer. However, one of the most disturbing findings of recent studies of cancer survivors is the apparent prevalence of chemotherapy-associated adverse neurological effects, including vascular complications, seizures, mood disorders, cognitive dysfunctions, and peripheral neuropathies. In addition, chemotherapy triggers changes in ion channels on dorsal root ganglia and dorsal horn neurons that generate secondary changes resulting in neuropathic pains. Although a number of protective agents have been developed, their effects are not satisfactory. Chemotherapy drugs can cause changes in hippocampal neurogenesis and plasticity. A review reported in the Neural Regeneration Research (Vol. 8, No. 17, 2013) focuses on chemotherapy-induced neurodegeneration and hippocampal dysfunctions and related mechanisms as measured by in vivo and in vitro approaches, which is helpful in determining how best to further explore the causal mechanisms of chemotherapy-induced neurological side effects and in providing direction for the future development of novel optimized chemotherapeutic agents.

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Article: “Neurotoxicity of cancer chemotherapy,” by Miyoung Yang1, 2, Changjong Moon1 (1 Department of Veterinary Anatomy, College of Veterinary Medicine and Animal Medical Institute, Chonnam National University, Gwangju 500-757, Republic of Korea; 2 Department of Physiology and Neuroscience Program, Michigan State University, East Lansing, MI 48824, USA)

Yang MY, Moon CJ. Neurotoxicity of cancer chemotherapy. Neural Regen Res. 2013;8(17):1606-1614.

Contact:

Meng Zhao eic@nrren.org 86-138-049-98773 Neural Regeneration Research http://www.nrronline.org/

Full text: http://www.sjzsyj.org:8080/Jweb_sjzs/CN/article/downloadArticleFile.do?attachType=PDF&id=629

UAB researchers cure type 1 diabetes in dogs

Contact: Octavi López Coronado octavi.lopez@uab.cat 34935813301 Universitat Autonoma de Barcelona

Introducing a ‘glucose sensor’ by gene therapy eliminates the symptoms of the disease

Researchers from the Universitat Autònoma de Barcelona (UAB), led by Fàtima Bosch, have shown for the first time that it is possible to cure diabetes in large animals with a single session of gene therapy. As published this week in Diabetes, the principal journal for research on the disease, after a single gene therapy session, the dogs recover their health and no longer show symptoms of the disease. In some cases, monitoring continued for over four years, with no recurrence of symptoms.

The therapy is minimally invasive. It consists of a single session of various injections in the animal’s rear legs using simple needles that are commonly used in cosmetic treatments. These injections introduce gene therapy vectors, with a dual objective: to express the insulin gene, on the one hand, and that of glucokinase, on the other. Glucokinase is an enzyme that regulates the uptake of glucose from the blood. When both genes act simultaneously they function as a “glucose sensor”, which automatically regulates the uptake of glucose from the blood, thus reducing diabetic hyperglycemia (the excess of blood sugar associated with the disease).

As Fàtima Bosch, the head researcher, points out, “this study is the first to demonstrate a long-term cure for diabetes in a large animal model using gene therapy.”

This same research group had already tested this type of therapy on mice, but the excellent results obtained for the first time with large animals lays the foundations for the clinical translation of this gene therapy approach to veterinary medicine and eventually to diabetic patients.

The study was led by the head of the UAB’s Centre for Animal Biotechnology and Gene Therapy (CBATEG) Fàtima Bosch, and involved the Department of Biochemistry and Molecular Biology of the UAB, the Department of Medicine and Animal Surgery of the UAB, the Faculty of Veterinary Science of the UAB, the Department of Animal Health and Anatomy of the UAB, the Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), the Children’s Hospital of Philadelphia (USA) and the Howard Hughes Medical Institute of Philadelphia (USA).

A safe and efficacious gene therapy

The study provides ample data showing the safety of gene therapy mediated by adeno-associated vectors (AAV) in diabetic dogs. The therapy has proved to be safe and efficacious: it is based on the transfer of two genes to the muscle of adult animals using a new generation of very safe vectors known as adeno-associated vectors. These vectors, derived from non-pathogenic viruses, are widely used in gene therapy and have been successful in treating several diseases.

In fact, the first gene therapy medicine ever approved by the European Medicines Agency, named Glybera®, makes use of adeno-associated vectors to treat a metabolic disease caused by a deficiency of lipoprotein lipase and the resulting accumulation of triglycerides in the blood.

Long-term control of the disease

Dogs treated with a single administration of gene therapy showed good glucose control at all times, both when fasting and when fed, improving on that of dogs given daily insulin injections, and with no episodes of hypoglycemia, even after exercise. Furthermore, the dogs treated with adeno-associated vectors improved their body weight and had not developed secondary complications four years after the treatment.

The study is the first to report optimal long-term control of diabetes in large animals. This had never before been achieved with any other innovative therapies for diabetes. The study is also the first to report that a single administration of genes to diabetic dogs is able to maintain normoglycemia over the long term (more than 4 years). As well as achieving normoglycemia, the dogs had normal levels of glycosylated proteins and developed no secondary complications of diabetes after more than 4 years with the disease.

Application in diabetic patients

There have been multiple clinical trials in which AAV vectors have been introduced into skeletal muscle, so the strategy reported in this study is feasible for clinical translation. Future safety and efficacy studies will provide the bases for initiating a clinical veterinary trial of diabetes treatment for companion animals, which will supply key information for eventual trials with humans. In conclusion, this study paves the way for the clinical translation of this approach to gene therapy to veterinary medicine, and eventually to diabetic patients.

Diabetes mellitus

Diabetes mellitus is the most common metabolic disease, and a large number of patients need insulin treatment to survive. In spite of the use of insulin injections to control the disease, these patients often develop serious secondary complications like blindness, kidney damage or amputation of limbs. Moreover, in order to achieve good blood glucose control, insulin has to be injected two or three times a day, which brings a risk of hypoglycemia episodes (lowering of blood sugar): an additional problem that comes on top of the other hardships of the treatment.

Man’s best friend: Common canine virus may lead to new vaccines for deadly human diseases

Public Affairs News Service

Tuesday, Nov. 27, 2012

Writer: James  E.  Hataway, 706/542-5222, jhataway@uga.edu Contact: Biao He, 706/542-2855, bhe@uga.edu

Athens, Ga. – Researchers at the University of Georgia have discovered that a virus commonly found in dogs may serve as the foundation for the next great breakthrough in human vaccine development.

Although harmless in humans, parainfluenza virus 5, or PIV5, is thought to contribute to upper respiratory infections in dogs, and it is a common target for canine vaccines designed to prevent kennel cough. In a paper published recently in PLOS ONE, researchers describe how this virus could be used in humans to protect against diseases that have eluded vaccine efforts for decades.

“We can use this virus as a vector for all kinds of pathogens that are difficult to vaccinate against,” said Biao He, the study’s principal investigator and professor of infectious diseases in UGA’s College of Veterinary Medicine. “We have developed a very strong H5N1 flu vaccine with this technique, but we are also working on vaccines for HIV, tuberculosis and malaria.”

PIV5 does not cause disease in humans, as our immune system is able to recognize and destroy it. By placing antigens from other viruses or parasites inside PIV5, it effectively becomes a delivery vehicle that exposes the human immune system to important pathogens and allows it to create the antibodies that will protect against future infection.

This approach not only ensures full exposure to the vaccine but also is much safer because it does not require the use of attenuated, or weakened, pathogens. For example, an HIV vaccine delivered by PIV5 would contain only those parts of the HIV virus necessary to create immunity, making it impossible to contract the disease from the vaccine.

“Safety is always our number one concern,” said He, who is also a Georgia Research Alliance distinguished investigator and member of the Faculty of Infectious Diseases. “PIV5 makes it much easier to vaccinate without having to use live pathogens.”

Using viruses as a delivery mechanism for vaccines is not a new technique, but previous efforts have been fraught with difficulty. If humans or animals already possess a strong immunity to the virus used for delivery, the vaccine is unlikely to work, as it will be destroyed by the immune system too quickly.

“Pre-existing immunity to viruses is the main reason most of these vaccines fail,” He said.

But in this latest study, He and his colleagues demonstrate that immunity to PIV5 does not limit its effectiveness as a vaccine delivery mechanism, even though many animals-including humans- already carry antibodies against it.

In their experiments, the researchers found that a single dose inoculation using PIV5 protected mice from the influenza strain that causes seasonal flu. Another single dose experimental vaccine also protected mice from the highly pathogenic and deadly H5N1 virus commonly known as bird flu.

This recent work is a culmination of more than fifteen years of research and experimentation with the PIV5 virus, and He has confidence that it will serve as an excellent foundation for vaccines to treat diseases in both animals and humans.

“I believe we have the best H5N1 vaccine candidate in existence,” He said. “But we have also opened up a big field for a host of new vaccines.”

UGA Faculty of Infectious Diseases The University of Georgia Faculty of Infectious Diseases was created in 2007 to address existing and emerging infectious disease threats more effectively by integrating multidisciplinary research in animal, human and ecosystem health. Researchers from across the university focus on epidemiology, host-pathogen interactions, the evolution of infectious diseases, disease surveillance and predictors and the development of countermeasures such as vaccines, therapeutics and diagnostics. For more information about the Faculty of Infectious Diseases, see fid.ovpr.uga.edu.

UGA College of Veterinary Medicine The UGA College of Veterinary Medicine, founded in 1946, is dedicated to training future veterinarians, to conducting research related to animal and human diseases, and to providing veterinary services for animals and their owners. Research efforts are aimed at enhancing the quality of life for animals and people, improving the productivity of poultry and livestock, and preserving a healthy interface between wildlife and people in the environment they share. The college enrolls 102 students each fall out of more than 800 who apply.

Mushroom-Derived Compound Lengthens Survival in Dogs With Cancer, Study Suggests: Yunzhi mushroom

ScienceDaily (Sep. 10, 2012) — Dogs with hemangiosarcoma that were treated with a compound derived from the Coriolus versicolor mushroom had the longest survival times ever reported for dogs with the disease. These promising findings offer hope that the compound may one day offer cancer patients — human and canine alike — a viable alternative or complementary treatment to traditional chemotherapies.

The study was conducted by two University of Pennsylvania School of Veterinary Medicine faculty. Dorothy Cimino Brown is professor and chair of the Department of Clinical Studies and director of the Veterinary Clinical Investigation Center. Jennifer Reetz is an attending radiologist in the Department of Clinical Studies. They published their findings in an open-access article in the journal Evidence-Based Complementary and Alternative Medicine.

The Coriolus versicolor mushroom, known commonly as the Yunzhi mushroom, has been used in traditional Chinese medicine for more than 2,000 years. The compound in the mushroom that is believed to have immune-boosting properties is polysaccharopeptide, or PSP. In the last two decades, some studies have suggested that PSP also has a tumor-fighting effect.

“There have been a series of studies looking at groups of people with cancer,” Cimino Brown said. “The issue with those studies is that they weren’t necessarily measuring what most people would think is the most clinically important result, which is, do people taking PSP live longer?”

To address this critical question, Cimino Brown and Reetz pursued a study in dogs with naturally occurring hemangiosarcoma, an aggressive, invasive cancer that arises from the blood cells and typically affects the spleen. It commonly strikes golden retrievers and German shepherds.

Fifteen dogs that had been diagnosed with hemangiosarcoma participated in the trial. Divided into three groups of five, each group received a different dose — 25, 50 or 100 mg/kg/day — of I’m-Yunity, a formulation of PSP that has been tested for consistency and good manufacturing processes.

The owners were instructed to give their dog capsules of I’m-Yunity, compounded by Penn pharmacists, daily. Each month, the owners brought their dogs to Penn’s Ryan Veterinary Hospital for follow-up visits. There, the researchers took blood samples and conducted ultrasounds to determine the extent that tumors developed or grew and spread in the dogs’ bodies.

Based on the ultimate endpoints — how quickly the tumors progressed and how long the dogs actually lived — the results of the researchers’ trial suggest that the I’m-Yunity was effectively fighting the tumors.

“We were shocked,” Cimino Brown said. “Prior to this, the longest reported median survival time of dogs with hemangiosarcoma of the spleen that underwent no further treatment was 86 days. We had dogs that lived beyond a year with nothing other than this mushroom as treatment.”

There were not statistically significant differences in survival between the three dosage groups, though the median survival time was highest in the 100 mg group, at 199 days, eclipsing the previously reported median survival time.

The results were so surprising, in fact, that the researchers asked Penn Vet pathologists to recheck the dogs’ tissue biopsies to make sure that the dogs really had the disease.

“They reread the samples and said, yes, it’s really hemangiosarcoma,” Cimino Brown said.

Chemotherapy is available for treating hemangiosarcoma, but many owners opt not to pursue that treatment once their dog is diagnosed.

“It doesn’t hugely increase survival, it’s expensive and it means a lot of back and forth to the vet for the dog,” Cimino Brown said. “So you have to figure in quality of life.”

While I’m-Yunity is not inexpensive, if proven effective, it would offer owners a way of extending their pet’s life without regular trips to the vet. As an added benefit, Cimino Brown and Reetz have found no evidence of adverse effects from the PSP treatment.

The researchers are now getting ready to pursue further trials of I’m-Yunity in dogs with hemangiosarcoma to confirm and refine their results. One trial will compare I’m-Yunity to a placebo for those owners who opt not to pursue chemotherapy in their pet and another will compare the compound to standard-of-care chemotherapy.

Depending on those results, veterinarians could eventually prescribe the compound for treating hemangiosarcoma, and perhaps other cancers, in dogs. The company that manufacturers I’m-Yunity may also pursue large-scale clinical trials in humans.

“Although hemangiosarcoma is a very sad and devastating disease,” Cimino Brown said, “in the long term, if we prove that this works, this treatment can be a really nice alternative for owners to have increased quality time with their pet at the end of its life.”

The study was funded by a grant from Chinese Medicine Holdings LTD