A gene found only in humans and active in the cerebral cortex can enlarge the ferret brain

Medical Xpress | January 08, 2019

The human brain owes its characteristic wrinkled appearance to its outer layer, the cerebral cortex. During human evolution, the neocortex, the evolutionarily youngest part of the cerebral cortex, expanded dramatically and had to fold into wrinkles to fit inside the restricted space of the skull. The human neocortex supports advanced cognitive skills such as reasoning and language. But how did the human neocortex become so big? The answer may lie in genes that are unique to humans, such as ARHGAP11B.
Researchers at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden found that this human-specific gene, when introduced into the developing brain of ferrets, can cause an enlargement of their neocortex. ARHGAP11B causes neural progenitor cells, which are cells that produce neurons, to make more of themselves for a longer period of time. The result is an expanded neocortex. The human neocortex is roughly three times bigger than that of our closest relatives, the chimpanzees, and is the seat of many of the higher cognitive functions that are unique to humans, such as our speech or the ability to learn. A key question for scientists is how in human evolution the neocortex became so big.

Spotlight

Across a wide variety of cancer types, a protein called KRAS can get hyperactivated and transmit an overload of unwanted growth signals to the cells, causing them to divide and form a tumour.A tumour doesn't just contain cancer cells, though. It also has some non-cancer cells in there, such as immune cells and fibroblasts (cells that make the dense support structure that keeps cells stuck together).

Spotlight

Across a wide variety of cancer types, a protein called KRAS can get hyperactivated and transmit an overload of unwanted growth signals to the cells, causing them to divide and form a tumour.A tumour doesn't just contain cancer cells, though. It also has some non-cancer cells in there, such as immune cells and fibroblasts (cells that make the dense support structure that keeps cells stuck together).

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INDUSTRIAL IMPACT

Gilead and MacroGenics Announce Oncology Collaboration to Develop Bispecific Antibodies

Gilead and MacroGenics | October 18, 2022

Gilead Sciences, Inc. and MacroGenics announced an exclusive option and collaboration agreement to develop MGD024, an investigational, bispecific antibody that binds CD123 and CD3 using MacroGenics’ DART® platform, and two additional bispecific research programs. The collaboration agreement grants Gilead the option to license MGD024, a potential treatment for certain blood cancers, including acute myeloid leukemia and myelodysplastic syndromes. A leader in the bispecific antibody space, MacroGenics has extensive experience applying its proprietary DART platform to develop novel therapeutics. MGD024 is a next-generation, bispecific that incorporates a CD3 component that is designed to minimize cytokine-release syndrome a potentially life-threatening toxicity, while increasing the magnitude of antitumor activity with a longer half-life to permit intermittent dosing. “MacroGenics’ bispecific expertise naturally complements Gilead’s portfolio strengths in immuno-oncology and our growing hematology franchise. We believe MGD024, with its potential to reduce CRS and permit intermittent dosing through a longer half-life, could translate to more patient-friendly dosing and enhanced clinical outcomes for people living with AML and MDS. This partnership is the latest in our efforts to develop and advance transformative new cancer therapies as we deepen our portfolio across oncology indications.” Bill Grossman, MD, PhD, Senior Vice President, Oncology Clinical Development, Gilead Sciences Scott Koenig, MD, PhD, President, and CEO, MacroGenics said, “Rapid advances over the last decade have made CD123 a very promising target in oncology research. Advancing our bispecific DART molecule, MGD024, through a strategic collaboration with the team at Gilead will accelerate our ability to drive further development of MGD024 to the potential benefit of people living with blood cancers.” MacroGenics will be responsible for the ongoing Phase 1 study for MGD024 during which Gilead may elect to exercise its option to license the program at predefined decision points. The Phase 1 study will include a dose escalation segment and an expansion segment that is intended to evaluate MGD024 as monotherapy and in combination with other therapies across multiple indications. About MacroGenics, Inc. MacroGenics is a biopharmaceutical company focused on developing and commercializing innovative monoclonal antibody-based therapeutics for the treatment of cancer. The company generates its pipeline of product candidates primarily from its proprietary suite of next-generation antibody-based technology platforms, which have applicability across broad therapeutic domains. The combination of MacroGenics' technology platforms and protein engineering expertise has allowed the company to generate promising product candidates and enter into several strategic collaborations with global pharmaceutical and biotechnology companies. About Gilead Sciences Gilead Sciences, Inc. is a biopharmaceutical company that has pursued and achieved breakthroughs in medicine for more than three decades, with the goal of creating a healthier world for all people. The company is committed to advancing innovative medicines to prevent and treat life-threatening diseases, including HIV, viral hepatitis, and cancer. Gilead operates in more than 35 countries worldwide, with headquarters in Foster City, California.

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INDUSTRIAL IMPACT

New Data Reveal Molecular Drivers of Thyroid Eye Disease (TED) May Remain Activated In Patients with Low Clinical Activity Score (CAS)

Horizon | October 03, 2022

Horizon Therapeutics plc announced the presentation of new data defining molecular patterns in TED and further implicating the role of insulin-like growth factor-1 in patients with low CAS. These data were presented during the American Academy of Ophthalmology Annual Meeting Sept. 30 – Oct. 3 in Chicago. TED is a progressive and potentially vision-threatening rare autoimmune disease, which has been historically characterized as biphasic: acute, which is traditionally believed to be patients with high CAS and earlier in their TED journey; and chronic, traditionally believed to be patients with low CAS and later in the course of their disease.1 This analysis reveals that in patients with both high and low CAS, there is clear activation of IGF-1 and related pathways, as well as the extracellular matrix organization, a structural network that supports cellular processes.2 “By demonstrating that disease activity remains in patients with low CAS, this analysis may help explain why many patients who have lived with Thyroid Eye Disease for several years are still struggling with challenging symptoms that can be debilitating. It is important for physicians to be aware of the continued activation of IGF-1 throughout the course of the disease and its potential impact on treatment decisions.” Shoaib Ugradar, M.D., The Jules Stein Eye Institute at University of California, Los Angeles The study analyzed genome ribonucleic acid sequencing and pathway analysis in orbital tissue from patients with a CAS of ≥ 3 and patients with a CAS ≤ 2, as well as five control subjects. Though high CAS patients are often distinguished by activation of immune system pathways, which remain largely unaffected in low CAS patients, IGF-1 and its related pathways were found to be upregulated in both stages of disease. Additional analysis suggests that IGF-1 activity plays a central role in linking immune and ECM pathways in people with TED.2 The upregulation of IGF-1 found in low CAS patients with extended disease duration is further supported by a growing body of evidence that outlines the impact of TED on people who have lived with it for several years.3 One assessment published in the journal Ophthalmology and Therapy in 2021 found that disease burden continues well into the chronic phase, affecting daily lives with appearance and persistent visual changes, increasing risk for anxiety and depression.4 “This study, which represents one of the first molecular analyses of the continuum of Thyroid Eye Disease, confirms this challenging disease may not simply subside after a few years of obvious symptoms,” said Jeffrey W. Sherman, M.D., FACP, executive vice president, chief medical officer, Horizon. “We are committed to pioneering research like this to better understand drivers of the evolution of this disease in order to better support patients living with Thyroid Eye Disease across the course of their lifetimes.” About Thyroid Eye Disease. TED is a serious, progressive and potentially vision-threatening rare autoimmune disease.1 TED often occurs in people living with Graves’ disease, but is a distinct disease that is caused by autoantibodies activating an IGF-1R-mediated signaling complex on cells within the retro-orbital space.5,6 This leads to a cascade of negative effects, which may cause long-term, irreversible damage, including blindness. Early signs and symptoms of TED may include dry eyes and grittiness; redness, swelling and excessive tearing; eyelid retraction; proptosis; pressure and/or pain behind the eyes; and diplopia.7,8 About Horizon Horizon is a global biotechnology company focused on the discovery, development and commercialization of medicines that address critical needs for people impacted by rare, autoimmune and severe inflammatory diseases. Our pipeline is purposeful: We apply scientific expertise and courage to bring clinically meaningful therapies to patients. We believe science and compassion must work together to transform lives.

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CELL AND GENE THERAPY

Bicycle Therapeutics Announces BT5528 Phase I Dose Escalation Results in Patients with Advanced Solid Tumors

Bicycle Therapeutics | September 08, 2022

Bicycle Therapeutics plc a biotechnology company pioneering a new and differentiated class of therapeutics based on its proprietary bicyclic peptide technology, today announced Phase I dose escalation top-line results from its Phase I/II trial of BT5528, a BTC targeting EphA2, in patients with advanced solid tumors. “The therapeutic profile from the dose escalation portion of the Phase I/II trial of BT5528 in patients with late-line disease suggests both differentiated safety and promising activity, most notably in ovarian and urothelial cancers. Significant safety concerns seen with antibody drug conjugate approaches have limited the ability to effectively address EphA2, a target which correlates with tumor progression and is overexpressed in many cancers. Based on BT5528’s promising and differentiated safety profile, we hope to demonstrate the true therapeutic potential of this target, this program and our broader Bicycle Toxin Conjugate platform.” Dominic Smethurst, Chief Medical Officer of Bicycle Therapeutics “Smaller size, tumor penetration, pharmacokinetic and other qualities distinguish BT5528 and other members of our BTC platform from traditional toxin delivery systems and may confer significant advantages,” said Kevin Lee, Ph.D., Chief Executive Officer of Bicycle Therapeutics. “Clinical data emerging from our BT5528 study continues to elucidate these potential advantages, and supports the continued, rapid advancement of our Bicycle-targeted therapeutics platform, all with the ultimate goal of creating unique, impactful medicines that transform the lives of patients. Enrollment continues on schedule in the expansion portion of this trial, and we anticipate providing further updates next year.” BT5528, a BTC targeting EphA2, a target for which prior antibody-based approaches have been unsuccessful, has demonstrated anti-tumor activity and differentiated tolerability. Bicycle has established an RP2D dose and is enrolling ongoing expansion cohorts. Bicycle advancing BT5528 in ongoing expansion cohorts. In June 2022, Bicycle announced the dosing of the first patient in the part B dose expansion portion of the Phase I/II trial. Up to 56 patients will be enrolled in the initial expansion cohorts, with the ability to further expand enrollment based on results from these cohorts. Dose expansion is taking place in urothelial (n=14) and ovarian (n=14) cancers as well as in a basket cohort of other solid tumors (n=28), including non-small cell lung, triple-negative breast, head and neck, and esophageal cancers. Conference Call Details Bicycle Therapeutics will host a conference call and webcast today, September 7, 2022, at 8:30 a.m. ET to review the BT5528 trial data. To access the call, please dial at least 10 minutes prior to the start time and ask to be joined to the Bicycle Therapeutics call. A live webcast of the presentation will be available on the Investors & Media section of the Bicycle website, About Bicycle Therapeutics Bicycle Therapeutics is a clinical-stage biopharmaceutical company developing a novel class of medicines, referred to as Bicycles, for diseases that are underserved by existing therapeutics. Bicycles are fully synthetic short peptides constrained with small molecule scaffolds to form two loops that stabilize their structural geometry. This constraint facilitates target binding with high affinity and selectivity, making Bicycles attractive candidates for drug development. Bicycle is evaluating BT5528, a second-generation Bicycle Toxin Conjugate targeting EphA2; BT8009, a second-generation BTC targeting Nectin-4, a well-validated tumor antigen; and BT7480, a Bicycle TICA® targeting Nectin-4 and agonizing CD137, in company-sponsored Phase I/II trials. In addition, BT1718, a BTC that targets MT1-MMP, is being investigated in an ongoing Phase I/IIa clinical trial sponsored by the Cancer Research UK Centre for Drug Development. Bicycle is headquartered in Cambridge, UK, with many key functions and members of its leadership team located in Lexington, Massachusetts.

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