The findings are published in PNAS in an article titled, “Direct neuronal conversion of microglia/macrophages reinstates neurological function after stroke.”

“Although generating new neurons in the ischemic injured brain would be an ideal approach to replenish the lost neurons for repairing the damage, the adult mammalian brain retains only limited neurogenic capability,” wrote the scientists. “Here, we show that direct conversion of microglia/macrophages into neurons in the brain has great potential as a therapeutic strategy for ischemic brain injury.”

“When we get a cut or break a bone, our skin and bone cells can replicate to heal our body. But the neurons in our brain cannot easily regenerate, so the damage is often permanent,” explained Kinichi Nakashima, PhD, a professor at Kyushu University’s Graduate School of Medical Sciences. “We therefore need to find new ways to replace lost neurons.”

One possible strategy is to convert other cells in the brain into neurons. The researchers focused on microglia.

“Microglia are abundant and exactly in the place we need them, so they are an ideal target for conversion,” said first author, Takashi Irie, PhD, from Kyushu University Hospital.

In prior research, the scientists demonstrated that they could induce microglia to develop into neurons in the brains of healthy mice. In the current study, the scientists showed that this strategy of replacing neurons also works in injured brains and contributes to brain recovery.

The scientists caused a stroke-like injury in mice by temporarily blocking the right middle cerebral artery. A week later, the researchers examined the mice and found that they had difficulties in motor function and had a marked loss of neurons in a brain region known as the striatum.

The researchers then used a lentivirus to insert DNA into microglial cells at the site of the injury. The DNA held instructions for producing NeuroD1, a protein that induces neuronal conversion. By eight weeks, the new induced neurons had successfully integrated into the brain’s circuits.

At only three weeks post-infection, the mice showed improved motor function in behavioral tests. These improvements were lost when the researchers removed the new induced neurons.

“These results are very promising. The next step is to test whether NeuroD1 is also effective at converting human microglia into neurons and confirm that our method of inserting genes into the microglial cells is safe,” said Nakashima.

Furthermore, the treatment was conducted in mice in the acute phase after stroke, when microglia were migrating to and replicating at the site of injury. The scientists also plan to see if recovery is also possible in mice at a later, chronic phase.

The post Novel Approach Restores Brain Function after Stroke-Like Injury in Mice appeared first on GEN - Genetic Engineering and Biotechnology News.

Over the next year, a series of clinical milestones and regulatory decisions—what companies and investors like to call “inflection points”—will set for years to come the direction of what has been until now the fledgling biotech segment focused on genome editing.

Yet this week, investors received a reminder that in genome editing, inflection points don’t always lead to big stock gains: Beam Therapeutics (BEAM) shares skidded 12% in early trading, reaching a new 52-week low as it slid from $20.80 to $18.36, after the company announced a restructuring and reprioritization of its pipeline of base editing therapies that will include elimination of about 100 jobs—some 20% of its workforce.

Beam said it will prioritize development of its ex vivo and in vivo sickle cell disease programs—including BEAM-101, which applies the company’s Engineered Stem Cell Antibody Paired Evasion (ESCAPE) non-genotoxic conditioning strategy, and in vivo delivery to hematopoietic stem cells (HSCs).

Beam also said it will:

• Prioritize development of its in vivo base editor BEAM-302 for the treatment of alpha-1 antitrypsin deficiency (AATD).

• Conduct an initial clinical trial in the U.S. assessing BEAM-301 as a treatment for glycogen storage disease 1a (GSD1a).
• Seek partnerships for BEAM-201 and other potential ex vivo CAR-T programs, including ongoing research to create next-generation allogeneic cell therapies with multiplex base editing. For BEAM-201, Beam plans to generate a focused clinical dataset in T-cell acute lymphoblastic leukemia (T-ALL).
• Focus near-term spending on research and platform applications that apply Beam’s in vivo editing capabilities in the liver, targeting both rare genetic and common disorders, as well as select opportunities in hematology and immunology/oncology.
• Pause its hepatitis B virus program and seek for it a partner “given the requirement of specialized development and commercial capabilities.”

“From the beginning, Beam’s strategy has been to develop base editing technology broadly across a diverse portfolio of programs and delivery modalities, and our science and pipeline continue to progress across the board,” Beam CEO John Evans stated. “In this challenging market environment, however, we need to make the difficult decision to focus our resources on those clinical programs and research areas we believe have the highest potential for near-term value creation, while continuing to build a strong company for the future.”

Intellia Therapeutics (NTLA) shares fell about 3% on Wednesday from $29.05 to $27.96, and dipped another 3% on Thursday, to $27.10, despite the company sharing more positive news.

Intellia’s NTLA-2001 became the first first-ever investigational in vivo CRISPR-based gene editing therapy cleared to enter late-stage clinical development when the FDA cleared the company’s Investigational New Drug (IND) application for NTLA-2001 for the treatment of transthyretin (ATTR) amyloidosis with cardiomyopathy. The decision paves the way for a global Phase III study of NTLA-2001 that is expected to start by year-end 2023.

In a statement, Intellia president and CEO John Leonard, MD, said the company will share details about that pivotal trial on its third-quarter earnings call with analysts, set for November 9.

“Details on trial design at 3Q call Nov 9 should clarify next steps and further move the stock. We expect (+)ve [positive] readthrough to other editing cos [companies] too,” Jefferies equity analyst Maury Raycroft, PhD, wrote Wednesday in a research note. “The bar for FDA has been unclear, and NTLA now sets precedent for others to follow.”

He said Intellia had noted to him that while global trial start-up activities will start, “actual dosing may begin early ’24 depending on how fast things move.”

Raycroft added that he and other Intellia watchers will be seeking more specifics about the size and duration of the Phase III trial compared to the pivotal trials for other non genome-edited therapy developers of ATTR amyloidosis-caused cardiomyopathy treatments.

Pfizer (PFE) crossed the proverbial finish line first when it won FDA approval in 2019 for its wild-type or hereditary ATTR amyloidosis treatments, Vyndaqel^® (tafamidis meglumine) and Vyndamax^® (tafamidis). Each uses a different form of active ingredient tafamidis (micronized meglumine salt and free acid form, respectively), and each is taken a different dosage.

The Pfizer drugs are expected to be joined soon by treatments being developed by other companies—a group that includes Anlylam Pharmaceuticals (ALNY), BridgeBio Pharma (BBIO), and the tandem of Ionis Pharmaceuticals and AstraZeneca (IONS/AZN). Those treatments “pose substantial headwinds” to Intellia’s NTLA-2001, observed David Nierengarten, PhD, managing director and head of equity research focusing on biotech for Wedbush Securities, according to Investor’s Business Daily.

However, whatever headwinds Alnylam posed to Intellia have been significantly stilled.

As Raycroft commented, Alnylam saw a setback to development of patisiran for cardiomyopathy of ATTR amyloidosis on October 9 when the FDA refused to approve Alnylam’s supplemental NDA for the RNA interference (RNAi)-based therapy already marketed as Onpattro^® for polyneuropathy of hereditary ATTR amyloidosis in adults. Instead, the agency sent Alnylam a Complete Response Letter stating that data from the company’s Phase III APOLLO-B trial (NCT03997383) had not established the clinical meaningfulness of patisiran’s treatment effects in ATTR amyloidosis. Alnylam responded by saying it was no longer pursuing the additional indication in the U.S.

Earlier this year, BridgeBio and Ionis/AstraZeneca announced positive Phase III results for their ATTR amyloidosis candidates—acoramidis and eplontersen, respectively.

Intellia is among a half-dozen genome editing therapy developers with key clinical and regulatory inflection points to watch in coming months. Following is a roundup of those companies, their anticipated events, and recent actions by analysts covering the company:

Beam Therapeutics (BEAM)

Inflection Points: BEAM restructured operations and reprioritized its pipeline on Thursday (see above), listing first its ex vivo and in vivo sickle cell disease programs, which include BEAM-101—for which the company anticipates reporting initial data in 2024 on multiple patients from its Phase I/II BEACON trial (NCT05456880) assessing BEAM-101 in severe SCD.

In August, BEAM said it anticipated having enough currently consented patients to fill a three-patient sentinel cohort and launch an expansion cohort. Beam will continue adding additional patients to the BEACON trial through the end of year and beyond, until it reaches a total target of 45 treated patients. The trial has an estimated primary completion date of February 1, 2025.

Significance: BEAM-101 is an ex vivo therapy that produces base edits designed to potentially alleviate the effects of SCD by mimicking genetic variants seen in individuals who have hereditary persistence of fetal hemoglobin.

Other catalysts: BEAM is also prioritizing development of BEAM-302 in AATD, saying in August it expected to submit a regulatory filing in the first quarter of 2024 to begin a clinical trial. A similar filing is expected in the first half of 2024 for BEAM-301 in GSD1a, with BEAM saying Thursday that an initial clinical trial is still planned.

BEAM-301 is a liver-targeting lipid nanoparticle (LNP) formulation of base editing reagents designed to correct the R83C mutation—the most common mutation responsible for causing GSD1a. BEAM-302 is a liver-targeting LNP formulation of base editing reagents designed to correct the PiZ allele, the most common gene variant associated with severe AATD.

However, BEAM is seeking a partner for BEAM-201, for which it dosed the first patient with BEAM-201 in a Phase I/II trial (NCT05885464) assessing the CD7+ relapsed/refractory T-ALL/T-LL (T-cell lymphoblastic leukemia) in August. The trial has an estimated primary completion date of December 2031. BEAM-201 is, according to Beam, the first quadruplex-edited, allogeneic CAR-T cell therapy candidate in clinical-stage development, and the first treatment with a base editing candidate in the U.S.

Analyst action: Cantor Fitzgerald’s Rick Bienkowski on Tuesday lowered his firm’s 12-month price target on Beam shares 43%, from $56 to $32, but maintained its “Overweight” rating.

Caribou Biosciences (CRBU)

Inflection Point: CRBU expects to begin patient enrollment in the Phase I AMpLify trial by mid-2024. AMpLify is designed to assess the safety and tolerability of a single administration of CB-012 for relapsed or refractory acute myeloid leukemia (r/r AML) at dose level 1 (25×10⁶ CAR-T cells). The FDA has cleared Caribou’s IND for the trial, the company said Wednesday.

Caribou said it is beginning Part A of AMpLify, a 3+3 dose escalation design that will evaluate the safety and tolerability of CB-012 at ascending dose levels to determine the maximum tolerated dose and/or the recommended doses for expansion. Part B, the dose expansion portion, has as its primary objective determining antitumor response, assessed by overall response rate (ORR), after a single dose of CB-012. AMpLify will include patients who have not responded to or relapsed after standard treatment and will exclude patients who have been treated with more than three prior lines of therapy and patients with proliferative disease.

Significance: According to CRBU, CB-012 is the first allogeneic CAR-T cell therapy with both checkpoint disruption through a PD-1 knockout, and immune cloaking through a B2M knockout and B2M–HLA-E fusion transgene insertion.

Analyst action: Nothing since July 26, when HC Wainwright’s Robert Burns lowered his firm’s price target 8%, from $25 to $23, but maintained its “Buy” rating.

CRISPR Therapeutics (CRSP) and Vertex Pharmaceuticals (VRTX)

Inflection points: The FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee will meet October 31 to recommend how the agency should act on exagamglogene autotemcel (exa-cel), the companies’ autologous, ex vivo CRISPR/Cas9 gene-edited for severe sickle cell disease (SCD) and transfusion-dependent beta thalassemia.

The FDA, which typically heeds the advice of its “adcomms,” has set for December 8 its Prescription Drug User Fee Act (PDUFA) target action date on the companies’ biologics license application (BLA) for exa-cel in SCD. In beta thalassemia, the agency has set a PDUFA date of March 30, 2024.

Significance: If approved, exa-cel would be the first CRISPR-Cas9 gene-edited therapy to win FDA approval.

Other catalysts: Cardiovascular candidate CTX310, which applies in vivo editing of the ANGPTL3 gene, is expected to enter the clinic by year’s end; Atherosclerotic cardiovascular disease candidate CTX320 is expected to begin clinical trials in the first half of 2024.

Analyst action: Cantor Fitzgerald’s Eric Schmidt on Tuesday downgraded CRSP shares from “Overweight” to “Neutral.” Mizuho’s Salim Syed, however, initiated coverage of CRSP on September 27 with a “Buy” rating.

Editas Medicine (EDIT)

Inflection Point: Editas’ EDIT-301, an ex vivo autologous CRISPR gene edited gene-edited CD34+ hematopoietic stem and progenitor cell therapy candidate, received the FDA’s Regenerative Medicine Advanced Therapy (RMAT) designation on Monday. EDIT-301 is on track to dose 20 total sickle cell disease (SCD) patients in the Phase I/II RUBY trial (NCT04853576), and deliver a clinical update on the study, by the end of this year, the company said in August.

In June, Editas presented positive initial clinical safety and efficacy data from the RUBY trial in an oral presentation at the European Hematology Association (EHA) Hybrid Congress in Frankfurt, Germany, and in a company-sponsored webinar.

Significance: In EDIT-301, patient-derived CD34⁺ hematopoietic stem and progenitor cells are edited at the gamma globin gene (HBG1 and HBG2) promoters, where naturally occurring fetal hemoglobin (HbF) inducing mutations reside, by a highly specific and efficient proprietary engineered AsCas12a nuclease. Red blood cells derived from EDIT-301 CD34⁺ cells have shown a sustained increase in fetal hemoglobin production, which according to Editas could provide a one-time, durable treatment benefit for people living with severe SCD and TDT.

The RUBY trial marked the first time that a novel type of CRISPR gene-editing technology—CRISPR/CA12—was used in a human clinical study to alter the defective gene, according to the scientists.

Other catalysts: SCD is one of two indications for which Editas is developing EDIT-301; the other is transfusion-dependent beta thalassemia (TDT), for which Editas also has a clinical update planned by year’s end, from the Phase I/II EDITHAL trial (NCT05444894). Editas presented positive initial clinical safety and efficacy data from the first EDITHAL patient in June, in a company-sponsored webinar.

Analyst action: J.P. Morgan’s Brian Cheng on Wednesday upgraded his firm’s rating on EDIT stock from “Underweight” to “Neutral,” and announced a price target of $8 a share. However, Cantor Fitsgerald’s Eric Schmidt downgraded EDIT on Tuesday from “Overweight” to “Neutral.” Last month, Stifel’s Dae Gon Ha upgraded the stock from “Hold” to “Buy” and nearly doubled his firm’s price target, from $9 to $17.

Intellia Therapeutics (NTLA)

Inflection Point: Intellia said Wednesday its NTLA-2001, being co-developed with Regeneron Pharmaceuticals (REGN), won FDA clearance of its IND application for a trial assessing the in vivo CRISPR-based therapy as a treatment of transthyretin (ATTR) amyloidosis with cardiomyopathy. The decision paves the way for a global Phase III study of NTLA-2001 that is expected to start by the end of this year. In a statement, Intellia President and CEO John Leonard, MD, said the company will share details about that pivotal trial on its third-quarter earnings call with analysts, set for November 9.

Significance: NTLA-2001 is the first first-ever investigational in vivo CRISPR-based gene editing therapy cleared to enter late-stage clinical development when the FDA cleared. If approved by the agency, it could potentially be the first single-dose treatment for ATTR amyloidosis, according to Intellia.

Other catalysts: NTLA-2002, an in vivo CRISPR-based treatment candidate for hereditary angioedema, earlier this month was granted the European Medicines Agency (EMA)’s Priority Medicine (PRIME) designation. NTLA-2002 is set to start a global pivotal Phase III trial as early as Q3 2024 “subject to regulatory feedback,” Intellia said in August, following release of positive Phase I data including extended data announced in June. According to Intellia, NTLA-2002 is the first single-dose investigational treatment being explored in clinical trials for the potential to continuously reduce kallikrein activity and prevent attacks in people with HAE.

Analyst action: Nothing since September 13, when Cantor Fitzgerald’s Rick Bienkowski maintained his firm’s “Overweight” rating and $65 a share price target on the stock.

Prime Medicine (PRME)

Inflection Point: PRME expects to submit an IND in 2024 for its first clinical candidate to the FDA, the company’s co-founder, prime editing and base editing pioneer David R. Liu told an investor conference earlier this month.

While the company has not identified that candidate, its pipeline shows only one of its 18 programs has reached the phase of IND-enabling studies—a blood-targeting candidate for chronic granulomatous disease (CGD), designed to be administered ex vivo. Additional IND filings are anticipated in 2025, Prime Medicine said in a company presentation to investors last month.

Significance: If Prime wins FDA clearance for its IND, it could be the first drug developer to bring a base edited therapy into the clinic. By contrast, base editing technology, first disclosed in 2016 by Liu’s lab—is under investigation in six ongoing clinical trial.

Other catalysts: Three other programs in Prime’s pipeline are in lead optimization phases—a Wilson’s disease candidate targeting liver tissue and using lipid nanoparticle (LNP) delivery; a retinitis pigmentosa/rhodopsin candidate targeting eye tissue and using adeno-associated virus (AAV) vector delivery; and a neuromuscular tissue targeting candidate for Friedreich’s ataxia also delivered via AAV. The rest of Prime Medicine’s programs are in preclinical discovery phases.

Analyst action: BMO Capital’s Kostas Biliouris initiated coverage of PRME on October 9 with an “Outperform” rating and a price target of $19 a share. A month earlier on September 6, JonesTrading’s Justin Walsh initiated coverage with a “Buy” rating and a price target of $20 a share.

Leaders & Laggards

• Aldeyra (ALDX) shares plunged 66% on Monday, from $5.43 to $1.83, after it disclosed that according to minutes of a late-cycle review meeting with the FDA, the company “needs to conduct an additional clinical trial to satisfy efficacy requirements for reproxalap as a treatment for signs and symptoms of dry eye disease. Aldeyra quoted from the minutes: “[i]t does not appear that you have data to support the clinical relevance of the ocular signs to support your dry eye indication.” As a result, Aldeyra acknowledged, “the FDA may not be in the position to approve the NDA [New Drug Application] for reproxalap on or about the Prescription Drug User Fee Act (PDUFA) target action date of November 23, 2023 or afterwards, and it may issue a Complete Response Letter.”
• Assembly Biosciences (ASMB) shares rocketed 71%, from 73 cents to $1.25, after the company announced a 12-year partnership with Gilead Sciences (GILD) to advance R&D of novel antiviral therapies, focusing initially on herpes, hepatitis B, and hepatitis D viruses. Gilead agreed to pay Assembly Bio an initial $100 million consisting of $84.8 millionupfront and a $15.2 million equity investment. Gilead also agreed to pay at least $45 million per program after clinical proof-of-concept is achieved to opt into exclusive rights for each of Assembly Bio’s current and future programs,. If Gilead opts-in to any program, it will pay Assembly Bio up to $330 million per program tied to achieving regulatory and commercial milestones, plus royalties. Assembly Bio is also be eligible to receive three separate $75 million collaboration extension payments toward funding future R&D. Gilead shares rose 2% from $79.20 to $80.48.
• Evelo Biosciences (EVLO) shares plummeted 59% on Tuesday, from $2.91 to $1.20, after the company acknowledged that it had begun exploring strategic alternatives after its moderate psoriasis candidate EDP2939 failed the Phase II EDP2939-101 trial. EDP2939 missed the study’s primary endpoint of achieving a statistically significant difference in the proportion of patients who achieved an outcome of a 50% improvement from baseline in Psoriasis Area and Severity Index (PASI) score (PASI-50) between EDP2939 and placebo after 16 weeks of daily treatment. Evelo added that EDP2939 went from being inferior to placebo at week 16 (19.6% vs 25%) to being superior at the week 20 follow-up visit (33.9% vs. 26.9%).
• Nkarta (NKTX) shares more than doubled, zooming 112% on Tuesday from $1.48 to $3.14, after the company said the FDA had cleared its IND application to evaluate NKX019, its allogeneic, CD19-directed CAR NK cell therapy for lupus nephritis (LN). The company plans to launch a multi-center, open label, dose escalation clinical trial designed to assess the safety and clinical activity of NKX019 in patients with refractory LN. The study is designed to enroll up to 12 patients, with the first patient expected to be enrolled in the first half of 2024. Nkarta also disclosed plans to eliminate 18 jobs—about 10% of its workforce—among cost containment measures designed to extend its projected cash runway by one year into 2026.

Alex Philippidis is Senior Business Editor of GEN.

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Modern humans (Homo sapiens) from Africa began replacing Neanderthals 40,000 years ago in the western part of the Eurasian continent where Neanderthals had lived for hundreds of thousands of years. The replacement was not sudden but took place over several millennia which resulted in the integration of Neanderthal DNA into the H. sapiens genome.

“The worldwide expansion of modern humans started before the extinction of Neanderthals (Homo neanderthalensis). Both species coexisted and interbred, leading to slightly higher introgression in East Asians than in Europeans. This distinct ancestry level has been argued to result from selection, but range expansions of modern humans could provide an alternative explanation. This hypothesis would lead to spatial introgression gradients, increasing with distance from the expansion source,” write the researchers.

“We investigate the presence of Neanderthal introgression gradients after past human expansions by analyzing Eurasian paleogenomes. We show that the out-of-Africa expansion resulted in spatial gradients of Neanderthal ancestry that persisted through time. While keeping the same gradient orientation, the expansion of early Neolithic farmers contributed decisively to reducing the Neanderthal introgression in European populations compared to Asian populations. This is because Neolithic farmers carried less Neanderthal DNA than preceding Paleolithic hunter-gatherers. This study shows that inferences about past human population dynamics can be made from the spatiotemporal variation in archaic introgression.”

Genome sequencing and comparative analysis

Due to genome sequencing and comparative analysis, it’s established that Neanderthals and Sapiens interbred and that these encounters were sometimes fruitful, leading to the presence of about two percent of DNA of Neanderthal origin in present-day Eurasians. However, this percentage varies slightly between regions of Eurasia, since DNA from Neanderthals is somewhat more abundant in the genomes of Asian populations than in those of European populations.

One hypothesis to explain this difference is that natural selection would not have had the same effect on genes of Neanderthal origin in Asian and European populations. The team of Mathias Currat, PhD, senior lecturer in the department of genetics and evolution at the UNIGE Faculty of Science, is working on another hypothesis. His previous work, based on computer simulations, suggests that such differences could be explained by migratory flows: when a migrant population hybridizes with a local population, in their area of cohabitation, the proportion of DNA of the local population tends to increase with distance from the point of departure of the migrant population.

In the case of Sapiens and Neanderthals, the hypothesis is that the further one moves away from Africa, Homo sapiens’ point of origin, the greater the proportion of DNA from Neanderthal, a population mainly located in Europe. To test this hypothesis, the authors used a database made available by Harvard Medical School that includes more than 4,000 genomes from individuals who have lived in Eurasia over the past 40 millennia.

‘‘Our study is mainly focused on European populations since we are obviously dependent on the discovery of bones and the state of conservation of DNA. It turns out that archaeological excavations have been much more numerous in Europe, which greatly facilitates the study of the genomes of European populations,’’ explains Claudio Quilodrán, PhD, senior research and teaching assistant in the department of genetics and evolution at the UNIGE Faculty of Science, and co-first author of the study.

Paleolithic hunter-gatherers

Statistical analyses revealed that, in the period following the dispersal of Homo sapiens from Africa, the genomes of Paleolithic hunter-gatherers who lived in Europe contained a slightly higher proportion of DNA of Neanderthal origin than the genomes of those who lived in Asia. This result is contrary to the current situation but in agreement with paleontological data, since the presence of Neanderthals was mainly reported in western Eurasia (no Neanderthal bones have been discovered further east than the Altai region of Siberia).

Subsequently, during the transition to the Neolithic, i.e., the transition from the hunter-gatherer lifestyle to the farmer lifestyle, 10,000 to 5,000 years ago, the study shows a decline in the proportion of DNA of Neanderthal origin in the genomes of European populations, resulting in a slightly lower percentage than that of Asian populations (as currently observed). This decrease coincided with the arrival in Europe of the first farmers from Anatolia (Turkey’s western peninsula) and the Aegean area, who themselves carried a lower proportion of DNA of Neanderthal origin than the inhabitants of Europe at the same time. By mixing with the populations of Europe, the genomes of farmers from Anatolia “diluted’’ Neanderthal DNA a little more.

The study shows that the analysis of ancient genomes, coupled with archaeological data, makes it possible to trace different stages in the history of hybridized species. ‘‘In addition, we are beginning to have enough data to describe more and more precisely the percentage of DNA of Neanderthal origin in the genome of Sapiens at certain periods of prehistory. Our work can therefore serve as a reference for future studies to more easily detect genetic profiles that deviate from the average and might therefore disclose an advantageous or disadvantageous effect,’’ notes Currat, last author of the study.

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WuXiUI applies an intermittent-perfusion fed-batch (UI-IPFB) strategy in upstream production to realize a three- to six-fold increase in productivity in a typical culture duration of 14 days for a fed-batch process for different molecule modalities such as monoclonals, bispecifics, and recombinant proteins, according to Chris Chen, PhD, company CEO. For example, by leveraging WuXiUI, the titer of a bispecific antibody achieved 25 g/L in 14 days (five times higher than the same-scale traditional fed-batch process), he added.

“WuXiUI reduces drug substance manufacturing COGS by an estimated 60–80 percent compared to traditional fed-batch processes in single-use bioreactors, enhancing the competitiveness of commercial products,” continues Chen. “The platform is also easily adopted and can be scaled up/out in existing facilities without additional requirements for major equipment or complex operations, bringing minimum changes to the downstream process. Adhering to WuXi Biologics’ ESG (environmental, social, governance) strategy, WuXiUI has a lower carbon footprint than traditional or other intensified fed-batch processes due to more efficient media consumption and reduced waste generation.”

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This research is published in PLoS Biology in the paper, “Multi-drug resistant E. coli encoding high genetic diversity in carbohydrate metabolism genes displace commensal E. coli from the intestinal tract.”

“Antibiotic resistance has been hailed as one of the biggest health problems of our time by the World Health Organization, noted Alan McNally, PhD, professor at the Institute of Microbiology and Infection at the University of Birmingham, U.K. “There are further problems looming unless we get a better understanding of what is happening so that further drug resistance can be halted in its tracks.”

“Scientists have long questioned what makes certain types of E. coli successful multi-drug resistant pathogens,” McNally continues. “It seems that extra-intestinal pathogenic E. coli, which cause urinary tract and bloodstream infections, are particularly successful when it comes to developing resistance and are therefore especially tricky to treat. Our study provides evidence that certain types of E. coli are more prone to develop antibiotic resistance than others.”

The researchers first showed that both multi-drug resistant and non-resistant gut-dwelling E. coli were found to easily colonize a mammalian gut. In addition, using mice colonized with non-MDR E. coli strains, a challenge with MDR E. coli (either by oral gavage or co-housing with colonized mice) resulted in displacement and dominant intestinal colonization by MDR E. coli ST131.

The researchers went on to determine, using a functional pangenomic analysis of 19,571 E. coli genomes, that “carriage of AMR genes is associated with increased diversity in carbohydrate metabolism genes.”

Although some strains of E. coli are harmless, others can cause illness, including diarrhea, urinary tract infections, and often-fatal bloodstream infections. More severe infections are usually treated with antibiotics but the rise in multidrug resistance strains of E. coli is concerning. Previous work shows that multi-drug resistance alone is not sufficient to drive strains to complete dominance.

This study suggests that “independent of antibiotic selective pressures, MDR E. coli display a competitive advantage to colonize the mammalian gut and points to a vital role of metabolism in the evolution and success of MDR lineages of E. coli via carriage and spread.”

The post Commensal <em>E. coli</em> in Gut Readily Displaced by Drug-Resistant <em>E. coli</em> appeared first on GEN - Genetic Engineering and Biotechnology News.

The findings were published in the Proceedings of the National Academy of Sciences in an article titled, “Viral nanoparticle vaccines against S100A9 reduce lung tumor seeding and metastasis.”

“Metastatic cancer accounts for 90% of all cancer-related deaths and continues to be one of the toughest challenges in cancer treatment,” wrote the researchers. “A growing body of data indicates that S100A9, a major regulator of inflammation, plays a central role in cancer progression and metastasis, particularly in the lungs, where S100A9 forms a premetastatic niche. Thus, we developed a vaccine against S100A9 derived from plant viruses and virus-like particles. Using multiple tumor mouse models, we demonstrate the effectiveness of the S100A9 vaccine candidates in preventing tumor seeding within the lungs and outgrowth of metastatic disease.”

A team led by Nicole Steinmetz, PhD, a professor of nanoengineering at the UC San Diego Jacobs School of Engineering, developed a vaccine candidate that can modulate the levels of S100A9 when it goes haywire. When injected subcutaneously, the vaccine stimulated the immune system in mice to produce antibodies against S100A9. The vaccine also increased the expression of immune-stimulating proteins with anti-tumor properties, while decreasing the levels of immune-suppressing proteins.

“S100A9 is known to form what is called a premetastatic niche within the lungs, creating an immunosuppressive environment that allows for tumor seeding and growth,” said study first author Young Hun (Eric) Chung, a UC San Diego bioengineering PhD alumnus from Steinmetz’s lab. “By reducing S100A9 levels, we can effectively counteract the formation of this premetastatic niche, leading to a reduced attraction and increased clearance of cancer cells to the lungs.”

“This is a clever, new approach to vaccination in that we are not targeting tumor cells, but rather the tumor microenvironment so that it prevents the primary tumor from making new tumors,” said Steinmetz, who is also the founding director of the UC San Diego Center for Nano-ImmunoEngineering and co-lead of the university’s Materials Research Science and Engineering Center (MRSEC). “We are essentially changing the whole immune system to be more anti-tumor.”

The vaccine consists of nanoparticles made from a bacterial virus called Q beta. The nanoparticles were grown from E. coli bacteria and isolated. Afterward, a piece of the S100A9 protein was attached to the surface.

“With this form of immunotherapy, we are not necessarily knocking out all of the protein, but we are reducing the levels everywhere,” said Steinmetz.

The vaccine was tested in metastatic mouse models of melanoma and triple-negative breast cancer. Healthy mice were first administered the vaccine, then challenged with either melanoma or triple-negative breast cancer cells through intravenous injection. Vaccinated mice exhibited a significant reduction in lung tumor growth compared to unvaccinated mice. In unvaccinated mice, the injected cancer cells circulated throughout the body and eventually homed in on the lungs to form metastatic tumors.

The researchers noted that this vaccine strategy combats tumor spread, not the primary tumor itself.

“While S100A9 does get overexpressed in certain primary tumors, it is mainly indicated in metastatic disease and progression,” said Chung. “The protein is involved in the formation of immunosuppressive tumor microenvironments. Therefore, we found that our vaccine is much more effective at reducing metastasis, and not in reducing the growth of the primary tumors.”

“These findings are the most clinically relevant, as they closely model what could happen in real-life scenarios,” said Steinmetz. “For instance, a patient diagnosed with an aggressive cancer who undergoes surgery to remove their tumor may be at risk of recurrence and metastasis to the lungs. We envision that this vaccine could be administered post-surgery to prevent such recurrence and outgrowth of metastatic disease.”

Before the vaccine can progress to human trials, more comprehensive safety studies are needed.

“S100A9 is an endogenous protein within the lungs, and there isn’t a lot of data out there that demonstrate what happens when S100A9 is abolished,” said Chung. “We know that S100A9 is important in the clearance of pathogens, and future studies should better test whether reducing S100A9 levels decreases the patient’s ability to fight infections, especially in cancer patients who may have weakened immune systems.”

Future work will also explore the vaccine’s effectiveness when combined with other cancer therapies, with the aim of improving its efficacy against hard-to-treat cancers.

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Producing living cells as a therapeutic product is a complex process. To date, autologous-based cells comprise the majority of clinically-evaluated CAR T-cell products. Although autologous therapies can indeed be effective and life-changing for patients, this approach poses time and logistics constraints. Allogeneic cell products, generated using cells from healthy donors, can potentially overcome these limitations and provide the generation of “off-the-shelf” products.

But the technologies, solutions, and equipment needed to bring allogeneic cell therapies to large-scale clinical trials and global commercialization are not yet commercially available and that is, besides the biological challenge to guarantee immune evasion of these cells, one of the key bottlenecks facing the industry.

To capture the potential of using healthy donor stem cells as the basis for cell therapies, cells must be programmed in a way to avoid attack by the recipient’s immune system. Recent developments in gene editing technologies support strategies to design immune evasion.

“So now, we have the basis for moving from a single-patient autologous therapy to a one-to-many allogeneic therapy. However, we need the technologies, solutions, and equipment to make that possible,” pointed out Aaron Dulgar-Tulloch, PhD, chief technology officer, Cytiva. Cytiva and Bayer share a vision and common view of the challenges limiting the advancement of allogeneic cell therapy and believe that together they can overcome these challenges.

The companies are collaborating to build a fully-automated, modular platform that can be utilized for scaleup and manufacturing of multiple cell therapy products. The concept will use fully-characterized individual equipment modules that can be incorporated in a plug-and-play scenario. Both Dulgar-Tulloch and Bieringer believe this will accelerate the learning curve.

Human cells are fragile

Dealing with living cells as a therapeutic product makes the processes more complex than traditional biotherapeutics. Depending on the therapeutic application, different types of cells must be processed. These cells, which may need to be grown as aggregates, cell suspensions, or single cells, show higher sheer and nutrient and waste sensitivity relative to classical bioproduction cell lines.

In essence, the cells want to “feel good” in the corresponding reactors, which means that they require the right media composition. In addition, oxygen transfer and metabolic stress need to be precisely controlled. To provide the cells the optimal environment both the underlying biological process and the equipment performance must be optimized.

Enabling genomic medicines

The collaboration is focused on what the companies envision the entire genomic medicine field needs to bring cell therapies to patients faster. “If we are successful, we believe the entire community of therapy developers, technology providers and most importantly, patients, will benefit from accelerated, cost-effective, and globally available, allogeneic cell therapies,” said Dulgar-Tulloch.

The process began by aligning on the boundary conditions of the platform, i.e., the way to define the modularity (hardware and software plug-and-play), the automation and the process control concept. The initial focus is on two components with a current immense need: a 3D expansion system for production at scale and a robust harvest solution. As additional needs are identified other devices may follow.

The ultimate goal is to gather insights and offer solutions to a wide range of users driving the creation of an allogeneic cell therapy consensus platform. Bieringer emphasized that this will drive economies of scale and simplify global manufacturing, ultimately driving down costs to make allogeneic cell therapies more accessible.

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“GBM has an aggressive effect in part because of a milieu of immunosuppressive factors surrounding the tumor, which enable the tumor’s growth by preventing the immune system from entering and attacking it,” said E. Antonio Chiocca, MD, PhD, chair of the BWH Department of Neurosurgery. “This study showed that with a virus we designed, we can reshape this ‘immune desert’ into a pro-inflammatory environment.” Chiocca is corresponding author of the investigators’ published report in Nature, titled “Clinical trial links oncolytic immunoactivation to survival in glioblastoma.” In their report the team concluded, “These results provide human validation that intralesional oHSV treatment enhances anticancer immune responses even in immunosuppressive tumor microenvironments, particularly in individuals with cognate serology to the injected virus. This provides a biological rationale for use of this oncolytic modality in cancers that are otherwise unresponsive to immunotherapy.”

Glioblastoma is an aggressive form of high-grade glioma (HGG) brain cancer that is notoriously resistant to treatment. Recurrent HGG (rHGG), including rGBM are associated with survival of less than 10 months, the authors wrote.

Immunotherapies that are designed to mobilize the body’s immune defenses against cancer have not been effective for GBM, in part because the tumor microenvironment (TME) is largely impenetrable to assaults from the body’s immune system. This immunosuppressive TME defines these tumors as “lymphocyte depleted,” the investigators stated. “For rGBMs and several other highly immunosuppressive solid cancers, there is a need to find treatment modalities that can convert the TME into one that is more amenable to immunotherapy and immune activation.”

For the reported Phase I trial, Chiocca and colleagues examined the safety of the oncolytic virus CAN-3110, which was designed and taken through preclinical testing by researchers at BWH, a founding member of the Mass General Brigham healthcare system. The cancer-attacking oncolytic herpes simplex virus is the same type of virus used in a therapy approved for the treatment of metastatic melanoma.

Unlike other clinical oHSVs, CAN-3100 includes the ICP34.5 gene, which is often excluded from clinical oHSV candidates because it causes human disease in unmodified forms of the virus. However, the researchers hypothesized that this gene may be necessary to trigger a robust, proinflammatory response necessary for attacking the tumor. For their clinical candidate they designed a version of oHSV1 that contains the ICP34.5 gene but is also genetically programmed not to attack healthy brain cells. “To take advantage of ICP34.5’s functions that enhance viral replication/persistence and minimize neurotoxicity, CAN-3110 (former designation, rQNestin34.5v.2) was engineered to express a copy of the viral ICP34.5 gene under transcriptional control of the promoter for nestin, restricting viral replication and virulence to HGG/GBM cells,” the team explained.

Overall, the trial demonstrated the safety of CAN-3110 in 41 patients with high-grade gliomas, including 32 with recurrent GBM. The most serious adverse events were seizures in two participants. Notably, GBM participants who had pre-existing antibodies to HSV1 virus (66% of the patients) had a median overall survival of 14.2 months, compared to 7.8. months for seronegative patients. In patients with pre-existing antibodies, the researchers saw markers of several changes in the tumor microenvironment associated with immune activation. They hypothesized that the presence of HSV1 antibodies resulted in a rapid immune response to the virus, which brought more immune cells to the tumor and increased the levels of inflammation in the tumor microenvironment.

The authors also observed an increase in diversity of the T cell repertoire after CAN-3110 treatment, suggesting that the virus induces a broad immune response, perhaps by eliminating tumor cells resulting in the release of cancer antigens. The immunological changes observed after treatment were also shown to be associated with improved survival. “In summary, single-timepoint intralesional injection of rHGG/rGBM with CAN-3110 enriches the tumor microenvironment with TILs [tumor infiltrating lymphocytes], inducing defined changes in peripheral and tumor T cell repertoires and tumor transcriptomic signatures,” the team commented in their discussion. “These findings therefore provide human immunological and biological evidence supporting intralesional oncolytic modalities to convert the immunosuppressive TME characteristic of many solid cancers into a TME that is more favorable to immunologic rejection of the tumor.”

Going forward, the researchers plan to complete prospective studies to further investigate the effectiveness of the oncolytic virus in patients who do and do not have antibodies to HSV1. Having demonstrated the safety of one viral injection, they are proceeding to test the safety and efficacy of up to six injections over four months, which, like multiple rounds of vaccination, may increase the effectiveness of the therapy. “We are now set to determine whether multiple-timepoint injections lead to further improvements in this therapy,” the authors confirmed.

“Almost no immunotherapies for GBM have been able to increase immune infiltration to these tumors, but the virus studied here provoked a very reactive immune response with infiltration of tumor-killing T-cells,” Chiocca said. “That’s hard to do with GBM, so our findings are exciting and give us hope for our next steps.”

Brigham and Women’s Hospital own the patents related to oHSV and CAN-3110, with Chiocca as a co-inventor. The patents have been licensed to Candel Therapeutics.

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Reporting in ACS Central Science (“Deep Learning-Predicted Dihydroarteminsinin Rescues Osteoporosis by Maintaining Mesenchymal Stem Cell Stemness through Activating Histone 3 Lys 9 Acetylation,”) the team said their collective studies suggested that “… DHA could be a promising therapeutic agent for treating osteoporosis by maintaining BMMSC stemness.”

Osteoporosis is a degenerative disease that affects the skeletal system and is characterized by the loss of bone density and destruction of the bone microstructure. In healthy people, there is a balance between the osteoblasts that build new bone and osteoclasts that break it down. But when the “demolition crew” becomes overactive, it can result in bone loss and osteoporosis, which typically affects older adults. BMMSCs, which are the precursors of osteoblasts, play a crucial role in osteoporosis, the authors wrote. “BMMSCs maintain a constant flow of functional osteoblasts by committed differentiation and a local population through steady proliferation and refreshment, which together constitute the stemness of BMMSCs under physiological motion.” Maintaining the stemness of BMMSCs is thus “crucial for bone homeostasis and regeneration,” they continued.

However, during osteoporosis, these multipotent cells tend to turn into fat-creating adipocytes and have “diminished regenerative potential,” the authors continued. “Because BMMSCs provide a continuous supply of osteoblasts for bone repair, it is critical to find ways to restore their functions.”

Previously, Zhengwei Xie, PhD, at Peking University, and colleagues, trained a deep learning algorithm to predict cellular responses with drug treatment and eventually accurately predicted the efficacies of new drugs by comparing the changes in gene expression profiles of diseased and drug-treated cells. “This deep learning-based efficacy prediction system (DLEPS) has already been successful in discovering new drugs for a range of diseases, including obesity, hyperuricemia, and NASH.” For their newly reported study, the investigators, joined by Yan Liu, PhD, and Weiran Li, PhD, at Peking University School and Hospital for Stomatology, wanted to use the algorithm to find a new treatment strategy for osteoporosis that focused on BMMSCs.

The team ran the program on a profile of differently expressed genes (DEGs) in newborn and adult mice. One of the top-ranked compounds identified was DHA, a derivative of artemisinin and a key component of malaria treatments. “From the top-ranked candidates, we identified dihydroartemisinin (DHA), a traditional Chinese herbal extract that can promote BMMSC stemness, which is beneficial for establishing healthier bone homeostasis,” the investigators noted.

In vivo studies showed that administering DHA extract for six weeks to an ovariectomized (OVX) mouse model of osteoporosis significantly reduced bone loss in the animals’ femurs and nearly completely preserved bone structure. “In general, oral administration of DHA rescued endogenous mBMMSC stemness in OVX mice, while correcting the biased differentiation inclination from adipogenesis to osteogenesis,” the scientists explained.

“Taken together, the therapeutic effect of MSN-ALN@DHA on osteoporosis was mainly achieved by the protection effect of DHA on the stemness of BMMSCs, while both MSN-ALN and DHA also played a certain role in inhibiting osteoclastic activity,” they wrote. “The use of the bone-targeting carrier, MSN-ALN, has improved the therapeutic efficacy of DHA. Compared to oral administration of DHA, the application of MSN-ALN@DHA ensures treatment efficacy while reducing the frequency of drug administration.”

The researchers say that this work demonstrates that DHA is a promising therapeutic agent for osteoporosis. “These findings also demonstrate the potential of deep learning approaches to accelerate drug development and facilitate precision medicine,” they commented in their paper.

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To date, no validated biomarkers have been identified to predict immunotherapy responsiveness across head and neck squamous cell carcinomas (HNSCC) patients. Now, researchers from Akoya Biosciences and the University of Queensland, Brisbane, Australia, have optimized and applied an ultra-high plex, single-cell spatial protein analysis in HNSCCs. Tissues were analyzed with a panel of 101 antibodies that targeted biomarkers related to tumor immune, metabolic, and stress microenvironments.

“This work brought together the latest advances in spatial biology and paired these with ultra-high plex antibody panels and profiled real-world patient samples,” noted Arutha Kulasinghe, PhD, senior research fellow, Frazer Institute, University of Queensland, Australia, where he also leads the Clinical-oMx Lab.

This work is published in GEN Biotechnology in the paper, “Mapping the Spatial Proteome of Head and Neck Tumors: Key Immune Mediators and Metabolic Determinants in the Tumor Microenvironment.”

HNSCCs are tumors that develop in the lip, oral cavity, larynx, salivary glands, nose, sinuses, or the skin of the face. They are the seventh most common cancer globally causing more than 300,000 deaths annually. Immune checkpoint inhibitors have shown promise in treating recurrent/metastatic cases.

Here, researchers present a framework for single-cell spatial analysis of proteins to analyze HNSCCs. First, they developed an ultra-high plex antibody panel with antibodies for detection of immune cells, cancer cells, and markers that identify cellular metabolism, apoptosis and stress, tumor invasion, and metastasis, as well as cellular proliferation and deregulation.

“It’s a significant step forward,” noted Kulasinghe. “Usually, we profile 10–20 markers on tissue routinely. This study developed and tested 101 markers focused on the hallmarks of cancer pathways. It’s a technological breakthrough and now lends itself for high throughput applications such as clinical studies.”

The data uncovered a “high degree of intra-tumoral heterogeneity intrinsic to HNSCC” and provided unique insights into the biology underlying the disease.

This study showed, explained Kulasinghe, that tumors are highly heterogeneous and have areas akin to “north” and “south” poles for treatment sensitivity. “Understanding this and visualizing this is very powerful for the field of immunotherapy and precision medicine,” he asserted.

Single-cell spatial phenotyping of the human FFPE head and neck squamous cell carcinoma revealed six spatial neighborhoods across 14 distinct cell types. In addition, functional phenotyping based on key metabolic and stress markers identified four distinct tumor regions with high intra-tumoral heterogeneity and differential protein signatures.

More specifically, the authors noted that one region was marked by infiltration of CD8+ cytotoxic T cells and overexpression of a proapoptotic regulator—suggesting strong immune activation and stress. Another adjacent region within the same tumor had high levels of expression of G6PD and MMP9. These proteins are known to drive the processes of tumor resistance and invasion, respectively.

The research provides a more complete understanding of the tumor immune microenvironment. It also provides insights into the metabolic state and biology of different regions within the tumor. The data describe an interplay between immune infiltration and the metabolic and stress responses of tumor cells in certain areas. In addition, the findings demonstrate that heterogenous niches and competing microenvironments may underpin variable clinical responses.

Lastly, noted Kulasinghe, “The study sets the framework and workflow for true highplex discovery studies for clinical applications.”

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