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Researchers develop cell therapy to improve memory and stop seizures in mice following traumatic brain injury – Newswise

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Newswise Irvine, Calif. November 15, 2019 Researchers from the University of California, Irvine developed a breakthrough cell therapy to improve memory and prevent seizures in mice following traumatic brain injury. The study, titled Transplanted interneurons improve memory precision after traumatic brain injury, was published today in Nature Communications.

Traumatic brain injuries affect 2 million Americans each year and cause cell death and inflammation in the brain. People who experience a head injury often suffer from lifelong memory loss and can develop epilepsy.

In the study, the UCI team transplanted embryonic progenitor cells capable of generating inhibitory interneurons, a specific type of nerve cell that controls the activity of brain circuits, into the brains of mice with traumatic brain injury. They targeted the hippocampus, a brain region responsible for learning and memory.

The researchers discovered that the transplanted neurons migrated into the injury where they formed new connections with the injured brain cells and thrived long term. Within a month after treatment, the mice showed signs of memory improvement, such as being able to tell the difference between a box where they had an unpleasant experience from one where they did not. They were able to do this just as well as mice that never had a brain injury. The cell transplants also prevented the mice from developing epilepsy, which affected more than half of the mice who were not treated with new interneurons.

Inhibitory neurons are critically involved in many aspects of memory, and they are extremely vulnerable to dying after a brain injury, said Robert Hunt, PhD, assistant professor of anatomy and neurobiology at UCI School of Medicine who led the study. While we cannot stop interneurons from dying, it was exciting to find that we can replace them and rebuild their circuits.

This is not the first time Hunt and his team has used interneuron transplantation therapy to restore memory in mice. In 2018, the UCI team used a similar approach, delivered the same way but to newborn mice, to improve memory of mice with a genetic disorder.

Still, this was an exciting advance for the researchers. The idea to regrow neurons that die off after a brain injury is something that neuroscientists have been trying to do for a long time, Hunt said. But often, the transplanted cells dont survive, or they arent able to migrate or develop into functional neurons.

To further test their observations, Hunt and his team silenced the transplanted neurons with a drug, which caused the memory problems to return.

"It was exciting to see the animals memory problems come back after we silenced the transplanted cells, because it showed that the new neurons really were the reason for the memory improvement, said Bingyao Zhu, a junior specialist and first author of the study.

Currently, there are no treatments for people who experience a head injury. If the results in mice can be replicated in humans, it could have a tremendous impact for patients. The next step is to create interneurons from human stem cells.

So far, nobody has been able to convincingly create the same types of interneurons from human pluripotent stem cells, Hunt said. But I think were close to being able to do this.

Jisu Eom, an undergraduate researcher, also contributed to this study. Funding was provided by the National Institutes of Health.

About the UCI School of Medicine: Each year, the UCI School of Medicine educates more than 400 medical students, as well as 200 doctoral and masters students. More than 600 residents and fellows are trained at UC Irvine Medical Center and affiliated institutions. The School of Medicine offers an MD; a dual MD/PhD medical scientist training program; and PhDs and masters degrees in anatomy and neurobiology, biomedical sciences, genetic counseling, epidemiology, environmental health sciences, pathology, pharmacology, physiology and biophysics, and translational sciences. Medical students also may pursue an MD/MBA, an MD/masters in public health, or an MD/masters degree through one of three mission-based programs: the Health Education to Advance Leaders in Integrative Medicine (HEAL-IM), the Leadership Education to Advance Diversity-African, Black and Caribbean (LEAD-ABC), and the Program in Medical Education for the Latino Community (PRIME-LC). The UCI School of Medicine is accredited by the Liaison Committee on Medical Accreditation and ranks among the top 50 nationwide for research. For more information, visit som.uci.edu.

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Researchers develop cell therapy to improve memory and stop seizures in mice following traumatic brain injury - Newswise

ISSCA Conference at University of Miami Attracts Regenerative Medicine Experts and Physicians from across the Globe – PRUnderground

The International Society for Stem Cell Application (ISSCA), in collaboration with SISDET, held a highly successful three-day medical conference on the University of Miami campus on October 24-26. The conference featured a host of international experts in regenerative medicine and introduced new standards in regenerative medicine protocols to those in attendance. The Miami conference is part of the ISSCAs growing commitment to increasing the awareness and practice of regenerative medicine across the globe in an effort to help alleviate suffering for those diagnosed with degenerative diseases.

Around 200 physicians, scientists, and researchers interested in regenerative medicine traveled to the University of Miami campus for the event. The conference focused on providing attendees with information on todays most successful stem cells treatment protocols and the latest advances in regenerative medicine. Attendees heard from more than 20 expert speakers within the stem cells field, with lecturers from Europe, the US, and Latin America on the conference agenda.

This three-day event included recognized keynote speakers, as well as aspiring young physicians discussing the latest advances in stem cell biology in an informal and collaborative setting, said Benito Novas, Vice President of Public Relations for ISSCA. Our goal with all of our events is to strengthen the cooperative and dynamic spirit in this research area. We would also like to thank the University of Miami for hosting this event, as it was a great honor partnering with such a prestigious university.

ISSCA is a global leader in stem cells research, applications, and education, partnering with major global institutions and locations worldwide to host its independent medical congresses. To learn more about the ISSCA and its all of its past and upcoming events, visit http://www.issca.us

About International Society for Stem Cells Applications

The International Society for Stem Cells Applications (ISSCA) is a multidisciplinary community of scientists and physicians, all of whom aspire to treat diseases and lessen human suffering through advances in science, technology, and the practice of regenerative medicine. Incorporated under the Republic of Korea as a non-profit entity, the ISSCA is focused on promoting excellence and standards in the field of regenerative medicine.

ISSCA bridges the gaps between scientists and practitioners in Regenerative Medicine. Their code of ethics emphasizes principles of morals and ethical conducts.

At ISSCA, their vision is to take a leadership position in promoting excellence and setting standards in the regenerative medicine fields of publication, research, education, training, and certification. ISSCA serves its members through advancements made to the specialty of regenerative medicine. They aim to encourage more physicians to practice regenerativemedicine and make it available to benefit patients both nationally and globally.

For more information, please visit https://www.issca.us/ or send an email to info@stemcellsgroup.com

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ISSCA Conference at University of Miami Attracts Regenerative Medicine Experts and Physicians from across the Globe - PRUnderground

How maternal Zika infection results in newborn microcephaly – Baylor College of Medicine News

The current study was initiated when a patient presented with a small brain size at birth and severe abnormalities in brain structures at the Baylor Hopkins Center for Mendelian Genomics (CMG), a center directed by Dr. Jim Lupski, professor of pediatrics, molecular and human genetics at Baylor College of Medicine and attending physician at Texas Childrens Hospital, said Dr. Hugo J. Bellen, professor at Baylor, investigator at the Howard Hughes Medical Institute and Jan and Dan Duncan Neurological Research Institute at Texas Childrens Hospital.

This patient and others in a cohort at CMG had not been infected by Zika virus in utero. They had a genetic defect that caused microcephaly. CMG scientists determined that the ANKLE2 gene was associated with the condition. Interestingly, a few years back the Bellen lab had discovered in the fruit fly model that ANKLE2 gene was associated with neurodevelopmental disorders. Knowing that Zika virus infection in utero can cause microcephaly in newborns, the team explored the possibility that Zika virus was mediating its effects in the brain via ANKLE2.

In a subsequent fruit fly study, the researchers demonstrated that overexpression of Zika protein NS4A causes microcephaly in the flies by inhibiting the function of ANKLE2, a cell cycle regulator that acts by suppressing the activity of VRK1 protein.

Since very little is known about the role of ANKLE2 or VRK1 in brain development, Bellen and his colleagues applied a multidisciplinary approach to tease apart the exact mechanism underlying ANKLE2-associated microcephaly.

The team found that fruit fly larvae with mutations in ANKLE2 gene had small brains with dramatically fewer neuroblasts brain cell precursors and could not survive into adulthood. Experimental expression of the normal human version of ANKLE2 gene in mutant larvae restored all the defects, establishing the loss of Ankle2 function as the underlying cause.

To understand why ANKLE2 mutants have fewer neuroblasts and significantly smaller brains, we probed deeper into asymmetric cell divisions, a fundamental process that produces and maintains neuroblasts, also called neural stem cells, in the developing brains of flies and humans, said first author Dr. Nichole Link, postdoctoral associate in the Bellen lab.

Asymmetric cell division is an exquisitely regulated process by which neuroblasts produce two different cell types. One is a copy of the neuroblast and the other is a cell programmed to become a different type of cell, such as a neuron or glia.

Proper asymmetric distribution and division of these cells is crucial to normal brain development, as they need to generate a correct number of neurons, produce diverse neuronal lineages and replenish the pool of neuroblasts for further rounds of division.

When flies had reduced levels of Ankle2, key proteins, such as Par complex proteins and Miranda, were misplaced in the neuroblasts of Ankle2 larvae. Moreover, live imaging analysis of these neuroblasts showed many obvious signs of defective or incomplete cell divisions. These observations indicated that Ankle2 is a critical regulator of asymmetric cell divisions, said Link.

Further analyses revealed more details about how Ankle2 regulates asymmetric neuroblast division. They found that Ankle2 protein interacts with VRK1 kinases, and that Ankle2 mutants alter this interaction in ways that disrupt asymmetric cell division.

Linking our findings to Zika virusassociated microcephaly, we found that expressing Zika virus protein NS4A in flies caused microcephaly by hijacking the Ankle2/VRK1 regulation of asymmetric neuroblast divisions. This offers an explanation to why the severe microcephaly observed in patients with defects in the ANKLE2 and VRK1 genes is strikingly similar to that of infants with in utero Zika virus infection, Link said.

For decades, researchers have been unsuccessful in finding experimental evidence between defects in asymmetric cell divisions and microcephaly in vertebrate models. The current work makes a giant leap in that direction and provides strong evidence that links a single evolutionarily conserved Ankle2/VRK1 pathway as a regulator of asymmetric division of neuroblasts and microcephaly, Bellen said. Moreover, it shows that irrespective of the nature of the initial triggering event, whether it is a Zika virus infection or congenital mutations, the microcephaly converges on the disruption of Ankle2 and VRK1, making them promising drug targets.

Another important takeaway from this work is that studying a rare disorder (which refers to those resulting from rare disease-causing variations in ANKLE2 or VRK1 genes) originally observed in a single patient can lead to valuable mechanistic insights and open up exciting therapeutic possibilities to solve common human genetic disorders and viral infections.

Others who contributed in this study are Hyunglok Chung, Angad Jolly, Marjorie Withers, Burak Tepe, Benjamin R. Arenkiel, Priya S. Shah, Nevan J. Krogan, Hatip Aydin, Bilgen B. Geckinli, Tulay Tos, Sedat Isikay, Beyhan Tuysuz, Ganesh H. Mochida, Ajay X. Thomas, Robin D. Clark and Ghayda M. Mirzaa. They are affiliated to one or more of the institutions: Baylor College of Medicine, Texas Childrens Hospital and the Jan and Dan Duncan Neurological Research Institute in Houston, TX; University of California at Davis and San Francisco; Zeynep Kamil Maternity and Children's Training and Research Hospital, Istanbul, Turkey; Marmara University School of Medicine, Istanbul, Turkey; Dr. Sami Ulus Research and Training Hospital of Women's and Children's Health and Diseases, Ankara, Turkey; Boston Childrens Hospital; Harvard Medical School, Boston, MA; Massachusetts General Hospital, Boston, MA; Loma Linda University Medical Center, Loma Linda, CA; University of Washington, Seattle, WA; and Seattle Children's Research Institute, Seattle, WA.

The study was funded by the National Institutes of Healths F32NS092270, NIH/NINDS R35NS105078, NIH U54NS093793, NIH R24OD022005, NIH/NINDS K08NS092898, Howard Hughes Medical Institute (HHMI), Medical Research Fellowship, Jordans Guardian Angels, a jointly funded NHGRI and NHLBI grant to the Baylor-Hopkins Center for Mendelian Genomics (UM1 HG006542) and the Huffington Foundation.

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How maternal Zika infection results in newborn microcephaly - Baylor College of Medicine News

Next generation cell and gene therapies: fine tuning the promise – Business Weekly

On 19 November, the UK BioBeat19 summit goes to Stevenage to discuss the potential of cell and gene therapy and how to accelerate these transformational medicines.

Victoria Higgins of GSK and Miranda Weston-Smith from BioBeat spoke to two panellists who gave a sneak peek of their remarks and agree wholeheartedly that the discovery side and clinical side work best when they are teamed up.

Sophie Papa, an oncologist at Guys Cancer at Guys and St Thomas NHS Trust, and Aisha Hasan, a clinical development lead at GSK, both recognise the big challenge ahead for cell therapy researchers: to dial up efficacy and dial down toxicity.

Cell and gene therapies, with their remarkable potential to transform medicine, have seen some important but hard-won milestones: it took 20 years of combined academic and industry research to deliver the first gene therapy approval in 2016 and today there are two CAR-Ts approved for haematological malignancies.

Whilst CAR-Ts recognise proteins expressed on the tumour cell surface, making them ideal for targeting blood cancers, more complicated but with greater potential to address solid tumours are the gene modified TCR-T technologies.

These harness the power of T cells to specifically target and destroy tumours even on the inside of cells. TCR-Ts come with an additional level of complexity, but potentially open the door to a range of untreatable cancer types.

Looking at the TCR opportunity is where Sophie Papa sees the inherent trade-off between risk and benefit as an academic clinician whos now evaluating modified T-cell based therapies in clinical trials.

Sophie urges her peers to take courage. It is important to be brave and tolerant of certain toxicities. Academic clinicians and drug researchers need to work closely together to engage the regulators in early discussion, so that we can move cell therapies earlier in treatment schedules as soon as feasible.

Timing is critical to enable patients to be treated when they are physically fit so they can better tolerate these complex and potentially toxic treatments.

From her perspective, this is not an either/or, but an area where discussion and open dialogue will allow us to make the most of the opportunity. By allowing clinical academics to play a lead role in developing guidelines to manage patient safety, we can address legitimate concerns but not let them stand in the way of clinical development, she says.

Aisha brings the perspective of drug discovery and development and starts by asking what is in the realm of the possible from a design perspective.

She says: A superior T-cell therapy will require engineering approaches that enhance efficacy on one-end while also incorporating switches to minimise toxicity.

For example, in a counter-intuitive way, a T-cell with high-killing capacity actually can create dangerous levels of inflammation in the body, due to the rapid death of cancer cells. But the beauty of drug design opens up options:By building a switch within the engineered T-cells, researchers can inactivate the T-cells and prevent harm to the patient, says Aisha.

But this creative problem solving requires open dialogue between clinicians and pharma. Aisha says: The more we talk about clinical need and toxicity benchmarks, the more sophisticated we can be when developing the next generation of enhanced engineered cell therapies.

Theres no doubt that the challenges of delivering cell and gene therapy span the full spectrum of issues related to medicine development. However, the potential for both curative therapy and commercial opportunity is tremendous.

The scientific, clinical, technical, regulatory and commercial challenges are all surmountable when everyone in the ecosystem work together towards a shared goal, united by an unwavering focus on the patient.

Sophie and Aisha are speaking about the translational journey from science to bedside at the BioBeat19 summit.

The BioBeat19 summit on Accelerating cell and gene therapy, 1-6pm, Tuesday 19 November, GSK Stevenage. Guarantee your place by registering at http://www.biobeat19.org

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Next generation cell and gene therapies: fine tuning the promise - Business Weekly