Now, researchers at the Salk Institute have created what they describe as the first microprotein atlas of the human frontal cortex with and without Alzheimer’s disease. The study, “A microprotein atlas of the human frontal cortex in Alzheimer’s disease,” was published in Nature Aging. The resource integrates transcriptomics, mass spectrometry, and deep-learning-predicted spectra across postmortem brain samples to identify microproteins that have been overlooked in standard protein catalogs.

“We still do not fully understand the molecular mechanisms of healthy aging, and that is especially true for microproteins, which have been inadvertently overlooked for decades,” said senior and co-corresponding author Alan Saghatelian, PhD, professor and the Dr. Frederik Paulsen Chair at Salk, in a press release. “Our atlas allows scientists to systemically investigate microproteins in aging and neurodegeneration, which should bring us closer to understanding and tackling diseases like Alzheimer’s or Parkinson’s.”

Saghatelian told GEN the work began with a basic limitation in how proteomes are annotated. “Every reference proteome is built on gene models that exclude smORFs by construction. So the first motivation was straightforward: build a search database that can actually see these sequences, and point it at the deepest human brain proteomics data that exists.”

The atlas was built using data from hundreds of postmortem human frontal cortex samples from individuals with and without Alzheimer’s disease, including samples made available through the Religious Orders Study/Memory and Aging Project cohort. The team analyzed existing native transcriptomic and mass spectrometry data with custom computational tools, including ShortStop, an AI-powered microprotein-finding tool developed in Saghatelian’s lab.

“We were able to take all these technologies and tools and reapply them to existing data from nearly 500 brains to find new microproteins,” said first and co-corresponding author Brendan Miller, PhD, a postdoctoral researcher in Saghatelian’s lab. “We were able to create an entirely new database that researchers can download and use to better interpret functions of genes.”

In total, the researchers identified 1,067 previously uncharacterized microproteins absent from reviewed UniProtKB entries, supported by high-confidence spectral support, according to the paper. Some of these microproteins were expressed differently in Alzheimer’s disease samples compared with non-Alzheimer’s samples, and the paper reports that Alzheimer’s disease cells tended to show higher overall microprotein expression.

The investigators then focused on microglia, which are known to change with aging and neurodegeneration. Their analysis highlighted a small open reading frame at the MKKS locus encoding a 63-amino-acid microprotein that appeared to be the predominant translation product at that locus and is downregulated in Alzheimer’s disease. When the researchers knocked out the microprotein-making gene in microglia, mitochondrial respiration was impaired, suggesting a role for the microprotein in microglial bioenergetics.

The MKKS finding also underscored a broader issue with relying only on canonical protein annotations. “The general implication is uncomfortable: the most abundant and most tissue-relevant protein product at a locus can be the one that isn’t annotated,” added Saghatelian.

He also cautioned that not every microprotein identified in the atlas should be assumed to be functional. “There are two ways to read an expressed microprotein. It may be a marker—evidence that its gene’s transcription or splicing is disrupted—without the peptide itself doing anything. Or it may be a bioactive molecule with biology distinct from the canonical product at that locus.”

The findings point to a possible connection between microproteins and immune cell dysfunction in Alzheimer’s disease. “There is sometimes an assumption that we know everything about our genome, and we know all the genes our cells can make—that’s just not true,” Saghatelian said. “What we know is constantly expanding, and this atlas makes it that much easier to study microproteins in life science research.” Beyond Alzheimer’s disease, the publicly available atlas could serve as a framework for mapping microproteins in other brain regions, tissues, and disease contexts.

The post Microprotein Atlas Links Brain Immune Cell Dysfunction to Alzheimer’s appeared first on GEN - Genetic Engineering and Biotechnology News.

Exosomes are microscopic packages released by cells that carry proteins and other molecules throughout the body. The research team found that a shingles infection can cause nerve cells to release inflammatory signals and become highly active. When investigators exposed healthy nerve cells in the lab to exosomes collected from the blood of people with PHN, they found that the exosomes triggered in the nerve cells many of the same harmful changes seen during viral infection, even though no virus was present.

The findings suggest that PHN may develop because the body fails to fully turn off the healing response after shingles. Even after the virus has been cleared, exosomes continue delivering damaging messages that prevent nerves from recovering normally.

The study results indicate that chronic shingles pain may not simply be the result of damage caused during the initial infection, the study authors noted. Instead, biological signals carried by exosomes may continue to keep nerve cells in an irritated, dysfunctional state and prevent them from healing. The researchers describe this as a “failure-to-resolve” model, where the nervous system becomes stuck in a cycle of inflammation and abnormal nerve remodeling. This opens the door to entirely new approaches for predicting, preventing, and treating post-herpetic neuralgia.

The researchers, headed by Andrew Bubak, PhD, associate professor of neurology at CU Anschutz who studies the role of exosomes in infectious disease, reported their findings in Annals of Neurology, in a paper titled, “Circulating Exosomes Drive Persistent Neuronal Dysfunction in Post-Herpetic Neuralgia Patients,” concluding, “These findings establish a failure-to-resolve model in which persistent exosome-mediated signaling sustains maladaptive neuronal remodeling after viral clearance, identifying circulating exosome cargo as previously unreported mechanistic contributors to PHN pathogenesis and potential therapeutic targets.”

Varicella zoster virus can establish lifelong latency in sensory ganglia subsequent to primary infection and reactivate to cause herpes zoster—HZ; shingles—the authors explained. “Whereas most individuals recover from HZ, a substantial subset develop post-herpetic neuralgia (PHN), commonly defined as pain persisting for more than three months after rash …”. However, the mechanisms driving the change from acute viral injury to chronic neuropathic pain aren’t well understood. Bubak said, “We can completely stop the infection, yet in some patients the pain does not go away.”

The team’s prior work had demonstrated that plasma-derived exosomes from individuals with acute zoster infection, while non-infectious, carry prothrombotic and immunoregulatory cargo, and can activate platelets and induce proinflammatory cytokine production in vascular cells, promoting an inflammatory state.

Through their newly reported study the scientists discovered that nerve cells infected with the shingles virus in the laboratory became inflamed and showed signs of stress and irritation. Exposure to PHN patient-derived exosomes triggered inflammation in nerve cells and reduced the ability of nerves to grow and repair themselves. Exosome exposure also caused structural changes that may make nerves function abnormally and led to increased production of molecules associated with chronic pain. The exosomes didn’t kill the nerve cells and rather appeared to keep them in an unhealthy, dysfunctional state.

The researchers expected to see increases in the usual pain-signaling channels found on nerve cells. Instead, they found those channels were actually reduced. At the same time, levels of substance P, a chemical messenger involved in pain transmission, increased. This suggests that chronic shingles pain may be driven less by traditional nerve firing and more by ongoing chemical signals that keep the pain system activated. “Collectively, our findings point toward a potential ‘failure-to- resolve’ model in which PHN arises not from a fundamentally distinct biological process, but from the persistence and amplification of an initially adaptive, exosome-driven neuronal response,” the authors noted. Bubak said the findings could lead to new therapies to target these exosomes and relieve the pain.

Typical antiviral therapies such as acyclovir and valacyclovir target the replicating virus but do not consistently prevent PHN, “… reinforcing the notion that mechanisms independent of ongoing viral replication sustain the pathological state,” the team continued. “This is consistent with our findings, which suggest that non-infectious circulating exosomes, once generated during acute infection, persist and drive neuronal dysfunction independently of ongoing viral replication.”

At the same time, Bubak said, if the exosomes maintain this irritable state within the cell, they could also carry therapeutic agents to the target that block specific proteins and help nerves recover and regrow normally after shingles. “If exosome cargo contributes to the maintenance of the irritable nociceptor state, then circulating exosomes may represent both a source of therapeutic targets and a minimally invasive biomarker platform,” the authors also noted. “Early exosome profiles during acute HZ could potentially identify individuals at risk of developing PHN, enabling stratification and targeted intervention prior to the establishment of chronic symptoms.”

Bubak added: “This is an important discovery, one that offers hope to those who continue to struggle with often intense pain following infection with shingles.”

The post Exosomes Linked to Nerve Irritation, Dysfunction, and Lingering Pain After Shingles appeared first on GEN - Genetic Engineering and Biotechnology News.

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Emily Gaither

Engineer III, Downstream Purification
Thermo Fisher Scientific

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Panelist

Emily Gaither

Emily Gaither is a bioprocessing engineer specializing in downstream purification at Thermo Fisher Scientific. She has over five years of experience in downstream process development, with expertise in downstream process development, characterization, scale up and manufacturing implementation. Prior to joining Thermo Fisher Scientific in 2021, Emily worked at the University of Illinois Urbana-Champaign, where she supported bioengineering research and laboratory automation. Emily holds a bachelor’s degree in biology from North Central College.

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Bispecific antibodies can create purification challenges that conventional monoclonal antibody platform polishing is not always equipped to solve, with product-related variants “misbehaving” and closely resembling the desired heterodimer. Effective and efficient process development depends not only on identifying the appropriate selectivity from a toolbox of chromatography resins, but also how efficiently complementary unit operations interconnect for manufacturing.

In this GEN webinar, our expert speaker, Emily Gaither, will present a systematic path from high-throughput resin screening to the selection and sequencing of two polishing steps, using emicizumab, an asymmetric IgG4 bsAb as a case study. She will compare alternative process configurations and examine the purity, recovery, and process-performance tradeoffs used to identify a preferred downstream polishing train. Key takeaways from the webinar include:

• A systematic approach to screening polishing resins for bsAbs
• Strategies for matching resin selectivity to key impurities
• Insights into how polishing resin selection affects process performance
• Criteria for balancing purity, yield, loading, and robustness

A live Q&A session will follow the presentation, offering you a chance to pose questions to our expert panelist.

Produced with support from:

The post Right Resin, Right Order: A Two-Step Polishing Strategy for Bispecific Antibodies appeared first on GEN - Genetic Engineering and Biotechnology News.

FJBio is a global antibody discovery and engineering partner. Founded in 2012, the company works on taking programs from target to preclinical candidate within a single integrated workflow, run by one team across three centers of excellence: Porto (Portugal), Cambridge (U.K.), and San Diego (U.S.). The antibody company completed more than 1,400 programs for over 250 industry partners across pharma, biotech, and academia, with 20 partner assets in clinical trials.

The volume and complexity of experimental data generated across those programs made consistent, structured records a scientific and operational priority for FJBio, according to Sapio Sciences’ CCO Mike Hampton, who added that the company’s AI platform will serve as the informatics backbone across all of FJBio’s discovery and cell sciences operations.

Provides a single entity registry

Sapio’s ELN solution will record experimental data across phage display, screening, and cell sciences programs, replacing the need for scientists to capture data on paper templates before manually re-entering results into spreadsheets. As FJBio’s program portfolio has grown across three sites, the Sapio LIMS gives the company a single entity registry, from target registration through clone identification and screening results, searchable across programs, points out Hampton.

The solution is also designed to ensure integration of lab instruments, connecting instrument output directly to Sapio’s experiment records and eliminating manual data transcription at the bench. Structured client data reports, that were assembled by hand from individual experiment records will now come straight out of the platform, expected to return up to 40% of scientific staff time back to discovery, says a Sapio spokesperson.

“FairJourney Bio runs discovery programs of genuine depth and complexity across multiple international sites,” comments the spokesperson. “The Sapio Scientific AI platform gives their scientists a single, structured environment where experimental records connect directly to client deliverables and where time spent on data consolidation becomes time spent on science.”

“As our operations have grown across three international sites, we needed an informatics platform that could keep pace with that responsibility,” says Vidal. “The Sapio Platform gives our scientists a single connected environment for every experiment, every sample and every result, and it holds that data to the integrity and security standards our clients expect.”

Elain brings intelligence directly into FJBio’s scientific workflows, says Hampton. Working across the structured experimental data held within the Sapio Platform, Elain enables scientists to interact with their data using natural language, without leaving the environment where their experiments, samples and results are managed, he explains.

The post Consolidating Antibody Discovery Data with an AI Platform appeared first on GEN - Genetic Engineering and Biotechnology News.

The investment will add downstream fermentation technology to the site, increasing capacity for the development and manufacture of complex pharmaceutical intermediate. Creating approximately 50 new jobs, the expansion will further reinforce the Fermas site as one of Evonik’s key biotechnology hubs, said Lauren Kjeldsen, member of the management board and COO at custom solutions, Evonik.

“Today is an important step in our strategy to expand our biotechnology platform and support our customers with innovative, scalable, and sustainable manufacturing solutions,” continued Kjeldsen. “Biotechnology demonstrates how economic growth and sustainability can go hand in hand.”

Compared with conventional chemical synthesis, fermentation-based processes can offer a more sustainable route to selected intermediates by reducing the need for organic solvents and minimizing process-related waste. The Fermas site already operates on 100 percent green electricity and uses renewable and certified raw materials in selected production processes.

“This investment demonstrates the company’s confidence in biotechnology and in Slovakia as a location where innovation turns into industrial scale products,” added Miroslav Havlik, general manager of Evonik Fermas.

Evonik Fermas, which was founded in 1992, has evolved from amino acid production into a biotechnology manufacturing hub serving the pharmaceutical, personal care, nutrition, and specialty chemical industries. In recent years, the site has also become a major location for Evonik’s biotechnology activities, including the launch of an industrial-scale rhamnolipid biosurfactant production facility.

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There are currently over 100 different serotypes of S. pneumoniae. While it is known that different subtypes of S. pneumoniae can lead to varying infection rates in different populations, important gaps remain in our collective understanding of how things such as humidity, temperature, and air pollution impact the timing of disease, and how risks vary by individual age and bacterial subtype.

Now, researchers suggest that the subtype of S. pneumoniae, together with air pollution exposure, impacts the rate and timing of invasive disease—with some strains linked to immediate infection after air pollution exposure, and others taking several weeks. The findings also suggest that older adults and young children are more vulnerable during periods of high air pollution, and that improving air quality could lower disease risk. Understanding what type of bacterial strains are circulating, and how environmental factors shape infection rates, could inform future public health policies, protect those most at risk, and prepare hospitals for outbreaks.

The work is published in Nature Microbiology in the paper, “Pneumococcal population structure influences the effects of air pollution on invasive disease risk in South Africa.”

“While we found that temperature and air pollution generally increase the risk of invasive pneumococcal diseases, such as bacterial meningitis, our research also suggests that it is the bacterial subtypes a person is carrying that modulate infection rates,” notes Sophie Belman, PhD, previously at the Wellcome Sanger Institute and Barcelona Supercomputing Center, and currently an assistant professor at Yale School of Public Health. “The strain of bacteria impacts the timing of disease and who might be more at risk depending on their respiratory microbiome, meaning that the risk is not the same in every situation or for every person. By extending our findings to other parts of the globe, we will better understand who has the highest health risk from environmental exposures, and what factors need to be addressed in different regions, such as improving air quality in cities.”

This new study examined roughly 59,000 cases of IPD across 19 years from South Africa’s national GERMS-SA surveillance program. In South Africa, between 40-60 per cent of children carry S. pneumoniae. The researchers found that different subtypes of S. pneumoniae responded differently to higher air pollution exposure, noting three subtypes (14, 19A, and 8) were linked to the greatest risk of IPD following exposure.

Additionally, they found that different subtypes were linked to differences in the timing of disease risk. While the highest risk of IPD peaked roughly two weeks after air pollution exposure, in areas where subtypes 4, 8, 23F, and 19F were common, there was an immediate increase in disease risk, occurring within the same week.

The team accounted for other factors including temperature, humidity, and population density to ensure that the effects were measured as accurately as possible. They also noted that high temperatures were associated with an immediate increase in disease risk, and cold temperatures led to a delayed rise in cases. The team suggests that cold weather slows bacterial transmission or that damage from seasonal viruses could make it easier for bacterial infections to follow.

The authors suggest that integrating environmental monitoring with genomic surveillance of S. pneumoniae could help predict infection spikes, inform vaccination strategies, and support healthcare providers prepare during periods of poor air quality. The study also provides further evidence that reducing air pollution may yield important benefits for infectious disease prevention, particularly in areas with high levels of exposure, such as cities.

The post Pneumococcal Subtypes Influence the Impact of Air Pollution on Disease Risk appeared first on GEN - Genetic Engineering and Biotechnology News.

“People with this genetic variant have dramatically hastened onset of disease, but we didn’t know why,” said Michael Hayden, MBChB, PhD, professor at the Centre for Molecular Medicine and Therapeutics at UBC. “This work answers that question and provides dramatic evidence that repeated expansion of the mutation is an important driver of Huntington disease and a potential treatment target.” Hayden is senior author of the researchers’ published paper in Neuron, titled “Loss of interruption in the HTT CAG repeat is associated with increased somatic expansion and loss of medium spiny neurons in HD.”

Huntington disease is a rare, inherited neurological disorder that causes the progressive breakdown of nerve cells in the brain. The condition affects movement, thinking and emotional well-being, and there is currently no cure or treatment to slow progression.

One way to think about the process is like a typo in a document that keeps getting copied. With every copy, the mistake is replicated and interferes with the message. “HD is caused by 36 or more uninterrupted CAG repeats in exon 1 of the Huntingtin gene (HTT), and the number of inherited CAG repeats is the primary determinant of the age at which symptoms first emerge,” the authors explained.

In Huntington disease the mutation continues to repeat and expand within neurons over time. As those repeats become longer, they interfere with normal cell function and make brain cells increasingly vulnerable to damage and death. “Medium spiny neurons (MSNs) are gradually lost in HD and undergo selective somatic CAG expansion, but it is unclear how somatic expansion relates to MSN pathology,” they continued.

Hayden added, “When we looked at the neurons that are dying in Huntington disease, we saw much greater expansion of the genetic mutation. This continues to strengthen the argument that DNA expansion is an important cause of disease.”

A small proportion of people with HD have a particular genetic variant, and researchers have known for years that these individuals develop Huntington disease earlier in life. “CAG and CCG loss-of-interruption (CAG-CCG LOI) variant hastens the onset of HD motor symptoms by up to 12.5 years and accelerates clinical measures of disease progression when compared with patients with the canonical sequence,” the team noted.

But it wasn’t known why this seemingly small change in DNA had such a dramatic effect on disease onset and progression. People carrying the variant had dramatically larger expansions of the Huntington mutation inside their neurons, occurring about five times more frequently than in patients without the variant. They also had fewer surviving neurons and earlier loss of particularly vulnerable nerve cells.

For their reported study the researchers analyzed blood samples and post-mortem brain tissue. “Here, we apply complementary approaches to assess somatic HTT CAG expansion from peripheral blood, postmortem brain tissues, and isolated MSNs of HD patients with and without the CAG-CCG LOI modifier variant and quantify MSN loss in the CAG-CCG LOI donor caudate.” They found a clue that helps explain one of the mysteries of Huntington disease, which is why a mutation that is present in every cell of the body primarily damages the brain.

Although the mutation exists throughout the body, the researchers found that the expansion process appears to be highly concentrated in certain cells of the brain. Blood samples, by contrast, showed little evidence of the dramatic changes that take place within the brain’s neurons. “Our interrogations of somatic expansion in blood, brain, and striatal MSNs of donors with and without the CAG-CCG LOI show this modifier does not increase small expansions in blood or bulk brain tissues, yet profoundly increases the proportion of genomic large (111–150) and very large (>150) CAG expansions in affected striatal MSNs,” they wrote.

“The mutational expansion seems to be selective for the brain,” Hayden added. “That may help explain why Huntington disease, even though the mutation is in every cell, is fundamentally a brain disease.”

The findings suggest blood tests are not a reliable indicator of the disease unfolding inside the brain, which is an important consideration for future Huntington disease research and clinical trials. “Peripheral blood DNA does not capture increased somatic expansion in MSNs, suggesting that blood DNA is a poor biomarker for disease-relevant somatic expansion in HD-affected neurons,” they noted.

While other factors besides expansion likely contribute to neuron loss, the findings provide some of the strongest human evidence to date that expansion of the Huntington mutation is a key factor in disease progression. “It validates repeat expansion of the DNA as an important therapeutic target in Huntington disease,” Hayden said. “If we can suppress that expansion, it may be possible to delay progression or delay the onset of disease.” And as the authors further commented, “Our study further underscores the need for cell-type-specific studies across other repeat expansion disorders that preferentially affect specific neuron populations.”

Several experimental therapies in development aim to slow or prevent this mutation growth before the damage occurs. While more research is needed, this study’s findings show research is moving in the right direction for a disease which has been so difficult to treat.

The post Why Does a Particular Genetic Variant Lead to Accelerated Huntington Disease Development? appeared first on GEN - Genetic Engineering and Biotechnology News.

Arguably the most dramatic loss faced by Novartis is satisfaction with its direction by major investors—one of which, Artisan Partners, went public with criticism of the company’s board.

M. David Samra, managing director at Artisan Partners and founding partner of International Value Group, called on the board—specifically, its chairman Giovanni Caforio—to strengthen its oversight of the company’s acquisitions.

“I think he needs to make changes at the board level. One of them should be on improving the team that’s doing ​these deals because clearly they have been uninspiring at best,” Samra told Reuters in an interview.

“The party is over,” Samra declared, complaining that the acquisition deals lowered the value of Novartis shares. “The acquisition track record is not very good.”

Among the acquisitions cited by Samra were Novartis’ $12 billion buyout of Avidity Partners, a deal completed in February with the aim of bolstering the buyer’s neuroscience pipeline with three late-stage programs—del-desiran and two other candidates in a new class of RNA therapeutics that Avidity and now Novartis call Antibody Oligonucleotide Conjugates (AOCs).

The companies have reasoned that the AOC approach can safely and effectively treat serious genetic neuromuscular disorders by delivering RNA to muscle tissue via TfR1 mAb, in order to enable modulation of the genetic mechanism of disease.

But that argument was undermined when Novartis acknowledged that del-desiran failed the pivotal trial (HARBOR, NCT06411288) by missing the study’s primary endpoint of statistically significant improvement vs. placebo in video Hand Opening Time (vHOT) through week 54. vHOT is a frequently used measure of hand myotonia, according to a 2024 study, and involves clinical experts reviewing videos to measure the time from hand grip to opening.

Del-desiran is an AOC candidate designed to target the underlying cause of DM1. The therapy consists of a muscle-targeting monoclonal antibody that binds to the transferrin receptor 1 (TfR1) and is conjugated to a small interfering RNA (siRNA) designed to induce degradation of the disease-causing toxic myotonic dystrophy protein kinase (DMPK) mRNA.

Del-desiran has received the FDA’s Orphan Drug, Fast Track, and Breakthrough Therapy designations, as well as the European Medicines Agency’s Orphan Medicinal Product Designation.

“Needs to be penalized”

“If you do a $12 billion deal and it goes to zero, the management needs to be penalized for that,” Samra said, though he acknowledged that the Avidity acquisition may yet yield successful candidates that can be developed into marketable drugs.

Samra also took issue with Novartis’ acquisition of MorphoSys for €2.7 billion ($3.1 billion), completed in May 2024. That deal was intended to bolster the buyer’s oncology pipeline with what seemed like a promising late-stage myelofibrosis candidate in pelabresib, as well as an early-stage candidate under study in patients with solid tumors or lymphomas.

Within months, Novartis delayed earlier plans to pursue mid-2024 approval filings for pelabresib and later said more time was needed to decide a regulatory path for the drug based on 48-week data from the Phase III MANIFEST-2 trial (NCT04603495). However, the combination of pelabresib plus ruxolitinib met the study’s primary endpoint, a reduction of at least 35% in spleen volume from baseline (SVR35) at 24 weeks: 65.9% of pelabresib-ruxolitinib patients (N=214) vs. 35.2% of placebo-ruxolitinib patients (N=216)

Earlier this year, Novartis launched the Phase III MANIFEST-3 trial (NCT07357727) assessing pelabresib in combination with ruxolitinib in patients with myelofibrosis. Novartis markets ruxolitinib outside the United States as Jakavi®, while Incyte markets the drug Stateside as Jakafi®. The trial’s estimated completion date is May 2028.

Del-desiran was one of three clinical setbacks for Novartis within a week. On September 4, the company and partner Ionis Pharmaceuticals (Nasdaq: IONS) acknowledged that their co-developed pelacarsen failed the Phase III Lp(a)HORIZON trial (NCT04023552) by missing its primary endpoint of reducing the risk, compared with placebo, of cardiovascular events.

Two days earlier, Novartis paused eight trials assessing its autoimmune and neurological disease candidate rapcabtagene autoleucel (rap-cel), after three patients treated with the personalized, CD19-directed chimeric antigen receptor T cell (CAR T) therapy died after experiencing immune effector cell-associated hemophagocytic syndrome.

Not Blaming CEO

Samra stopped short of blaming Vas Narasimhan, who has been Novartis’ CEO since 2018, for the company’s clinical setbacks, saying the chief did a “very good job”—with Reuters suggesting by juxtaposition a possible explanation: The company’s shares have jumped 60% in value during his tenure at the helm.

But Novartis’ primary shares in Switzerland have only risen 2% from CHF 108.50 ($132.88) so far this year and climbed 11% from CHF 101.78 ($124.65) year-over-year.

Worse, the announced failure of del-desiran on September 8 propelled Novartis shares to their worst one-day selloff since March 2020, early in the COVID-19 pandemic. Shares trading on the SIX Swiss Exchange skidded 11% from CHF 125.46 ($153.64) to CHF 111.80 ($136.91), while Novartis’ American depositary shares traded on the New York Stock Exchange slid 14% from $159.99 to $137.72.

Both shares all but plateaued for the rest of the week, failing to regain momentum. At the end of trading Friday, the SIX Swiss shares inched up 0.2% to CHF 112.04 ($137.21), while the NYSE shares dipped a further 0.4%, finishing the week at $137.16.

Artisan’s flagship fund, the Artisan International Value Fund, listed Novartis as fourth among its top 10 holdings, accounting for 3.6% of its total portfolio as of June 30, according to its most recent quarterly fact sheet. As of that date, Artisan reported $45.184 billion in assets, which would have made the value of Artisan’s stake in Novartis approximately $1.627 billion.

That stake likely increased later in the summer before the del-desiran news, since Artisan’s website lists the total value of the value fund at $46.001 billion as of August 31.

In addition to del-desiran, Novartis acquired delpacibart zotadirsen (del-zota), an Exon 44-targeting AOC designed to treat Duchenne muscular dystrophy (DMD), and delpacibart braxlosiran (del-brax), an AOC intended to treat facioscapulohumeral muscular dystrophy (FSHD) by targeting DUX4.

Del-zota is under evaluation in the Phase II EXPLORE44OLE (NCT06244082) trial following completion in November 2024 of the Phase I/II EXPLORE44 (NCT05670730) study. Del-brax is being assessed in the Phase III FORTITUDE-3 trial (NCT07038200).

In June, Novartis trumpeted positive data from the FORTITUDE Phase I/II trial (NCT05747924) of del-brax, saying the study’s biomarker cohort met its primary and key secondary endpoints, with reductions in KHDC1L (cDUX) and creatine kinase biomarker levels indicating both strong target engagement and reduction in muscle damage in patients with FSHD.

Investors weigh in

Samra’s criticism of Novartis’ board was echoed by what Reuters said was some of seven other representatives of shareholders, five of whom were quoted by name in a follow-up article.

“It’s ​going to take a while for confidence to return,” said Gillian Hollenstein, lead manager at Point Capital Navigator Fund, which, as of September 10, listed Novartis as tenth of its top 10 holdings, accounting for 1.8% of its total portfolio. The fund reported CHF 124.38 million ($152.33 million) in total assets as of that date, making Point Capital’s stake total CHF 2,238,840 (more than $2.7 million).

“They ​would have been better off doing some more smaller acquisitions, bolt-on ones rather than trying to hit it out of the park,” Hollenstein added.

Avidity was the largest of 11 biopharma acquisitions Novartis has carried out since 2023. They all could total up to $32.9 billion if Novartis achieves the milestones called for in five of the deals.

“It’s a little bit premature to call for heads at this point,” said Daniel Bolanowski, portfolio manager at investor Arctic Asset Management, since Avidity-created del-zota and del-brax could ultimately succeed in the clinic and generate revenue. But Bolanowski added that the stock selloff suggested “a deeper trust issue” with the company’s business development approach, beyond the failure or reduced value of del-desiran.

Arctic Aurora, as of June 30, had a Novartis investment it quantified as 2,660 shares valued at a total NOK 4,124,818 ($443,994.25), accounting for 1.23% of its portfolio.

Michael Hannig, a buy-side analyst covering global healthcare and portfolio manager of a DACH [Germany, Austria, and Switzerland] small- and mid-cap fund at DJE Kapital, suggested to Reuters that Novartis could regain investor confidence and replenish its pipeline following patent cliff exclusivity expirations by pursuing deals in the $5 billion to $10 billion range for late-stage assets or ​drugs nearing approval, subject to due diligence: “Larger transactions will likely be assessed carefully by ‌investors considering ⁠the mixed market reception to several prior deals.”

DJE Kapital has disclosed having more than €18.9 billion ($21.9 billion) in total assets under management across its funds as of  but does not disclose the portfolio details of its individual funds.

Executives at two other Novartis investors, Bellevue Asset Management and Union Investment, defended Novartis: Guy Bettschart-Ghassabi, healthcare analyst at Bellevue Asset Management, noted that the HARBOR study was designed by Avidity before its acquisition by Novartis, while Markus Manns, portfolio manager at Union Investment, said the failure of del-desiran and pelacarsen was unfortunate but within normal probabilities of drug development success.

“They have to work harder to fulfill their post-2030 goals,” Manns said, “but it’s in the same camp as most other pharma companies.”

Bellevue Asset Management finished last year with AUM of CHF 5.3 billion (nearly $6.5 billion) while Union Investment reported €534.6 billion (about $620.3 billion), according to public disclosures that also exclude portfolio details.

Good news for competitors

Myles R. Minter, PhD, a partner and biotechnology analyst with William Blair, wrote in a research note that Novartis’ clinical miss for del-desiran is a positive development for several potential competitors, which, like the Swiss pharma giant, are also developing drugs designed to treat DM1 by targeting DMPK. These include:

• Dyne Therapeutics (Nasdaq: DYN), which is developing zeleciment basivarsen (z-basivarsen or DYNE-101), an anti-TfR1 FAb-conjugated antisense oligonucleotide (ASO). Z-basivarsen is under study in the Phase III HARMONIA trial (NCT07486934), after generating positive strength and cognition data in March from the Phase I/II ACHIEVE trial (NCT05481879), set to read out new one-year data later this month. Topline data is expected from ACHIEVE’s registrational expansion cohort in the first quarter of 2027.
• Sarepta Therapeutics (Nasdaq: SRPT) and Arrowhead Pharmaceuticals (Nasdaq: ARWR), which are co-developing SRP-1003 (formerly ARO-DM1), an RNA interference (RNAi) conjugate being assessed in a Phase I/IIa trial (NCT06138743) that generated positive early clinical results and is set to read out multiple ascending dose data later in the second half. Sarepta is in-licensing SRP-1003 from Arrowhead under a collaboration announced in 2024 that generated for Arrowhead $825 million in upfront cash and equity and could generate an eye-popping $10 billion in milestone payments.
• PepGen (Nasdaq: PEPG), which is developing PGN-EDODM1, which uses the company’s enhanced delivery oligonucleotide (EDO) technology to deliver a therapeutic oligonucleotide designed to restore the normal splicing function of MBNL1, a key RNA splicing protein. PGN-EDODM1 is under study in the Phase II FREEDOM2 trial, where PepGen has fully enrolled the 10 mg/kg MAD cohort, data from which are expected to be reported in November. In August, the trial’s independent data and safety monitoring board (DSMB) approved advancing to the highest dosage cohort of 12.5mg/kg.
• Vertex Pharmaceuticals (Nasdaq: VRTX) and Entrada Therapeutics (Nasdaq: TRDA), which are co-developing VX-670, which is expected to read out data from the Phase I/II GALILEO trial (NCT06185764) later in the second half of this year. VX-670 is a phosphorodiamidate morpholino oligonucleotide (PMO) connected to a cyclic peptide containing motif that Vertex in-licenses from Entrada under an up-to-$735 million collaboration announced in 2022.

“Today’s miss from del-desiran leaves open space to fill within the DM1 patient class, and we view Vertex/Entrada’s VX-670 as compelling,” Minter wrote, based on its endosomal escape vehicle (EEV) platform: “We view Entrada’s muscle-targeted EEV as possessing an impressive safety profile to date, which we view as important for entrance into higher dosing regimes that may be required for sufficient muscle tissue penetration and vHOT improvements to translate into a registrational trial setting.”

Lower projected sales

Novartis’ disappointing outcome for del-desiran in the HARBOR trial compelled analysts to cut their sales forecasts for the candidate, which Narasimhan projected had “$5 billion-plus peak sales potential” in an interview with Bloomberg TV.

Stefan Schneider, PhD, senior equity analyst, pharma with Vontobel Asset Management, removed the firm’s previous peak annual sales projection of $3 billion for del-desiran from its valuation model and cut its Novartis price target from CHF 128 ($156.77) to CHF 125 ($153.09). Vontobel previously gave Novartis a 50% probability of success for del-desiran.

Michael Schmidt, PhD, a senior biotech analyst and senior managing director at Guggenheim, slashed the firm’s risk-adjusted 2033 sales forecast for del-desiran by 45% from $1.76 billion to $960 million, with a 60% probability of success. The firm previously identified del-desiran and pelecarsen as critical to Novartis’ success from 2030 onward, along with a third candidate that recently succeeded in the clinic—remibrutinib, which generated positive topline data in the Phase III REMODEL-1 (NCT05147220) and REMODEL-2 (NCT05156281) in relapsing multiple sclerosis, Novartis said.

Remibrutinib is now marketed by the company as Rhapsido® in chronic spontaneous urticaria (CSU) in adults who remain symptomatic despite H1 antihistamine treatment.

Novartis has maintained its guidance to investors, foreseeing net sales growth at a compound annual rate of 5% to 6% at constant currencies between 2025 and 2030.

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The work was done by scientists from Georgia Tech and Vanderbilt University. The human lymphoid organoid was developed by a team led by Ankur Singh, PhD, a professor of bioengineering and director of the Center for Immunoengineering at Georgia Tech. They developed it by isolating B cells from human tonsil tissue and blood sources and growing them in an environment similar to lymphoid tissue. They used inactivated influenza virus to overcome challenges associated with culturing B cells and getting to transform into antibody secreting plasma cells. 

Meanwhile, scientists in the lab of Krishnendu Roy, PhD, dean of engineering and professor of biomedical engineering at Vanderbilt University, designed a microfluidics-based vascularized microenvironment for the bone marrow chip that mimics the conditions found in human bone marrow. Essentially, they tried to “mimic the structure, fundamental biological functions, and spatial microenvironments” of human bone marrow in order “to ask questions about human organ-like behavior in this more simplified model,” Roy explained. 

As explained by the developers, the final model is assembled within a three-by-five stack of 96-well plastic plates, that are each less than half-an-inch thick. It features multiple channels that are coated with a gel-like material similar to bone marrow with nutrients and growth factors to support plasma cell function and maintenance.  Its layers correspond to an area at the outer edge of the bone marrow cavity, known as the endosteal subniche, where plasma cells are stored. The model also replicates an area deeper inside the center of the bone marrow, the perivascular subniche, which surrounds a network of blood vessels, where plasma cells proliferate and are activated.

“It is nearly impossible to achieve high imaging resolution of plasma cells in living human bone marrow,” Singh said. Though it is possible to “do some level of imaging in the bone marrow of a mouse” which is where some previous efforts have been focused. 

Now with this new model, scientists will be able to run new types of experiments. “A fundamental question [that] our study addresses [is] why it is that when B cells are ready to make antibodies, they relocate from lymph nodes, the spleen, and other organs and enter and take up residence in bone marrow,” Singh said. “Another is a question of the role that the environment of bone marrow plays in orienting those cells and responses to reinfection.”

Furthermore, the model can be seeded with cells from unique patient populations to study things like the effects of aging on plasma cell function. It could also be used to study cells from people with autoimmune or allergic diseases to understand how autoimmunity or allergy-promoting plasma cells are produced and maintained. Other studies could focus on addressing questions such as why B cells show a stop-and-go pattern of movement and whether it is part of a migration pattern in the bone marrow. 

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However, a long-standing challenge in neuroscience and neuropathology has been how to continuously observe biological processes that unfold over hours, days, and even weeks in the brain.

Now, researchers at Johns Hopkins Medicine have demonstrated a new approach to brain imaging that enables continuous monitoring of brain activity and the physiologic changes associated with neurological disease progression for more than 24 hours in freely moving mouse models. The cloud-based miniaturized microscope, CloudScope, operates autonomously and allows scientists to access live imaging data remotely from anywhere in the world, creating new opportunities to study diseases as they develop over time.

The study demonstrates the ability to remotely capture and analyze changes in brain activity, blood flow, blood vessel remodeling, oxygenation and cellular behavior over extended periods, providing a more holistic picture of brain disease progression than conventional imaging approaches.

This work is published in Nature Methods in the paper, “A cloud-based miniscope for neurosurveillance of brain health and disease in freely behaving animals.”

“We started with a fundamental question: If we wanted to image a seizure or brain tumor formation continuously in a preclinical or animal model over 24 hours or longer, how would we do that?” says Arvind Pathak, PhD, professor of radiology, oncology, and biomedical and electrical engineering at Johns Hopkins. “The consequence of us working through this question and its associated challenges is what resulted in this innovation.”

Using this approach, the team captured spontaneous seizures occurring several hours after a drug-induced seizure in mice, events that would have been missed using conventional short-term imaging methods. In separate studies of brain cancer, researchers were able to characterize the behavior of individual cancer cells and observe dynamic changes in the brain’s microenvironment as the disease progressed. These findings suggest that continuous monitoring may reveal critical biological events that occur outside the limited observation windows typically used in laboratory research.

“Most central nervous system diseases develop over hours, days or even weeks. Yet modern imaging tools are designed to continuously probe only a small fraction of this time window,” says Janaka Senarathna, PhD, assistant professor of radiology at Johns Hopkins. “We developed a device to break this time barrier.”

In addition to advancing neuroimaging research, the investigators have also demonstrated a promising application involving artificial intelligence. By combining the first-ever 24-hour brain imaging dataset with video recordings of the lab animals’ behavior, the team successfully trained an AI framework to predict whether an animal was minimally mobile, moderately active, or running based solely on neuronal activity measurements made with the device. The researchers believe this approach could help scientists better understand the neurological effects of conditions such as stroke or Parkinson’s disease and potentially reveal new insights into the relationship between brain activity and behavior. Additionally, researchers say the device enables time-shared imaging from anywhere in the world, and it creates a pathway to reduce animal use while enabling neuroscientific and neuropathological insights. Lastly, CloudScope’s architecture enables “time-shared” imaging, which potentially reduces animal use.

To explore the effect of disease on different brain regions, the team plans to continue expanding the platform’s capabilities, such as imaging larger regions of the animals’ brains and leveraging AI to accelerate brain imaging and cancer cell tracking.

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