Natalie Ram, JD, professor of law at Maryland Francis King Carey School of Law discussed an often-overlooked aspect of genetic testing: the legal protections to patients. Ram began her talk pointing out that the federal acts many consider protective including Health Insurance Portability and Accountability Act (HIPAA) and Genetic Information and Nondiscrimination Act (GINA) are less protective to individuals than expected.

She explained that HIPAA “seeks to protect certain sensitive health information against non-consensual disclosure,” which seems to be protective over genomic data. However, HIPAA only applies to certain protected health information covered by a “health entity,” for example data that is curated in one’s medical health record. Data created and provided by alternate entities, like research programs, are not part of this entity, so it is currently unclear whether or to what extent HIPAA applies to this data until it is entered into the medical records under a healthcare provider.

However, even if the data is added to a medical record, it still may not be fully protected. “There are more than a dozen exceptions permitting non-consensual disclosure of protected health information,” Ram added.

The goal of GINA, as Ram explained, is that it “prohibits most access to and discrimination on the basis of genetic information, but only in the context of health insurance and employment.” There are a large number of exceptions to GINA protections, including exceptions for “life, disability, and long-term care insurance or in other domains like education, housing, or other kinds of settings.”

While this information on the limited value of protections for individual’s genetic data may be concerning, Ram clarified that states have developed their own protections in addition to the federally mandated ones provided by HIPAA and GINA.

Patchwork protections

State-level protections vary strikingly, which Ram presented visually using multiple maps that she and her colleagues developed to show state policies regulating the use of genetic information across a variety of different additional forms of insurance.

“State laws create a patchwork of policies seeking to regulate the use of and discrimination based on genetic information across life disability and long-term care insurers,” she said when showing the first map.

Using life insurance as a primary example, Ram explained that not only do the laws differ between states. “Many states have no policy about this at all. And among those who do, those policies vary quite widely in terms of how those protections operate.”

The level of protectiveness can range from no protection at all, giving insurers permission to consider genetic data in their decisions to a complete ban from considering genetic information in insurance underwriting. Some states provide protections in the middle ground, often requiring consent from applicants for insurers to use genetic data. However, she pointed out that there are significant loopholes that allow insurers to require consent for insurance consideration at all.

Long-term care and disability maps showed a similar patchwork landscape between states in terms of protections. While the patchwork nature of the maps is consistent between examples, the data does not overlay well. One state that may have good protections for individuals for life insurance, may have no protection for disability insurance, and little protection for long-term disability.

Unfortunately, the broader impact of these data and maps underscore the complexity of the situation and how difficult it is for individuals, including parents considering newborn screening, in their decision-making process. Ram concluded this part of her talk stating, “At a minimum, parents should really understand the kinds of risks that developing this kind of information may have for their babies in the future as those babies grow up.”

Unintended genomic data usage

At this point, Ram shifted her discussion to the use of genetic data by law enforcement. While there are only a few cases across the country in multiple states, use, or potential misuse of newborn genetic screening materials and data is not non-existent.

“Genomic newborn screening or sequencing would generate extensive individual level data that law enforcement might be very easily able to use to identify a suspect for investigation rather than confirm one they already have in mind,” she said. “So what does the legal landscape look like here? “

State-level laws regarding the use of genetic screening material or data by law enforcement agencies was just as patchy between states as the insurance laws were. Ram stated that “more than a quarter of states appear to have no clearly articulated policy that would govern law enforcement access,” though she pointed out that some of these states have not addressed this concern since samples and primary data is destroyed shortly after screening is reported. Of the remaining states, Ram said that “About a third of states have language in their enacted laws or regulations that might allow law enforcement to access either the data or the biospecimens.” Again, there is a middle ground within the legal landscape around protections, and many states have varying levels of protections, even varying in the protection for use of samples or data.

“I think that’s really problematic when it comes to trust and newborn screening, which is something that we think a lot about as we push into genomic sequencing,” she stressed.

Ram stressed that these are just a small sampling of the broader ramifications of using genetic information. She brought up questions on its potential use in education, or how screening programs may be impacted by screening laws, and vice versa. While newborn screening has many benefits for the infants and families that get important and often actionable medical information, the legal, societal, and financial impacts are still in flux.

“I focused here on some of the legal issues at the intersection of genetic privacy and genomic newborn sequencing,” Ram concluded, clearly indicating that there is much more to still explore.

The post The Legality of Genetic Privacy in Newborn Screening appeared first on Inside Precision Medicine.

The findings, in Science, suggest that changing diet to alter gut microbiome could reduce these inflammatory responses.

This could make vaccination more palatable to people, improve its uptake, and raise the likelihood of herd immunity.

The study also revealed that people who were vegetarian or vegan were less likely to experience fever after vaccination.

Importantly, neither diet nor the composition of the gut microbiome appeared to compromise the immune protection conferred by vaccination.

In a Perspective article accompanying the study, Bali Pulendran, PhD, from Stanford University, noted that dietary interventions can rapidly remodel the gut microbiome and the body’s inflammatory state.

“Diet, microbial ecology, and the metabolic state are not immutable, and people might one day prepare for vaccination as deliberately as the vaccine itself is formulated,” he speculated.

Fever and flu-like symptoms are among the most common adverse reactions to vaccines, particularly messenger (m)RNA- and lipid nanoparticle-based vaccines.

To investigate how gut microbes might affect this, Kelsey Huus, PhD, from the Max Planck Institute for Biology in Tübingen, and colleagues studied 171 healthy adults receiving the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine, most of whom were taking a third dose.

They discovered that participants whose body temperature increased at least 0.8°C after vaccination had distinct biological features beforehand.

This included low-grade intestinal inflammation and gut microbiomes that were rich in flagellated bacteria from the Lachnospiraceae family, including Waltera.

These bacteria express flagellin proteins that activate the Toll-like receptor 5 (TLR5) in immune cells, triggering inflammatory responses.

Among more than a thousand adults receiving SARS-CoV-2 vaccines, those who reported systemic vaccine reactions such as fever, headache, and muscle pain had gut microbiomes more abundant in the Lachnospiraceae family, and specifically Waltera.

The association with fever was stronger at the level of the broader Lachnospiraceae family than for Waltera specifically.

The team then conducted experiments to determine whether the observed associations were causal. They found that fecal products from people with greater vaccine-induced temperature increases induced stronger inflammatory responses in human colonic organoids grown in culture than those from people whose temperatures rose less.

When fecal microbiota from humans were transferred into germ-free mice, they elicited different inflammatory responses to SARS-CoV-2 vaccination dependent on the donor human’s post-vaccine temperature change.

Mice that received microbiota from people with greater temperature increases had stronger vaccine-induced hypothermia, which is typical of reactogenicity in mice, as well as higher serum concentrations of the proinflammatory molecule interleukin-6 (IL-6) compared with animals receiving microbiota from individuals with lower rises in temperature.

In mice genetically engineered to lack TLR5 and NLR family CARD domain-containing protein 4—which are extracellular and intracellular sensors of flagellin, respectively—the effects reduced but did not disappear entirely.

“Our data suggest a mechanism whereby overgrowth and motility of flagellated gut bacteria trigger flagellin-dependent inflammation and exacerbate the risk of vaccine-induced inflammatory responses,” the researchers summarize.

“We moreover demonstrate that industrialized dietary patterns drive microbiome flagellin production in vitro, exacerbate vaccine reactions in vivo, and associate with fever responses in healthy adults.

“Together, our results establish the possibility of microbiome-targeted interventions to attenuate vaccine-induced adverse events.”

The post Gut Microbes Implicated in Post-Vaccination Fever appeared first on Inside Precision Medicine.

“Immunotherapy works in many different cancer types, but the same approach has yielded only a 10% success rate in glioblastoma,” said Filippo Veglia, PhD, assistant professor at The Wistar Institute and senior author of the study. “Our study shows that combination therapy is paramount to making immunotherapy work for glioblastoma patients. We need to target two different populations of cells.”

One key barrier for immunotherapy in glioblastoma is the tumor’s unusual immune environment, which is dominated by myeloid cells that glioblastoma take advantage of to suppress nearby T cells. Another major obstacle concerns T cells entering an exhausted state that leaves them progressively less capable of killing tumor cells. 

Veglia’s team first investigated why myeloid cells become immunosuppressive inside glioblastoma tumors. Using single-cell RNA sequencing, they found that monocyte-derived macrophages and neutrophils were among the most abundant and suppressive myeloid populations in the tumors. Conditions of hypoxia were found to act as a driver of immune suppression by reprogramming myeloid cells to suppress T-cell activity.

The researchers then tested low-dose axitinib, a drug already used with immunotherapy in advanced kidney cancer, in mouse models of glioblastoma. Although the drug reduced tumor hypoxia and interfered with the immunosuppressive reprogramming of myeloid cells, it was only able to produce a modest benefit on its own.

“By reducing hypoxia, we can impair the immunosuppressive activity of myeloid cells, and this results in the accumulation of more T cells in the tumor microenvironment,” said Veglia. “But this is not enough, because when T cells go into the tumor, they become exhausted.”

Many of the T cells accumulating after axitinib treatment were beginning to show signs of exhaustion but still retained the capacity to attack cancer. They also expressed CD137, a receptor associated with recognition and activation of tumor-reactive T cells.

Combining axitinib with an agonist targeting CD137 proved substantially more effective than either treatment alone, extending median survival from 23 to 42 days in mice. When researchers later re-exposed surviving animals to glioblastoma cells, the tumors failed to grow, suggesting that the treatment had generated durable immune memory.

Veglia said the next step is to explore the approach in a clinical trial. His team also plans to test whether reducing tumor hypoxia could improve CAR T-cell therapy, an approach that has shown promise in blood cancers but has so far struggled against solid tumors. Because low-oxygen tumor environments are common in other treatment-resistant cancers, including pancreatic cancer, the strategy could eventually have applications beyond glioblastoma.

“There are no cures for glioblastoma, so this is an opportunity to make a real difference for patients,” Veglia said. “We are also excited to see if our findings extend to other types of recalcitrant cancer and ultimately improve outcomes for these patients, too.”

The post Combination Therapy Overcomes Key Barriers to Glioblastoma Immunotherapy appeared first on Inside Precision Medicine.

Meanwhile, its second in vivo CRISPR gene editing late-stage program, nexiguran ziclumeran (nex-z; NTLA-2001), intended to inactivate the transthyretin (TTR) gene for TTR amyloidosis (ATTR) is moving forward after serious liver toxicity prompted clinical holds, raising questions about patient selection and the risks of in vivo gene editing.

In this conversation with Inside Precision Medicine, Intellia CEO John Leonard discusses what could drive adoption of lonvo-z, how new genetic findings may help mitigate safety risks in its ATTR amyloidosis trials, and how the company plans to rebuild its pipeline as it transitions from a clinical-stage gene-editing pioneer into a commercial biotechnology company.

This interview has been edited for length and clarity.

Leonard: Doing well on a chronic therapy still means a lifetime of injections, infusions, or daily pills, recurring insurance reauthorizations, and the ongoing worry of a breakthrough attack.

Results from our Phase III HAELO study demonstrated a one-time infusion of lonvo-z reduced HAE attacks by 87% versus placebo, and 62% of treated patients were completely attack-free and therapy-free over the six-month efficacy period. Furthermore, all patients treated with lonvo-z remained free from long-term prophylaxis (LTP-free) through the latest follow-up.

The most common adverse events were infusion-related reactions, headache, fatigue, back pain, and upper respiratory tract infection. All adverse events were mild or moderate, with no serious adverse events in the lonvo-z arm. These data, and the durability demonstrated from our Phase I/II clinical study, suggest a profile that is differentiated clinically and has potential benefits to both physicians and payers from a lower lifetime cost of HAE management.

Our market research with patients and physicians also tells us the burden of HAE goes well beyond the attacks themselves, and the rapid enrollment success in our Phase III HAELO study showed us that an unmet need still remains and is significant.

We recognize a permanent treatment is a significant decision, and we’re focused on giving patients and physicians the full picture of the data. We plan to share key metrics that help define early commercial success as we approach potential approval of lonvo-z on March 10, 2027.

IPM: Phase III enrollment in the nex-z program has resumed after a patient with AATR with cardiomyopathy (ATTR-CM) experienced severe liver toxicity. Can you explain what happened, and are you confident that the mitigation measures address the underlying risk rather than just detecting liver injury earlier?

Leonard: In October 2025, a patient dosed with nex-z in our MAGNITUDE trial experienced Grade 4 liver transaminase elevations and increased total bilirubin, which met the protocol-defined pausing criteria, and the FDA placed both Phase III trials on hold. As reported by the principal investigator, the patient who later passed away had other complicating comorbidities, including sepsis secondary to a perforated duodenal ulcer, that ultimately contributed to his death.

We aligned with the FDA on protocol amendments, and the clinical holds were lifted in January for MAGNITUDE-2—in ATTR amyloidosis with polyneuropathy (ATTRv-PN)—and in March for MAGNITUDE in ATTR-CM. In addition to enhanced liver monitoring and guidance for short-term steroid treatment if elevated liver transaminases are observed in the initial period following dosing, the MAGNITUDE trial is excluding enrollment of patients who may be most susceptible to potential liver injury, have a recent history of cardiovascular instability, or an ejection fraction <25% at the time of screening. 

Subsequent to the removal of the clinical holds, we in collaboration with our partner Regeneron, also gained genomic insights that enhance our understanding of nex-z’s profile. We sequenced and analyzed data from over 600 patient samples across the nex-z trials. This work focused on HLAs (proteins on the surface of cells), which highlighted a statistically significant finding that the highest transaminase elevations occurred in patients carrying one specific HLA allele. That gives us a mechanistic explanation for a general signal we’d already flagged and a way to identify patients who are more likely to be affected before it happens. We’re discussing the findings with the FDA and other health authorities, and we’re providing HLA genotyping results to investigators and patients in our Phase III trials.

IPM: Intellia has increasingly concentrated its resources around its late-stage programs. After lonvo-z hits the market, how do you restructure/rebuild the pipeline? How are you evaluating new in vivo editing programs? What must be scientifically and commercially true to invest heavily in earlier-stage in vivo editing programs?

Leonard: We have ongoing, active research projects that leverage CRISPR gene editing and other core technologies, many of which are in competitive spaces, so we are unwilling to talk about our progress today and will provide more updates on our pipeline development efforts in due course. We look at a number of factors when evaluating new programs, starting with delivery mechanisms where our clinically validated platform can be applied again. As we evolve into a fully integrated company in the U.S. upon lonvo-z launch, we will look to leverage these new capabilities in bringing products to market for patients.

IPM: The gene-editing field is evolving incredibly quickly, with new editors, delivery technologies, and approaches emerging all the time. How does Intellia make sure its technology keeps pace? Are you developing next-generation editing and delivery systems internally, looking to partner or acquire new technologies, or confident that your platform can support your goals?

Leonard: We continue to serve as leaders in the CRISPR field and its derivative forms in the research space. While various CRISPR systems have been described and featured by different companies, we have all the editing tools in house to produce the range of relevant therapeutic edits. We have a strong foundation in place and are focused on the application of core technologies that result in viable product concepts that bring value to patients and the company. As our pipeline continues to evolve, we look forward to sharing more about the innovations and programs we’re advancing when the time is right.

We also remain very open to collaboration and believe the right partnerships can be an important catalyst to bring new ideas and opportunities forward. With the momentum we’ve built to date, and a potential approval ahead, we’re excited about the milestones to come.

The post Intellia CEO John Leonard on <i>In Vivo</i> CRISPR Gene-Editing Commercial Launch appeared first on Inside Precision Medicine.

In an analysis of nearly 40,000 adults with 32 types of solid tumors, researchers at Memorial Sloan Kettering Cancer Center (MSK) found that limiting genetic testing based on age would miss 72% of patients found to carry a pathogenic germline variant.

The findings challenge the longstanding assumption that inherited cancer predisposition is primarily a concern in patients diagnosed at unusually young ages and add to growing support for offering germline testing much more broadly to people with cancer.

“The bottom line is that if we use age cutoff as a criterion for genetic testing, we are missing the vast majority, or 72%, of patients with a pathogenic variant,” said Zsofia Stadler, MD, a medical oncologist and clinical geneticist at MSK and one of the study’s principal investigators, in an interview with Inside Precision Medicine.

The study, published in Cancer Discovery, initially set out to answer a somewhat different question. Rather than applying a single cutoff—such as age 50—the researchers examined whether cancer-specific ages of onset could more accurately identify patients likely to carry inherited cancer-predisposition variants.

Patients were classified as having early-, average-, or late-onset disease according to the typical age of diagnosis for their particular cancer.

As expected, patients with early-onset cancers were enriched for pathogenic germline variants. But inherited variants were also found among patients diagnosed at average and older ages. Because cancer itself is much more common later in life, restricting testing to younger patients ultimately excluded large numbers of mutation carriers.

“Cancer under the age of 50 is still relatively rare,” Stadler explained. As a result, focusing testing on that group means “you end up missing the vast majority of patients with an inherited cancer predisposition syndrome.”

Moving beyond complex testing criteria

Current recommendations for germline testing vary substantially by cancer type. Guidelines already recommend broad testing for some malignancies, including ovarian and pancreatic cancers. For many other tumors, however, eligibility can depend on combinations of age, family history, ancestry, multiple primary cancers, or specific tumor characteristics.

Those criteria have expanded over time as researchers have learned more about hereditary cancer, but their complexity may itself limit access to testing.

“If you look up NCCN [National Comprehensive Cancer Network] guidelines, it’s incredibly complex,” Stadler said. “I think in some ways the complexity of who meets these criteria becomes essentially the gatekeeper for genetic testing.”

The new results point toward a simpler approach: offering germline testing to all adults diagnosed with a solid tumor.

“We’re not advocating for genetic testing for the entire population,” Stadler emphasized. “We’re advocating for genetic testing for all cancer patients. I do think that’s where the field needs to go.”

The distinction is important. People who have already developed cancer have a substantially greater likelihood of carrying clinically relevant inherited variants than the general population, making testing in this group potentially useful on several levels.

One test, three potential benefits

For patients, identifying an inherited mutation can reveal risks beyond the cancer they already have.

A woman with breast cancer who learns that she carries a germline BRCA2 variant, for example, may also face an elevated risk of ovarian cancer and could consider risk-reducing surgery when appropriate. A patient with colorectal cancer found to have Lynch syndrome may require more intensive colonoscopic surveillance and, depending on the individual, measures to reduce the risk of other Lynch-associated cancers.

The findings can also influence treatment of the existing cancer. Germline BRCA alterations can help identify patients whose tumors may be particularly susceptible to PARP inhibitors. Such therapies already have indications in several BRCA-associated cancers, including breast, ovarian, prostate, and pancreatic cancers.

But the implications extend beyond the individual patient.

Identifying an inherited cancer-predisposition variant creates an opportunity for cascade testing, in which relatives are tested for the same alteration. Family members who carry the variant can then begin intensified surveillance or consider preventive interventions before cancer develops.

“You’re not just potentially preventing cancers or future cancers in these cancer patients,” Stadler said. “You’re preventing cancers potentially in entire families.”

That ability to identify risk before disease develops may ultimately be one of the strongest arguments for expanding testing, she added.

“I think we would be missing a huge opportunity for cancer prevention if we didn’t do that,” Stadler said.

Findings extend across ancestry groups

The investigators also examined whether their conclusions held among patients of non-European ancestry, an important question because genetic databases and hereditary cancer research have historically included disproportionate numbers of people of European ancestry.

Although the MSK cohort was not as diverse as the U.S. population overall, its size provided a substantial subgroup for analysis: roughly 8,000 of the nearly 40,000 participants were of non-European ancestry.

The researchers observed similar findings in that group, Stadler said, providing evidence that the limitations of age-based testing are not confined to patients of European ancestry.

The study excluded pediatric cancers and hematologic malignancies, so its conclusions apply specifically to adults with solid tumors.

For precision oncology, however, the implications are broad. Germline testing is increasingly capable of informing not only why a cancer developed, but how it might be treated, which additional cancers a patient should be monitored for, and which relatives may face elevated risk.

Rather than requiring clinicians to determine whether each patient fits an increasingly complicated set of testing criteria, Stadler argues that cancer itself may be the most useful criterion.

“Risk stratification is really important for the future of cancer prevention and precision medicine,” she said, “ensuring that the people who are at higher risk get the surveillance or risk-reduction implementations that they need.”

The post Age-Based Genetic Testing Misses 72% of Patients with Inherited Cancer Variants appeared first on Inside Precision Medicine.

The large Swedish study, in The BMJ, indicates that HPV vaccination has broader implications for women’s and child health beyond its well-recognized benefits in preventing cervical cancer.

The benefits of HPV vaccine before pregnancy included a reduction in the risk of pre-term birth, which is a leading cause of neonatal mortality across the globe.

The risk reductions were generally greater among women vaccinated among younger ages, noted lead researcher Zhongsong Zhang, a PhD student from the Karolinska Institute in Stockholm, and colleagues.

“These findings highlight the importance of timely immunization through school-based programs and extend the benefits of human papillomavirus vaccination far beyond cancer prevention to the reduction of adverse pregnancy outcomes,” they reported.

HPV is one of the most common sexually transmitted infections and the quadrivalent vaccine targets four types of the virus, including two—HPV types 16 and 18—that are responsible for nearly three quarters of all cervical cancers.

Following indications that HPV infection and the treatment of precancerous cervical lesions are linked with adverse birth outcomes, researchers examined whether HPV vaccination might reduce this risk.

They studied 624,713 women, aged 16 to 35 years, who gave birth for the first time to a single baby in Sweden between 2006 and 2023. Of these, 92,620—equivalent to 14.8%—had received the quadrivalent HPV vaccination prior to pregnancy.

Women who had at least one adverse pregnancy outcome were matched with up to 10 women and, after accounting for potential confounding factors, HPV vaccination was associated with a lower odds of all the adverse pregnancy outcomes studied.

These included preterm birth before 37 weeks (adjusted OR [OR] =0.95), very preterm birth between 28 and 31 weeks of pregnancy (OR=0.85), spontaneous preterm birth (OR=0.95), preterm prelabor rupture of membranes (OR=0.93), and an infant severely small for gestational age (OR=0.92).

The researchers say the benefits of HPV vaccination may lie directly through prevention infection with the virus and also indirectly through the need for cervical excisional treatment.

They believe their findings contribute to a more comprehensive understanding of the broader health implications of HPV vaccination.

The team speculated: “Including potential reproductive benefits in future policy evaluations may further shift the overall cost-benefit balance towards vaccination, including in settings where human papillomavirus vaccination has not yet been implemented.”

The post HPV Vaccination Prevents Major Pregnancy Complications appeared first on Inside Precision Medicine.

Retinitis pigmentosa is an inherited, degenerative retinal disease that affects more than 1.5 million people worldwide and is characterized by progressive photoreceptor loss that can lead to irreversible blindness. It can result from a mutation in any one of more than 100 genes.

“Developing a separate treatment for every genetic cause of retinitis pigmentosa is proving tremendously difficult and costly,” said José-Alain Sahel, MD, director of the University of Pittsburgh Medical Center Vision Institute and first author of the study. “While we continue working on correcting specific gene defects, our goal is to develop a way to restore visual function regardless of which gene caused the disease.”

Sahal and colleagues explain in The New England Journal of Medicine that the aim of optogenetic therapy is to restore retinal responsiveness to light in people with blindness by introducing genes encoding light-sensitive proteins into surviving neurons. Direct treatment to the eye should mean that its effectiveness is independent of the specific genetic cause.

The approach developed by Sahal and colleagues involves injecting an adeno-associated viral vector that expresses ChrimsonR, a light-sensitive protein that responds to amber light, directly into the back of the eye.

The protein is activated when the patient wears specialized light-stimulating goggles with a built-in camera that sends visual information to a portable processor. The processor, in turn, converts the information into patterns of light. A projector within the glasses sends these patterns of light back to the eye at specific wavelengths designed to activate ChrimsonR in the modified retinal cells.

For the study, 10 individuals (mean age 55 years, 60% women) with blindness due to advanced retinitis pigmentosa received the optogenetic treatment to their worse-seeing eye.

At this early stage, the researchers were primarily interested in the safety of the therapy and the results were encouraging. There were 34 adverse events recorded among nine of the 10 participants including 23 mild events and 10 moderate events, which mostly involved temporary inflammation and short-lived increases in eye pressure.

One patient experienced a severe event—transient occlusion of the central retinal artery immediately after intravitreal injection, which resolved within minutes of treatment with iopidine.

After treatment, seven of the 10 participants had improved light sensitivity, and six made gains large enough to be considered clinically meaningful. While the treatment did not restore normal vision or the ability to read, some participants became better able to detect when an object such as a doorway was present, determine where it was located, and reach toward it accurately while using the goggles.

Of note, patients who spent more time learning to use the goggles tended to perform better on object-detection tests, suggesting that rehabilitation may be an important component of optogenetic therapy.

The researchers also used electroencephalography to test whether visual information was reaching the brain. They found evidence that visual signals reached and were processed by the visual cortex when participants viewed objects. Four participants showed consistent improvements across multiple real-world visual tasks over up to five years of testing.

“These results show that even in people with profound vision loss, the visual system retains a remarkable capacity to process new information,” said Sahel. “Potentially, the approach could also help patients with other blinding diseases in which the eye’s light-sensing cells have been lost, but other retinal cells—especially retinal ganglion cells—remain viable.”

The post Optogenetic Therapy Shows Early Promise for Retinitis Pigmentosa-Associated Blindness appeared first on Inside Precision Medicine.

“Our findings highlight that the immune response in Parkinson’s disease is more nuanced than simply being beneficial or harmful,” said George Tofaris, MD, PhD, professor of neurology and translational neuroscience at the University of Oxford and a consultant neurologist at the John Radcliffe Hospital. “We have identified a population of human microglia that can actively remove pathological alpha-synuclein from neurons. Understanding how to enhance and monitor such beneficial microglial functions, without triggering damaging inflammation, could open up new avenues for developing disease-modifying treatments.”

Parkinson’s disease affects more than 10 million people worldwide. This neurodegenerative condition is marked by the progressive loss of dopamine-producing neurons and the accumulation of abnormal alpha-synuclein aggregates inside nerve cells.

While microglia are known to respond to injury and clearing cellular debris, their role in Parkinson’s disease is complex. While persistent activation of these immune cells can contribute to inflammation and neuronal damage, the new findings suggest that, under certain circumstances, microglia can instead perform a targeted protective function.

Tofaris and colleagues developed human stem-cell models using induced pluripotent stem cells (iPSCs) to study human dopamine-producing neurons and microglia together. When alpha-synuclein aggregates formed inside neurons, microglia were found to reduce the accumulation of this protein by removing small portions of affected neurons through a process known as trogocytosis. Rather than engulfing and destroying an entire damaged neuron, the microglia effectively “nibbled” away sections containing the abnormal protein.

“What is striking is the precision of this response,” said Hung-Ju Chueh, postgraduate student at the University of Oxford and first author of the study. “The microglia were not simply engulfing damaged neurons but instead removing parts of the neuron containing aggregated alpha-synuclein, suggesting that, at certain stages of disease, microglia help neurons dispose of potentially harmful material.”

The response was found to be regulated by the P2RY12 and CD22 proteins, which helped control communication between the neurons and microglia. Meanwhile, the IL-10 cytokine acted as a self-regulating brake, helping prevent the immune cells from damaging healthy tissue. Using single-cell RNA sequencing, the researchers were also able to identify a distinct population of activated microglia associated with the beneficial clearance response.

“We also found that the protein glycoprotein non-metastatic melanoma protein B (GPNMB) appears to be an important part of this protective,” said Tofaris. “Genetic variation at the GPNMB locus has previously been associated with Parkinson’s disease through genome-wide association studies, but the functional role of GPNMB in disease has remained unclear.”

The team found that GPNMB levels increased in microglia exposed to neurons containing alpha-synuclein aggregates, and that the protein interacted with pathological alpha-synuclein inside the immune cells. GPNMB was also elevated in microglia within tissues showing early or established alpha-synuclein pathology within the substantia nigra, the brain region most severely affected by Parkinson’s. Using CRISPR interference to reduce GPNMB expression specifically in microglia, the cells became less effective at clearing alpha-synuclein aggregates from neurons.

Taken together, these findings provide the first evidence that GPNMB actively contributes to a protective microglial response and could therefore offer a new target for future therapeutics in Parkinson’s research. However, further work will be needed to determine whether enhancing this natural clearance mechanism can be translated into an effective treatment that can boost the natural beneficial activity of microglia without triggering the damaging inflammation associated with their prolonged immune activation.

The post Microglia Can ‘Nibble Away’ Toxic Proteins to Protect Neurons in Parkinson’s Disease appeared first on Inside Precision Medicine.

QC6352 and its clinical analog zavondemstat were previously thought to work by blocking KDM4, an enzyme that removes chemical marks called methyl groups from histones.

Zavondemstat, also called TACH101, is an experimental oral cancer drug developed by Tachyon Therapeutics. It entered clinical development as the first drug designed to inhibit KDM4 enzymes, but early Phase I trials were discontinued due to a business decision by the sponsor.

The new findings, published in Nature Chemical Biology, looked at the activity of QC6352 and identified the enzyme DHODH and pyrimidine synthesis as the main target for the drug, challenging how early clinical results should be interpreted.

“Target validation matters because a drug can work very well without acting through the protein we think it does. If the target is wrong, we can misinterpret the biology of the cancer and then spend years developing new drugs, biomarkers or treatment strategies around the wrong mechanism,” lead author Lenka Munoz, PhD, a professor at the University of Sydney, told Inside Precision Medicine.

“Confirming the true target helps ensure that we understand why the drug works and that future drug development is built on the correct biology.”

Munoz explained that she and her colleagues were originally screening a library of epigenetic inhibitors to find new targets for the aggressive brain cancer glioblastoma, and they found that QC6352 had strong anti-cancer activity against these cells.

It stopped the growth of all six glioblastoma cell models at very low concentrations, while having much less effect on normal human brain-supporting cells. It also slowed tumor growth and increased survival in model mice with the brain cancer.

“QC6352 had been developed as an inhibitor of KDM4, a family of epigenetic proteins involved in regulating gene expression, but very little was known about the role of KDM4 in glioblastoma,” she said.

“Because we urgently need new therapeutic targets and drugs for this devastating cancer, we wanted to understand exactly how QC6352 was killing glioblastoma cells.”

Initially they focused their studies on KDM4 inhibition, as QC6352 and zavondemstat can inhibit KDM4 in a purified biochemical assay, but when they tested another known KDM4 inhibitor on the same cells it showed no anti-cancer activity against glioblastoma. This made them question if KDM4 was the only target for QC6352.

“We followed the biology, and this ultimately led us to discover that QC6352 also potently inhibits another enzyme, DHODH, and that DHODH inhibition was a major driver of its anti-cancer activity,” she explained.

“DHODH is an enzyme that cells use to make pyrimidines, which are essential building blocks of DNA and RNA. Cancer cells divide rapidly and therefore have a very high demand for these building blocks. Blocking DHODH restricts the supply that cancer cells need to keep growing.”

Providing uridine or drug-resistant DHODH prevented the growth-inhibiting effect on the glioblastoma cells, offering strong evidence that DHODH was the key target.

“These findings… support growing evidence that targeting DHODH can produce potent anti-cancer effects and reinforce DHODH as an important therapeutic vulnerability in glioblastoma,” says Munoz.

“A drug may show strong anti-cancer activity, but unless we confirm which protein is actually responsible, we risk drawing the wrong conclusions about the underlying biology. Finally, our results show that QC6352 cannot be used as a tool to study KDM4 biology, because some effects attributed to KDM4 may actually result from DHODH inhibition.”

The researchers are now working to better understand DHODH as a potential target for glioblastoma treatments and plan to look into why some tumors are particularly sensitive to DHODH inhibition. They also want to look at whether targeting DHODH can create new vulnerabilities that make glioblastoma cells more sensitive to other cancer therapies.

The post Glioblastoma Drug Uses Unexpected Mechanism appeared first on Inside Precision Medicine.

In laboratory studies, the team found the chemotherapy CarboTaxol (carboplatin plus paclitaxel) can have an impact on cancer beyond its direct tumor-killing action. CarboTaxol’s “adjuvant” effects appear to depend on TCF1/β-catenin activity. With the chemotherapy actually expanding the number of stem-like TCF1+CD8+ T cells.  

In tests of other chemotherapies, the team found cyclophosphamide also boosted cancer vaccine effects, but gemcitabine did not. 

“So it is not all chemos doing this, and we will have to test others in the future,” Benoit Van den Eynde, MD, PhD, told Inside Precision Medicine. “But CarboTaxol is frequently used in various cancers, such as lung, cervix, and many others. So it is already relevant clinically.”  Van den Eynde is director of the de Duve Institute and Ludwig Institute for Cancer Research and a professor at UCLouvain and Oxford University. 

The paper appears in Cancer Cell this week. The senior author is Carol Sze Ki Leung, PhD, former senior immunologist at the Van den Eynde laboratory, and now group leader at the Nuffield Department of Medicine, Centre for Immuno-Oncology.

They found this potential therapeutic effect is further enhanced when the combined chemo/vaccine regimen is supplemented with anti-PD-1 immune checkpoint blockade (ICB). ICB prevents T cell exhaustion and thus intensifies T cell assault on tumors.

Therapeutic cancer vaccines are increasingly tested in clinical settings alongside standard-of-care treatments that often include chemotherapy. This group tested heterologous prime-boost viral vector vaccines in combination with various chemotherapy regimens to see if there were any synergistic effects.

“If correctly timed, the combination of these chemotherapies with a cancer vaccine can synergize with ICB to enhance tumor control and significantly extend survival,” said Leung. “This therapeutic effect stems from the direct modulation of key functional traits of CD8+ T cells by the chemotherapies, which enables a better response to subsequent vaccination and, possibly, to anti-PD-1 ICB as well.”

The team’s findings suggest a TCF1-dependent mechanism causes the immune adjuvant effect of chemotherapy. TCF1+CD8+ T cells are stem-like T cells, which have properties similar to stem cells—they can self-renew and give rise to more differentiated effector T cells that directly attack tumor cells. 

Van den Eynde said, “In particular these cells were shown to be the key T-cell subset responding to anti-PD-1 immune checkpoint blockade and leading to the impressive tumor responses seen in patients treated with immunotherapy based on immune checkpoint blockade (anti-PD-1). This explains the strong anti-tumor effect we see with the triple combination (vaccine + chemo + anti-PD-1): We generate more of the T-cell subset that respond to anti-PD-1 and it is tumor-specific (because it is induced by the vaccine).”

The authors say their findings provide a rationale for clinical evaluation of a triple combination therapy of chemo, vaccines, and ICB.

No clinical trials have been conducted yet, however. “We have some encouraging evidence in patients. In our study, we analyzed samples from two independent cohorts of cancer patients treated with CarboTaxol and observed an increase in TCF1+ CD8+ T-cell populations following chemotherapy, consistent with what we saw in our preclinical models,” says  Leung. “These patients were not receiving a cancer vaccine, so we cannot yet say that chemotherapy enhances vaccine responses in patients.”

She adds, “The next important step will be to test this in clinical trials, where the timing of chemotherapy and vaccination can be carefully controlled.”

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