experimental therapeutics Archives - Amazing Health Advances

Engineered ‘Cat Parasite’ Helps Deliver Drugs to Brain

The AHA! Team — Fri, 01 Nov 2024 05:35:21 +0000

Yulia Karra via Israel21c – Researchers discover method to penetrate the blood-brain barrier and deliver therapeutic proteins via Toxoplasma gondii. Researchers from Tel Aviv University (TAU) recently discovered a method to deliver neurological treatment to the human brain using an engineered version of Toxoplasma gondii, commonly known as “the cat parasite.” One of the biggest challenges in treating neurological diseases is getting the therapeutic drugs through the blood-brain barrier (BBB). “It is very difficult to deliver drugs to the brain via the bloodstream; this is especially true for large molecules such as proteins, the critical ‘machines’ that carry out many important functions inside the cell,” said Prof. Oded Rechavi from TAU’s Department of Neurobiology and Sagol School of Neuroscience, who led the study. The study was conducted in collaboration with Rechavi’s PhD student Shahar Bracha, and Prof. Lilach Sheiner, an Israeli scientist and toxoplasma expert from The University of Glasgow. The findings were recently published in the scientific journal Nature Microbiology. Cat parasite To solve the BBB problem, the research team utilized Toxoplasma gondii, which can infect a vast variety of organisms, including humans, but reproduces only in the guts of cats. It is estimated that a third of the global population is infected by the parasite at some point in their lives. “Most people don’t even feel the infection or only experience mild flu-like symptoms,” added Rechavi. What made the parasite the perfect candidate for the novel study is its ability to penetrate the human brain and survive there in a dormant state, without reproducing. This prompted the team to genetically engineer Toxoplasma gondii to secrete therapeutic proteins. “The parasite has three distinct secretion systems,” explained Rechavi. “One of the systems ‘shoots’ a ‘harpoon’ into the neuron, to enable penetration. Once inside, the parasite forms a kind of cyst in which it continues to secrete proteins permanently. We engineered the parasite’s DNA to make it produce and secrete the proteins we want, which have therapeutic potential.” The methodology As part of the study, the team injected transgenic model animals with the genetically engineered parasite to produce and secrete proteins that travel into cell nuclei. Transgenic animals normally have a foreign gene deliberately inserted into their genome. The scientists then gathered enough evidence to prove that the proteins had been delivered to the target area and remained active in the neurons’ nuclei. The current study focused primarily on a protein called MeCP2, whose deficiency is associated with Rett syndrome, a rare neurological disorder that affects the way the brain develops. Researchers emphasized, however, that the method could prove useful in the treatment of a series of diseases caused by deficiency or abnormal expression of a certain protein. To ensure the method’s safe and effective therapeutic implementation, for both drug delivery and genetic editing, a company named Epeius Pharma, was established in collaboration with Ramot, the technology transfer company of Tel Aviv University, and with the University of Glasgow’s research and innovation services. To read the original article click here.

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Brain Cell Grafts in Monkeys Jump-Start Human Trial for New Parkinson’s Treatment

The AHA! Team — Mon, 28 Oct 2024 05:21:55 +0000

University of Wisconsin–Madison via Newswise – People with Parkinson’s disease are receiving a new treatment in a clinical trial started after University of Wisconsin–Madison scientists demonstrated the safety and feasibility of the therapeutic delivery method in a study of non-human primates. People with Parkinson’s disease are receiving a new treatment in a clinical trial started after University of Wisconsin–Madison scientists demonstrated the safety and feasibility of the therapeutic delivery method in a study of non-human primates. Parkinson’s disease damages neurons in the brain that produce dopamine, a brain chemical that transmits signals between nerve cells. The disrupted signals make it progressively harder to coordinate even simple movements and cause rigidity, slowness and tremors that are the disease’s hallmark symptoms. Patients are typically treated with drugs like L-DOPA to increase dopamine production. Although the drugs help many patients, they present complications and lose their effectiveness over time. Parkinson’s disease damages neurons in the brain that produce dopamine Researchers at the Wisconsin National Primate Research Center successfully grafted brain cells called dopaminergic neuronal progenitor cells into the brains of cynomolgus macaque monkeys. California-based Aspen Neuroscience provided the cells, grown from multiple lines of human induced pluripotent stem cells, along with key pieces of the equipment for delivering them to specific parts of the brain. “By the time of diagnosis, it is common for people with Parkinson’s to have lost the majority of dopaminergic neurons, leading to progressive loss of motor and neurological function,” explains Edward Wirth III, an expert in cell therapies, study co-author and Aspen’s chief medical officer. “To replace these lost cells, we must target a very specific area of the brain with a high degree of surgical precision. Utilizing the latest advances in intraoperative MRI guided techniques, the patient’s new cells are transplanted, a few microliters at a time, to the exact area where they are most needed.” Working with potential cell therapies in pursuing treatments for Parkinson’s disease is a particular specialty of the team at Marina Emborg’s lab and their primate center colleagues. “Using autologous cells, a patient’s own cells, avoids the need to use immunosuppression to keep the patient’s body from rejecting or attacking the graft,” says Emborg, a UW–Madison professor of medical physics. “Aspen has developed the technological methods for manufacturing, for quality control, that makes it feasible at scale to make autologous cells and get them to the patients.” The researchers’ results in non-human primates, which supported Aspen’s successful Investigational New Drug application to the Food and Drug Administration to begin human trials, were published today in the Journal of Neurosurgery. “This study was an important step in our work to bring the promise of a cell-replacement therapy to people with Parkinson’s disease” “This study was an important step in our work to bring the promise of a cell-replacement therapy to people with Parkinson’s disease,” says Andrés Bratt-Leal, study co-author, Aspen Neuroscience co-founder and senior vice-president of research and development. “The results were instrumental in opening our first-in-human trial and informing how we deliver patients’ own cells to them in the study.” The UW–Madison scientists, led by Parkinson’s researcher Emborg, took up the Aspen-funded work fresh off their own success (published in 2021) reversing Parkinson’s symptoms in monkeys by grafting neurons grown from the monkeys’ own cells, called an autologous transplant. The 2021 study, using cells grown by UW–Madison stem cell researcher Su-Chun Zhang, added new dopamine-producing neurons to each animal’s brain through injections guided in real time by MRI to an area of the brain called the putamen. Dopamine production increased dramatically, as did the monkeys’ motor skills. At the same time, symptoms of depression and anxiety were reduced. The new study was designed to test the delivery of Aspen’s human cells. Wirth and Aspen scientists worked with Emborg’s team to bridge the monkey-to-human application. While Emborg’s previous study administered cells to the putamen through the top of the skull, the Aspen study examined cell administration through the back of the skull — an angle that could allow surgeons to reach their target with fewer insertions of the apparatus that delivers the new cells into the brain. “The core idea is to decrease the risk of infection, the trauma, the surgical time the patient spends under anesthesia,” Emborg says. “The fewer tracks you have to follow through the brain, the better for all of that.” Six monkeys received grafts of the human neurons Six monkeys received grafts of the human neurons through two paths in each side, or hemisphere, of their brains, with more cells deposited on one side of the brain than the other. A control group of three animals underwent the procedure without the cell delivery. “In tissue samples taken seven and 30 days after the procedures, we found the grafted cells persisted in five of the animals,” Emborg says. The researchers confirmed the presence of Aspen’s human neurons in the monkeys’ brains, finding more cells in the hemispheres that were injected with a higher dose, more cells in the 30-day tissue samples compared to the seven-day samples and the presence of a protein produced by young neurons working to integrate with neighboring cells — all signs the cells grafts were successful. It was a true collaboration, according to Emborg — between the Aspen scientists, her lab and the Wisconsin National Primate Research Center veterinarians and staff — to validate the company’s procedures and equipment before study co-author Paul Larson, a neurosurgeon at Banner – University Medical Center Tucson and professor of neurosurgery at the University of Arizona College of Medicine – Tucson, began Aspen’s first-in-human trial with people with Parkinson’s in April. The work done to refine the logistics, surgical equipment and techniques in the animal procedures will inform the way patients in the human trial receive and recover from the new therapy, providing hope for those struggling with a debilitating disease. “Our results were all so exciting,” Emborg says. “And then, when I saw they had been able to begin with a human patient this spring, I just had tears in my eyes.” To read the original article click here.

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A Potential New Treatment for Brain Tumors

AHA Publisher — Wed, 28 Sep 2022 07:00:11 +0000

University of Cincinnati via Newswise – A research question posed in Pankaj Desai’s lab has led to a decade of research, a clinical trial and major national funding to further investigate a potential new treatment for the most deadly form of brain tumors. Desai, PhD, and his team at the University of Cincinnati recently received a $1.19 million grant from the National Institutes of Health/National Institute of Neurological Disorders and Stroke to continue research into the use of a drug called letrozole to treat glioblastomas (GBM). Research Progression GBMs are aggressive brain tumors that patients often are unaware of until symptoms emerge and the tumor is substantial. Current treatments include immediate surgery to safely remove as much tumor as possible, radiation and chemotherapy, but the tumor often recurs or becomes resistant to treatments. The average patient survives no more than 15 months after diagnosis. The medication letrozole was approved by the U.S. Food and Drug Administration as a treatment for postmenopausal women with breast cancer in 2001. The drug works by targeting an enzyme called aromatase that is present in breast cancer cells and helps the cancer grow. In the fall of 2012, Desai and a doctoral student in his lab, Nimita Dave (now a senior pharmacologist at a biotech company in Boston), asked a question: Does aromatase play a similar role in GBM tumors, and if so, will letrozole work as an effective treatment? Early research in the lab found the enzyme was present in brain tumor cell lines, and further testing found a very high amount of aromatase at protein and mRNA levels in brain tumor samples from UC’s tumor bank. However, that did not guarantee that letrozole would be similarly effective in brain tumors like it is in breast cancer tumors. Desai explained a defense system called the blood-brain barrier only allows certain compounds into the brain based on their physical and chemical properties. “Otherwise any compound could come into the brain and cause havoc and neurotoxicity,” said Desai, professor and chair of the Pharmaceutical Sciences Division in UC’s James L. Winkle College of Pharmacy and a University of Cincinnati Cancer Center member. “There are other compounds similar to letrozole, but we went with letrozole because we figured that based on its properties, this compound actually has the best chance of getting through into the brain from the blood circulation.” Studies in animal models showed that letrozole was effective, and Desai’s research group moved to test the compound in cells derived from human brain tumor tissues. In this phase of work, key contributions were made by current doctoral student Aniruddha Karve who will continue to work with Desai as a postdoctoral fellow on the new NIH grant. “What we saw in the patient-derived cells is that letrozole is very effective in killing the tumor cells in cell culture models,” Desai said. With funding support from the Cancer Center and the UC Brain Tumor Center, Desai’s team launched a phase 0/1 clinical trial testing what dosage of letrozole is appropriate to treat glioblastomas. This trial was led by Trisha Wise-Draper, MD, PhD, an expert in phase 1 oncology trials with contributions from several other neuro-oncologists and neurosurgeons. The trial is set to be completed soon, but Desai said early results have shown the drug is “unequivocally” reaching its target of the brain tumor tissue safely. Preliminary results also show that doses of letrozole higher than those needed for breast cancer treatment can be safely achieved in GBM patients. New Research While the body of research results has been encouraging so far, Desai said GBMs remain a complicated, aggressive form of brain cancer. As promising as letrozole is, it is still unlikely that the drug will be a singular cure for the disease. “We hope that would work, but it’s not necessarily rooted in reality. It’s going to be a combination of drugs,” Desai said. Supported by the new NIH/NINDS funding, Desai and his team will research the preclinical effectiveness of combining letrozole with other chemotherapy compounds. The three-year grant began Aug. 1. “It’s really exciting to get this sort of reassurance from a peer reviewed grant application,” Desai said. “And it’s an exciting time. I think finding a cure for a disease like GBM is like finding a needle in a haystack, and we hope that it’s going to really work, and that’s what we are all striving for.” Desai said the research has been and continues to be a collaborative effort between UC colleagues from the College of Pharmacy, Cancer Center and Brain Tumor Center. “It’s really a beautiful collaboration, and I’m most grateful for that,” Desai said. “This is a disease where an urgent breakthrough is absolutely needed, and our team along with others in the field are really striving to make a difference.” David Plas, PhD, professor and Anna and Harold W. Huffman endowed chair in glioblastoma experimental therapeutics in the Department of Cancer Biology in UC’s College of Medicine and a Cancer Center member, and his research group are joining the team as the new project launches. Plas said his lab has focused on tumors deficient in a tumor-suppressing protein called PTEN, and the new research may reveal how letrozole in combination with other therapies may lead to a suitable treatment for PTEN-deficient glioblastomas. “This new collaboration will combine my group’s experience in glioblastoma experimental therapeutics with Dr. Desai’s experience in GBM therapeutics and pharmacokinetics,” Plas said. “By investigating possible combinations with letrozole for GBM therapy, this new project has the potential for faster translation to clinical trial. It is exciting to work with Desai on this new project.” To read the original article click here.

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