Radically different
Nature Medicine, Published online: 01 July 2026; doi:10.1038/s41591-026-04483-7
Local and systemic immune profiling after a controlled human influenza infection challenge in humans found that the participants with increased innate cell responsiveness were more likely to become symptomatically infected.
Researchers have uncovered the molecular mechanism bacteria use to build a family of natural anticancer compounds, a discovery that could help scientists engineer improved versions of histone deacetylase (HDAC) inhibitors for cancer treatment.
The study, published in Nature Communications, identifies the long-elusive biosynthetic pathway for FR-901375, a naturally occurring HDAC inhibitor closely related to the approved lymphoma drug Romidepsin. The findings also explain how bacteria “mix and match” components of these molecules to generate structurally diverse compounds, providing a blueprint for designing new drug candidates.
HDAC inhibitors block histone deacetylases—enzymes that help regulate which genes are switched on or off inside cells. By inhibiting these enzymes, the drugs can reactivate genes that suppress tumor growth or trigger cancer cell death. Romidepsin (Istodax) is already approved to treat certain T-cell lymphomas, but researchers have long been interested in developing additional members of this drug family that are more selective and effective.
Although FR-901375 has been known for decades, scientists had never identified the bacterial genes or molecular machinery responsible for producing it.
The new study fills that gap.
The researchers identified the previously unknown biosynthetic gene cluster for FR-901375 in Pseudomonas chlororaphis subsp. piscium and used genetic, biochemical, and structural approaches—including AlphaFold modeling, mutagenesis, mass spectrometry, and gene deletion experiments—to determine how the compound is assembled.
Like Romidepsin and related compounds, FR-901375 belongs to a family of cyclic molecules known as depsipeptides. These drugs are built inside bacteria by enormous enzyme complexes called PKS-NRPS hybrids, which combine two natural-product assembly systems to construct the finished molecule.
A key finding was the discovery of how small protein regions known as docking domains allow different sections of this assembly line to communicate. These molecular connectors enable the portion of the machinery that builds a conserved zinc-binding pharmacophore—the business end of the drug that inhibits HDAC enzymes—to link with a second set of enzymes that constructs a variable peptide “cap.” Differences in this cap influence how individual drugs interact with different HDAC enzymes.
“The βHD domain employs a mechanism to facilitate productive engagement of PKS and NRPS subunits, involving direct binding to a conserved epitope on the SLiM-bearing ACP domain,” the authors write.
The researchers found that one docking element, known as the β-hairpin docking (βHD) domain, plays the central role in joining the two biosynthetic systems. Surprisingly, another docking element previously thought to be equally important contributed relatively little to the interaction and was not essential for FR-901375 production inside bacterial cells.
Structural modeling and laboratory experiments showed that the βHD domain directly binds a conserved region of the acyl carrier protein, allowing the growing molecule to be transferred efficiently from one enzyme complex to the next. The same interaction was conserved across several related HDAC inhibitor pathways, suggesting bacteria use a common strategy to generate multiple drug variants.
“The observation that ACP-SLiM and βHD-C di-domains from noncognate depsipeptide HDAC inhibitor assembly lines engage productively supports the view that the interaction epitope between βHD and ACP domains… plays a key role in the biosynthesis of all members of this clinically important family of anticancer agents,” the authors write.
The team also reconstructed how the FR-901375 pathway likely evolved through gene transfer, duplication, and recombination events that modified the peptide-building portion of the biosynthetic machinery while preserving its ability to connect with the conserved pharmacophore assembly system.
According to the researchers, understanding this evolutionary process could help scientists design entirely new HDAC inhibitors using the same modular strategy that bacteria have refined over millions of years.
“Our work delivers deep insight into evolutionary mechanisms underpinning the combinatorial biosynthesis of depsipeptide HDAC inhibitors,” the authors conclude. “Moreover, it provides a rational basis for developing approaches to the creation of analogues of depsipeptide HDAC inhibitors and other hybrid polyketide-nonribosomal peptides via evolution-guided biosynthetic engineering.”
The findings could ultimately accelerate efforts to develop next-generation HDAC inhibitors with improved potency, greater selectivity, and fewer side effects for treating cancer.
The post Bacterial ‘Docking Domains’ May Open New Paths to Next-Generation HDAC Inhibitors appeared first on Inside Precision Medicine.
Researchers have developed AI tool to rival the behemoth of Google’s Alphafold 3 in predicting 3D shapes in RNA using less data.
RNAbpFLow could shed new light on the RNA conformational dynamics that underpin diverse cellular processes.
It could also lead to novel RNA-based treatments, such as the messenger RNA vaccines used to prevent COVID-19.
The invention, by two computer scientists at Virginia Tech, generates all-atom RNA conformational ensembles for single-chain RNA monomers.
Unlike several existing deep-learning methods, it can do this without using evolutionary information or homologous structural templates.
The approach is outlined in Nature Methods and the researchers have made the training data, and code freely available.
Study first author Sumit Tarafder, a PhD student, flagged the importance of knowing the shape of an RNA so that it could be targeted.
“In the shape, there are pockets where a drug can attach,” he explained. “If you can’t predict the shape, your pockets are wrong—and the drug won’t work.”
Growing interest in RNA-based therapeutics has driven efforts to determine the 3D structures of RNA.
However, the intrinsic conformational flexibility of RNA presents major challenges when using methods such as X-ray crystallography, nuclear magnetic resonance spectroscopy, and cryo-electron microscopy.
Computer-based methods have emerged as an attractive alternative, but several of these approaches are constrained by the scarcity of RNA structural data in the Protein Data Bank.
While a growing number of methods based on Deep Learning have emerged, most are highly dependent on explicit evolutionary sequence information derived from multiple sequence alignments (MSA) or implicitly make use of homologous information learned by biological language models.
Tarafder and associate professor Debswapna Bhattacharya therefore developed RNAbpFlow, a sequence- and base pair-conditioned all-atom RNA 3D structure generation method based on SE(3)-equivariant flow matching model.
RNAbpFlow incorporates conditions on the nucleotide sequence and base-pairing information from three complementary base pair annotation methods to comprehensively capture canonical and noncanonical interactions.
By incorporating a nucleobase center representation that enables the optimization of angles of all rotatable bonds of nucleobases, it directly outputs all-atom RNA structures in an end-to-end fashion.
This bypasses the need for a post-hoc geometry optimization module, which is impractical in the context of large-scale sample generation.
Base pair-centric auxiliary-loss functions maximize the realization of canonical and noncanonical base-pairing interactions. This enables efficient generation of all-atom RNA conformational ensembles while explicitly modeling nucleobase orientation and flexibility.
Experimental results demonstrated that the introduction of base-pairing conditioning led to improved performance and accuracy connected to the quality of the base pairs.
In blind testing, RNAbpFlow produced a correct overall structure for 12 of 14 RNA targets, compared with eight out of 14 for AlphaFold 3, from Google DeepMind.
“We wanted to keep it simple and predict the structure from scratch, using just the sequence and the base pairs,” Tarafder said.
“The model starts from complete noise and, guided by those base pairs, folds into the right 3D shape.
“That’s the beauty of flow matching, and we can generate as many structures as you want, which lets us capture how the molecule actually moves.”
The post AI Tool Outperforms Google Rival at 3D RNA Shape Prediction appeared first on Inside Precision Medicine.
Huntington’s disease therapeutics have reached a historic milestone—the first patient has successfully received an experimental neural stem cell therapy at UCI Health. This groundbreaking dose marks the world’s first human trial of embryonic stem cell-derived neural stem cells for the devastating neurodegenerative disorder.
The treatment, performed in May at University of California Irvine (UCI) Health, represents the culmination of more than 12 years of laboratory research and eight years of clinical planning led by scientists and physicians at the University of California, Irvine. Researchers hope the treatment, known as hNSC-01, could eventually slow disease progression, protect vulnerable brain cells and potentially restore damaged neural circuits.
To date, the first participant has not reported any serious adverse effects, according to the clinical team. A second patient is expected to receive the therapy in July.
“This clinical trial highlights the important role that an interdisciplinary academic and clinical team, together with the HD families, plays in advancing medicine,” Leslie M. Thompson, PhD, clinical trial sponsor as well as the Donald Bren Professor of psychiatry and human behavior UC Irvine, told Inside Precision Medicine. “We are grateful to our patients and their incredible families for their bravery to provide hope for others with very few options.”
Huntington’s disease, caused by a mutation in the huntingtin gene, destroys brain cells, causing involuntary movements, cognitive decline, and psychiatric symptoms that begin between 35 and 50 and worsen over time. Without a cure, the fatal disorder burdens patients and families emotionally, physically, and financially, often requiring daily and long-term care.
Current treatments for Huntington’s disease primarily focus on managing symptoms rather than altering the underlying disease process. Drugs such as tetrabenazine and deutetrabenazine can reduce involuntary movements known as chorea, while antidepressants, antipsychotics and mood stabilizers help address psychiatric symptoms. Physical therapy, speech therapy and occupational therapy can also improve quality of life. However, none of these approaches has been shown to slow or stop the progressive loss of neurons that drives the disease.
Over the past decade, researchers have pursued several experimental disease-modifying strategies. Among the most advanced are gene-targeting therapies designed to reduce production of the mutant huntingtin protein. These include antisense oligonucleotides (ASOs), which are delivered through repeated spinal injections, as well as RNA-targeting and gene-editing approaches intended to suppress or correct the faulty gene. While these strategies directly target the genetic cause of Huntington’s disease, clinical results have been mixed, and questions remain about long-term effectiveness, safety and the need for lifelong treatment.
The hNSC-01 neural stem cell therapy being tested at UCI Health takes a different approach. Rather than targeting the mutant gene itself, the therapy aims to protect vulnerable neurons, replace lost cells, rebuild damaged neural circuits and provide supportive factors that promote brain health.
The UCI researchers believe stem cell-based therapies may offer a new approach by addressing multiple aspects of the disease simultaneously. The experimental treatment, hNSC-01, consists of pluripotent neural stem cells derived from embryonic stem cells and manufactured through the UC Davis Good Manufacturing Practice facility.
Preclinical studies in animal models suggested the cells could perform several functions relevant to Huntington’s disease, including protecting existing neurons, replacing cells that have been lost, rebuilding damaged neural networks and releasing beneficial proteins such as brain-derived neurotrophic factor (BDNF). The cells were also shown to reduce harmful protein accumulations associated with neurodegeneration and demonstrated long-term safety in mice.
Unlike conventional drug therapies, the stem cells are delivered directly into the brain. During the approximately six-hour procedure, performed under general anesthesia, patients lie face down within an MRI scanner while neurosurgeons use a specialized stereotactic navigation and delivery system to implant the cells into the striatum, a deep brain structure heavily affected by Huntington’s disease.
The striatum plays a central role in motor control, decision-making, motivation and learning. Degeneration of this region contributes significantly to the hallmark symptoms of the disorder. The first intervention was delivered by UCI Health neurosurgeon Jefferson W. Chen, MD, and a multidisciplinary surgical team.
As a Phase Ib/IIa study, the trial’s primary objective is to evaluate safety. However, researchers will also track biomarkers and clinical indicators that may provide early clues about whether the treatment is affecting disease progression.
When asked which biomarkers would help identify how the therapy is working in patients, Thompson emphasized that current measurements are focused more on assessing treatment impact than revealing biological mechanisms. “We will be including HD relevant clinical endpoints and biomarkers, including NfL in plasma and NfL and PENK in CSF; however, these are geared to understanding whether the treatment is having a benefit to these outcome measures versus informing the mechanism of action,” Thompson said.
One of the most important early indicators will be whether disease-related biomarkers remain stable rather than continuing their expected decline. “The earliest sign first and foremost is safety in this initial trial,” Thompson said. “Initial signs that the therapy could be meaningfully altering disease progression would be if the blood-based or CSF-based biomarkers do not show progression.”
Reaching the point of treating the first patient required overcoming a series of scientific, manufacturing and logistical hurdles. According to Thompson, selecting the optimal cell line was among the most significant challenges, testing multiple cell lines in vitro and in vivo.
Researchers also had to establish quality-control standards for the final therapeutic product and create Good Manufacturing Practice cell banks following extensive testing in Huntington’s disease mouse models. The COVID-19 pandemic introduced additional delays. “Disruptions caused by COVID-19, in particular the safety and tumorigenicity studies, delayed the timeline,” Thompson explained.
Another major undertaking involved creating the clinical infrastructure necessary for a first-of-its-kind procedure. Thompson said that it’s not really a challenge, but getting the overall procedural pipeline in place is the first study of this kind at the UCI Health–Irvine hospital in the MRI suite.
Despite the complexity of the project, Thompson said interactions with regulators proceeded smoothly. “We actually had a very good experience in terms of regulatory activities. A very helpful pre-pre-IND, pre-IND and relevant feedback from the FDA on the clinical trial.”
Whether hNSC-01 will ultimately compete with or complement emerging gene-targeting therapies remains unclear. Gene-silencing approaches may be easier to distribute because they do not require brain surgery, but repeated administrations over many years could result in substantial cumulative costs. In contrast, hNSC-01 involves a specialized MRI-guided neurosurgical procedure that may initially be limited to major medical centers, but it is designed as a one-time treatment whose long-term costs could compare favorably with chronic therapies if benefits prove durable.
Thompson believes the infrastructure requirements may be less of a barrier than many assume. “Yes, major medical centers can eventually offer it, and several medical centers are now using this system for other indications,” she said. “The other aspect is this would be a one-time administration so an individual could even travel to a medical center that offers the procedure.”
The REGEN4HD trial plans to enroll 21 adults aged 18 to 65 with early-stage Huntington’s disease. Twelve participants will be included in a Phase Ib dose-escalation cohort, while nine additional participants will be enrolled in a Phase IIa expansion group. The study is funded through a $12 million grant from the California Institute for Regenerative Medicine and coordinated through the UC Irvine Alpha Clinic, one of nine state-supported regenerative medicine clinical research centers.
Even if the therapy proves safe and beneficial, researchers caution that it remains unclear whether stem cell transplantation alone will be sufficient to combat Huntington’s disease over the long term. “At this point we do not know whether this will be sufficient alone or will need to be delivered with other disease-modifying therapies,” said Thompson. “For example, ones that specifically target an HD mechanism such as somatic repeat instability,” Thompson said. “However, these cells also have the potential to exert therapeutic effects directly while serving as vehicles for the delivery of additional interventions.”
For families affected by Huntington’s disease, the first successful treatment in the REGEN4HD trial represents more than a scientific milestone. It marks the beginning of a new chapter in regenerative medicine—one that researchers hope could eventually transform the outlook for a disease that has long remained untreatable.
The post First Huntington’s Disease Patient Dosed with Neural Stem Cell Therapy appeared first on Inside Precision Medicine.
Nature Biotechnology, Published online: 30 June 2026; doi:10.1038/s41587-026-03201-5
Each year, Nature Biotechnology highlights companies that received sizeable early-stage funding in the previous year. Liberate Bio is developing a lipid nanoparticle toolbox to deliver genetic medicine to previously inaccessible cells inside the body.