Monthly Archives: March 2021

Bluebird Bio is tamping down cancer concerns regarding a gene therapy approach to preventthe sickling of blood cells (above).

By Jocelyn KaiserMar. 10, 2021 , 3:00 PM

Gene therapy researchers are breathing easier after a company reported today that the modified virus it used to treat sickle cell disease in a person who later developed leukemia was very unlikely to have caused the cancer.

The leukemia case, which Bluebird Bio disclosed on 16 February, led the company to halt its two sickle cell disease trials and suspend sales of a similar treatment for beta-thalassemia. The following week, the U.S. Food and Drug Administration (FDA) put a hold on the companys two sickle cell disease trials and two beta-thalassemia trials.

But the company has now done various lab tests and found important evidence demonstrating that it is very unlikely our BB305 lentiviral vector played a role in this case, said Chief Scientific Officer Philip Gregory in a press release. The company is now in discussions with FDA about lifting the trial hold.

The studies use a modified virus called a lentivirus to insert a curative gene into the chromosomes of patients blood stem cells. About 2 decades ago, a different viral vector was tested to treat the blood stem cells of patients with an inherited immune disorder, and several later developed leukemia as a result.

This did not happen in the sickle cell trial, Bluebird suggests. The company had reported on 25 February that the patients leukemia cells had mutations and other changes in some known leukemia genes, suggesting these changeswhich are typical in leukemiacontributed to the cancer.

That didnt completely rule out a role for the lentiviral vector, which the company had said earlier inserted its DNA into the patients leukemia cells. But today the company reports that the gene where that DNA landed, VAMP4, plays no known role in cancer. Moreover, the DNA inserted into VAMP4 did not turn on or off any nearby genes, tests showed.

Gene therapy researcher Donald Kohn of the University of California, Los Angeles, agrees with the companys conclusion. There is no evidence that the integrant was affecting expression of any genes near its integration site, says Kohn, who is one of several academic researchers who consulted with Bluebird. That makes the case quite different from the cases years ago. (Bluebird is paying Kohn for his time, but he says that didnt influence his opinion.)

Bluebird had also reported that a different patient had developed a preleukemic condition called myelodysplastic syndrome (MDS). But the company has walked back that concern. It now says the person had some possible signsanemia and an extra chromosome in some bone marrow cellsbut did not turn out to have abnormal bone marrow cells that would indicate MDS.

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Viral vector unlikely to be cause of leukemia in gene therapy patient - Science Magazine

Brain cells called astrocytes derived from the induced pluripotent stem cells of patients with bipolar disorder offer suboptimal support for neuronal activity. In a paper in the journal Stem Cell Reports, researchers show that this malfunction can be traced to an inflammation-promoting molecule called interleukin-6 (IL-6), which is secreted by astrocytes. The results highlight the potential role of astrocyte-mediated inflammatory signaling in the psychiatric disease, although further investigation is needed.

Our findings suggest that IL-6 may contribute to defects associated with bipolar disorder, opening new avenues for clinical intervention, said co-senior study author Fred Gage of the Salk Institute for Biological Studies.

Approximately 1-3% of individuals suffer from bipolar disorder, which is characterized by recurrent mood states ranging from high energy and elation, known as mania, to low energy and depressive episodes. Several lines of evidence suggest a link between imbalanced inflammatory signaling and bipolar disorder. For example, these patients show signs of chronic inflammation and have a higher prevalence of inflammation-related conditions such as cardiovascular disease, diabetes, and metabolic syndrome. Moreover, they have higher concentrations of circulating pro-inflammatory cytokines such as IL-1 and IL-6, particularly during manic episodes.

While mild inflammation can be beneficial for many neural processes, the overproduction of IL-6 may worsen the symptoms of bipolar disorder and may be an important therapeutic target, said co-senior study author Maria Carolina Marchetto of the Salk Institute and the University of California San Diego Department of Anthropology.

Astrocytes are known to participate in the inflammatory cascade within the brain. These cells are activated by IL-1 and other pro-inflammatory cytokines and in turn secrete cytokines that participate in the process of neuroinflammation. Due to a growing understanding of the role of neuroinflammation in psychiatric disorders, we wondered whether altered inflammation-driven signaling in astrocytes was associated with bipolar disorder, said co-senior study author Renata Santos of Salk and the Institute of Psychiatry and Neuroscience of Paris.

The researchers previously developed a method for rapidly generating inflammation-responsive astrocytes from human induced pluripotent stem cells (iPSCs). In the new study, they compared the inflammation signatures in iPSC-derived astrocytes generated from six patients with bipolar disorder and four healthy individuals.

The response of astrocytes from patients to pro-inflammatory cytokines revealed a unique transcriptional pattern, which was characterized by higher expression of the IL-6 gene. As a result, these cells secreted more IL-6, which negatively impacted the activity of co-cultured neurons. Exposure to the culture medium of the astrocytes was sufficient to decrease neuronal activity, and this effect was partially blocked by IL-6-inactivating antibody. Moreover, blood levels of IL-6 were higher in patients compared to healthy individuals.

These results suggest that secreted factors from astrocytes play a role in regulating neuronal activity and that, in the case of bipolar disorder, IL-6 at least in part mediated the effects of inflammation-primed astrocytes on neuronal activity, said first author Krishna Vadodaria of Salk.

Moving forward, the researchers plan to further investigate the effect of IL-6 on neuronal activity. In the meantime, the findings should be interpreted with caution. The experiments may not mimic conditions of chronic inflammation associated with bipolar disorder, and the culture system did not include many cell types involved in potentially relevant immune responses. In addition, iPSC-derived astrocytes are relatively immature compared to those in the brains of bipolar patients, and there is a lack of reliable biomarkers for pinpointing exact developmental age.

At this moment, direct extrapolation of the results to patients remains challenging, Gage said. Despite these limitations, our findings elucidate aspects of the understudied role of astrocytes in neuroinflammation in psychiatric disorders.

This research was supported by the Robert and Mary Jane Engman Foundation, Lynn and Edward Streim, the Paul G. Allen Family Foundation, Bob and Mary Jane Engman, the Leona M. and Harry B. Helmsley Charitable Trust, Annette C. Merle-Smith, the G. Harold & Leila Y. Mathers Foundation, the National Institute of Mental Health, and the Department of Veterans Affairs.

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Astrocytes Derived from Patients with Bipolar Disorder Malfunction - UC San Diego Health

Three professors from the UC Santa Barbara College of Engineering and one from the Department of Molecular, Cellular and Developmental Biology (MCDB) have been named Fellows of the prestigious American Institute for Medical and Biological Engineering (AIMBE), recognizing their interdisciplinary achievements.

Nominated by their peers, fellows represent the top 2% of the medical and biological engineering community.

Mechanical engineers Linda Petzold, Sumita Pennathur and Megan Valentine, and MCDBs Dennis Clegg, are among this years 174 new AIMBE fellows. Members are nominated by their peers and represent the top two percent of the medical and biological engineering community, having made transformational contributions to the medical and biological engineering (MBE) community in academia, industry, government and education.

We are extremely proud to have four UC Santa Barbara faculty members selected as AIMBE Fellows for 2021, saidRod Alferness, dean of the UCSB College of Engineering. Being named an AIMBE Fellow is a particularly notable achievement, first, because it is highly competitive and second, and perhaps more importantly, because it recognizes achievements at the intersection of science and engineering, which may have life-changing impacts. We offer our most sincere congratulations to Linda Petzold, Sumita Pennathur, Megan Valentine and Dennis Clegg on this significant achievement.

I congratulate all four professors from UC Santa Barbara on this honor, said Pierre Wiltzius, the Susan & Bruce Worster Dean of Science in the College of Letters & Science. AIMBE Fellows are known foremost for their transformative interdisciplinary research, which is something we champion on this campus. Our faculty have a long and fruitful history of integrating science and engineering, and I couldnt be happier to see the work of these leading scholars recognized.

Linda Petzold, also a professor of computer science, has been widely recognized for her impactful work on mathematical modeling and computational simulation in a variety of disciplines and applications. Her breakthrough 1982 paper Differential-Algebraic Equations (DAEs) are not ODEs [ordinary differential equations] opened up a new subfield in computational mathematics, and her public-domain software DASSL has enabled the simulation of countless systems in engineering and science.

It is a pleasure for me to receive this recognition from the AIMBE community for my work in medical and biological engineering, she said.I greatly enjoy working in this area, as it allows me the opportunity to address challenges and further understanding in a variety of diverse subject areas.

Petzolds algorithm and software (LSODA), described in a 1983 paper, has been used extensively and remains in widespread use, in particular as part of Mathematica (a modern and widely applied technical computing system), as well as in the chemical and pharmaceutical industries. More recently, her work has focused on algorithms and software for discrete stochastic systems, motivated by the need to model the inherent randomness of biochemical reactions in the cell. In this work, she and her collaborators have developed algorithms and the public-domain software StochSS for discrete stochastic simulation of biochemical systems. Her work on mathematical modeling of biological systems has elucidated a mechanism for the onset of coagulopathy, revealed the role of stochasticity in cell polarization, derived the network structure of neurons involved in Circadian Rhythm, and contributed in numerous other areas.

Petzold, a member of the National Academy of Engineering, has contributed extensively to the profession and to diversity in the sciences. She serves on the Board of Directors of the Society for Industrial and Applied Mathematics (SIAM), in 2016 receiving the SIAM Prize for Distinguished Service to the Profession. Committed to promoting and supporting diversity in the profession, she has served as director of the UCSB Institute for Collaborative Biotechnologies Diversity Program, focused on underrepresented students with a special emphasis on women in science.

Sumita Pennathur, a pioneer in nanofluidics, interfacial science and biological engineering,has a longstanding commitment to advancing human health through innovative science and engineering. Her seminal work has revealed unique physics at the nanoscale, making it possible to model, predict and, ultimately, control fluids and the molecules they contain. Researchers in the Pennathur laboratory invent, design and build nanoscale devices to measure key fluidic parameters with unprecedented accuracy and precision via a tight integration of theory, modeling and reduction to practice.

Pennathur has applied her discoveries to develop novel biomedical technologies, leading her to found three startup companies:Asta Fluidics, for rapid diagnosis of potentially lethal complications during pregnancy;Alveo Technologies, which is developing an in-home diagnostic for COVID-19; and Laxmi Therapeutic Devices,amicroneedle based continuous glucose monitoring company.

I am honored to be recognized alongside a cohort of amazing biomedical engineers and innovators, Pennathur said. I fully supportthe AIMBE mission to advance medicine and bioengineering innovations and commend the society of their impact in funding for medical science and education.

For her early academic research accomplishments, Pennathur in 2010 received a coveted PECASE award (Presidential Early Career Awards for Scientists and Engineers) from President Obama. She also was awarded the Defense Advanced Research Programs Administration (DARPA) Young Faculty Award in 2008, the UC Regents Junior Faculty Fellowship in 2009, and the ADA Pathway to Stop Diabetes Visionary Award in 2017.

Megan Valentine is an internationally recognized leader in biomaterials science, cellular mechanics and mechanotransduction. Her pioneering research establishes how forces are generated, transmitted and sensed in soft living matter, and how to capture the properties of living systems in synthetic materials. Her innovative approaches bridge length scales from molecular to macroscopic and combine her significant biological expertise with innovative tool development and a deep understanding of physical phenomena to impact multiple areas of biomedical engineering.

It's an honor to be selected as an AIMBE Fellow and a testament to the collaborative and interdisciplinary nature of both my work and UC Santa Barbara, Valentine said. Ive dedicated my career to working across disciplines: my undergraduate and graduate degrees are in physics, I completed a post-doc in biological sciences and am a professor of mechanical engineering. Each specialty has its own jargon and culture, and I am proud that my ability to innovate across boundaries has been recognized. I am eager to continue working with doctors, scientists and engineers from diverse communities to address pressing societal needs.

Valentines groundbreaking studies have provided a critically important understanding of the molecular mechanisms underlying normal cell division. Her work has established the use of microrheology for unprecedented measurements of the interplay among structure, mechanics and dynamics of complex biomaterials, such as cytoplasm.

By developing innovative imaging methods and mechanical testing devices, she has established the role of mechanosensation in regulating vascular growth dynamics, as well as the response of cells to high strain and high strain-rate impacts, providing novel insight into vascular regeneration and traumatic brain injury, respectively.

Finally, Valentine has become a leader in the area of bio-inspired materials, with an emphasis on developing high-performance adhesives and load-bearing composites. She established the nonlinear elastic and fracture behavior of natural materials, and is developing new classes of strong stimuli-responsive polymeric materials, with applications to healthcare, packaging and robotics.

Valentine is a devoted advocate for women and underrepresented minority students both at UCSB and in the broader bioengineering community. Particularly invested in engaging student veterans in hands-on research, she has developed two NSF-supported programs to support their summer internships at UCSB.

She is an active organizer in the American Physical Society March Meeting, and recently completed a three-year term on the Executive Committee of the Division of Biological Physics. She has served as a member of the Early Careers Committee of the Biophysical Society, where she led efforts in advocacy, training and professional development for graduate students and postdoctoral scholars. An AIMBE fellowship will provide her with new avenues of engagement and new opportunities to work for the betterment of our community and society.

Valentine is a co-director of the California NanoSystems Institute (CNSI) at UCSB and a fellow of the American Physical Society. She received a Career Award at the Scientific Interface (CASI) from the Burroughs Wellcome Fund, a UC Regents Junior Faculty Fellowship, a Hellman Family Faculty Fund Fellowship, a CAREER award from the National Science Foundation, and a Fulbright Scholar Award from the U.S. Department of State.

Dennis Clegg, a pioneer in translational regenerative medicine, achieved world renown for developing a bioengineered implant consisting of stem-cell-derived retinal cells on a synthetic parylene membrane. The technology is now in clinical trials for the treatment of dry age-related macular degeneration (AMD), a leading cause of blindness.

Cleggs lab discovered methods to differentiate pluripotent stem cells into retinal pigmented epithelial (RPE) cells, which degenerate in AMD. His group was the first to report that bona fide RPE cells could be derived from induced pluripotent stem cells (iPS). He established and is co-PI of the California Project to Cure Blindness, a multidisciplinary team comprising stem cell biologists, engineers and surgeons who developed the RPE implant and devised a surgical delivery strategy. Their Phase I trial has generated promising results for the dry form of AMD, a blinding condition with no treatment.

This is a great honor; it underscores the importance of thinking outside the disciplinary box, and collaboration between biologists and engineers, Clegg said of this election as an AIMBE Fellow. UCSB has provided a fertile ground for cutting-edge work, which will continue to thrive, resulting in advances in biomedical engineering.

Clegg has made impactful contributions to our understanding of cell-extracellular matrix interactions during ocular development. These studies informed further research of novel bio-mimetic materials that support survival and differentiation of stem cells. Clegg has navigated these discoveries all the way to clinical application.

Chair of MCDB from 2004-2009, and founder and co-director, since 2008, of the Center for Stem Cell Biology and Engineering, Clegg has served on the Chancellors Committee on Diversity, as director of an HHMI Undergraduate Program, and as director of two graduate training programs aimed at promoting underrepresented minorities and women in science. He was a speaker at the California Graduate Diversity Forum (2006-2014) and currently serves on Scientific Advisory Boards for biotechnology programs at California State University Channel Islands, which, like UCSB, is a Hispanic-Serving Institution.

Clegg also is noted for his ability to communicate complex science to general audiences, as evidenced in his 2012 TedX talk and in his extensive public outreach, particularly in educational activities related to stem cell biology and regenerative medicine.

All 160 members of the AIMBE College of Fellows Class of 2021 will be inducted at a ceremony to be held remotely March 26.

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Peer Recognition | The UCSB Current - The UCSB Current