Genetic Medicine Delivery Enhanced by Producer Cell Modifications

Gene editing has emerged as a powerful approach for targeting the genetic causes of disease, yet delivering the editing machinery into the correct cells efficiently, safely, and at the scale needed for therapies remains one of the biggest bottlenecks.  

Among the leading delivery vehicles are engineered virus-like particles (eVLPs), which can enter human cells similar to viruses but carry no viral genes. Instead, these delivery vehicles carry gene editing tools for therapeutic applications.  

In a new study published in Nature Communications titled, “Genome-wide screening reveals producer-cell modifications that improve virus-like particle production and delivery potency,” researchers from Whitehead Institute have developed a platform that systemically identifies which genes drive or block particle assembly to engineer cells that yield more potent delivery vehicles. 

“We can engineer the particles as much as we want, but if we don’t understand how the producer cells are actually making the particles, we’re limited in how much we can improve production,” said Aditya Raguram, PhD,  Valhalla Fellow at Whitehead Institute and corresponding author of the study.

As virus-like particles are assembled inside cultured human cells, the authors ran a genome-wide search to identify which genes are crucial in the production process by generating a large pool of producer cells in which nearly every gene in the human genome was switched off in the population. This approach generates eVLPs loaded with guide RNAs that identify the genetic perturbation in the cell that produced a particular particle. The team could then identify which gene shutdowns enabled and disabled particle production. 

“One thing that surprised me was how clearly the search was able to highlight specific pathways that play a major role in the production of these particles,” said Diana Ly, research technician at Whitehead Institute and first author of the study. 

The single gene whose removal most boosted production normally reduces the cell’s output of guide RNAs. Disabling this gene enabled cells to generate more guide RNA and particles to carry more functional cargo. 

The improvement also extended across different gene editing tools and particle designs. The team tested the modified producer cells with diverse gene editors and four other delivery-vehicle systems from external labs, and produced improved particles. 

“Because guide RNA loading is basically universal across different cargo types and particle types, this improvement could be quite broadly useful beyond the particles we’ve developed,” Raguram says. 

Looking ahead, the authors are extending the screening platform to expand beyond switching off one gene at a time to examine how other cellular changes influence particle production. The team is sharing its engineered cell lines with the research community to improve the delivery of gene editing tools into immune cells, neurons, and other cell types important for treating disease. 

For Raguram, the work speaks to a broader task facing the gene editing field. 

“This delivery challenge is one of the last remaining bottlenecks that really limits the widespread application of gene editing technologies,” he says. “Solving the challenges associated with production could move virus-like particles closer to being ready for use in patients.” 

The post Genetic Medicine Delivery Enhanced by Producer Cell Modifications appeared first on GEN – Genetic Engineering and Biotechnology News.

Milnacipran continuation during pregnancy in a patient with severe post-traumatic stress disorder and psychotic depression: a case report with 3-year pediatric follow-up

Evidence on milnacipran exposure during pregnancy is sparse, complicating treatment decisions when maternal stability depends on this antidepressant. We report a 31-year-old primigravida with severe post-traumatic stress disorder and a severe major depressive episode with psychotic features in the context of a chronic, difficult-to-treat psychiatric course marked by self-harm, dissociation, and recurrent suicidal behavior. Milnacipran 150 mg/day led to marked clinical improvement before pregnancy. After pregnancy confirmation, treatment was changed to sertraline plus quetiapine because of limited pregnancy safety data, but depressive symptoms and suicidal behavior reemerged within 2 weeks. Milnacipran was therefore re-established after risk-benefit evaluation and shared decision-making, with renewed improvement. Moderate hyperemesis gravidarum during the second trimester led to discontinuation of milnacipran by gestational week 22. Delivery occurred at gestational week 38 via primary cesarean section. No congenital anomalies or neonatal adaptation problems were observed. At 3-year follow-up, pediatric developmental screenings remained within expected limits. This case illustrates the challenge of balancing relapse risk, prior treatment response, and treatment feasibility during pregnancy when evidence for the effective medication is limited.

STAT+: Doctor, wife of acting U.S. attorney general appointed to NIH advisory council

Kristine Blanche, an integrative medicine doctor and wife of acting Attorney General Todd Blanche, has been named as a member to one of the advisory councils that provides critical funding recommendations to the National Institutes of Health. Her appointment, to serve on the advisory council to the National Center for Complementary and Integrative Health, is the first of such appointments to be made in over a year.

It’s unclear if Blanche’s selection — which has not been publicized by the NIH — is a sign of a thawing in the pipeline of advisory council appointments. But it’s done little to quiet simmering concerns among the wider research community about whether the Trump administration would attempt to stack councils with ideological allies who will use their positions to advance its political goals.  

It’s “the worst kind of political patronage,” Joshua Gordon, a former director of the National Institute of Mental Health, told STAT. He and others worry the move will erode taxpayers’ trust in how the largest funder of biomedical research in the world spends its $48 billion budget. “It’s clearly meant to contribute to an intentional degradation of confidence in the NIH.”

Continue to STAT+ to read the full story…

Medication Treatment for Tics and Tourette’s

There are several kinds of medication than can help kids with Tourette’s or another tic disorder. But it’s important to note that not all kids who develop tics need treatment. Tics are very common. They often go away on their own, and they tend to bother parents more than they do the children experiencing them. Drawing attention to them can make them worse. So doing nothing can be the best strategy — at least initially.

Treatment comes into play if tics are upsetting your child, giving them pain, or making it hard for them to function in everyday life — say they’re disrupting class or getting bullied because of their tics.

The first recommended step in treatment is a specialized form of therapy called comprehensive behavioral intervention for tics (CBIT). CBIT is centered on habit reversal training, in which the child learns to recognize when they have an urge to tic and substitute a competing response — an easier, more comfortable, or less noticeable action or behavior that makes the tic impossible. For instance, if a child’s tic is jerking their head to the side, the strategy might be to put their chin down instead.

But if therapy isn’t effective in reducing a child’s tics, medication can help.

Guanfacine and clonidine for tics

First-line medications for Tourette’s and other tic disorders are a class of drugs called alpha-2 agonists, explains Paul Mitrani, MD, PhD, a child and adolescent psychiatrist at the Child Mind Institute. Alpha agonists decrease the release of a neurotransmitter called norepinephrine, which stimulates the nervous system. Alpha agonists serve as a kind of dimmer switch — by calming down the system, they make the urge to tic less frequent, less intense, and by extension, easier to control.

The two alpha-2 agonists usually prescribed for tics are guanfacine and clonidine. Dr. Mitrani reports that he usually starts by prescribing guanfacine because it comes in a longer-acting form (Intuniv), which reduces symptoms for a full 24 hours. Clonidine’s long-acting form (Kapvay) is effective for 12 hours.

Dr. Mitrani adds that there is a new liquid form of clonidine called Onyda XR that lasts 24 hours, but there isn’t yet a strong body of evidence regarding its effectiveness for tics. Onyda XR is FDA-approved for ADHD, as are Kapvay and Intuniv.

While no alpha agonist medications are FDA-approved specifically for tics, Kapvay and Intuniv are frequently used off-label for them. There is ample research on their effectiveness for tics, and they are recommended by clinical practice guidelines.

Some children respond better to several doses of short-acting guanfacine or clonidine, Dr. Mitrani notes, rather than a smoother dose of a long-acting medication. This may be because medication can be timed to peak at times when kids need tic suppression most, such as at school.

Alpha agonists are the preferred first line medications for tic disorders because their side-effects, including drowsiness and low blood pressure, are relatively mild.

Antipsychotics for tics

If alpha agonists aren’t helping, the next step would be to try an antipsychotic medication, which can be more effective for treating tics, Dr. Mitrani notes, but their side effects are potentially more difficult to tolerate.

Aripiprazole (Abilify), which is FDA-approved for tics, is often Dr. Mitrani’s first choice among the antipsychotic medications. Abilify is a second-generation, or atypical, antipsychotic, a group of medications that have fewer side effects than older antipsychotics. Side effects of Abilify can include restlessness, agitation and weight gain.

Haloperidol (Haldol) is also effective for tics, but it’s an older antipsychotic with more side effect concerns, Dr. Mitrani notes. “I’ve only had one patient ever on Haldol, and he tolerated it well and it really helped with his tics when other things did not.”

Risperidone (Risperdal) is another atypical antipsychotic that can help, but its side effects tend to be worse than Abilify. Risperidone can cause more concerning weight gain and metabolic, neurological, and hormonal changes that can be harmful. Sometimes other medications are used to manage the weight gain from antipsychotics.

When kids with tics also have ADHD

More than three-quarters of kids diagnosed with a tic disorder also have another disorder. When a child has multiple disorders, a clinician will want to evaluate which is causing the child the most difficulty and prioritize treating that.

The most common co-occurring disorder with tics is ADHD. “If tics are the bigger problem, we would start with treating them,” says Dr. Mitrani. “If the ADHD is the bigger problem, which it typically is, we usually treat that first.”

In the past, it was recommended that children with tics and ADHD avoid stimulant medication, based on research that showed it made tics worse. But newer studies counter that finding, Dr. Mitrani notes, concluding that the old research was based on very high doses of amphetamine-based medications. To lower the risk of exacerbating tics, he recommends starting kids with ADHD and tics on methylphenidate-based medication.

“If your child is starting a stimulant,” he adds, “and you see worsening of tics — and it’s clearly related to when the stimulant is in their system — the best approach might be a lower dose of stimulant combined with guanfacine or clonidine.”

One advantage to that combination, he notes, is that kids with ADHD who have behavior problems can benefit from the guanfacine or clonidine being active in the mornings before the stimulant starts working and in the evenings when it’s out of their system.

Kids with other co-occurring disorders

When children with tics have other co-occurring disorders, such as anxiety, OCD, or depression, treating them with medication needs to be done very carefully, Dr. Mitrani says. Since children are typically not bothered by the tics themselves, it’s almost always the other disorder that is more problematic for them.  And, he adds, when the other problems cause distress, it can make the tics worse.

For anxiety, OCD, and depression, the first-line medication treatment is an antidepressant. Antidepressants can actually help alleviate tics indirectly, since they reduce anxiety. “Stress increases tics, so if there is significant anxiety and you treat the anxiety, the tics may get better,” Dr. Mitrani says. “And then maybe you don’t need the guanfacine or clonidine. But again, it depends on what the co-occurring disorders are and what’s the bigger problem for the child.”

Monitoring medication for tics

Due to the waxing and waning nature of tics, it can be challenging to see the full effect of medication and other interventions. It is important to give medication enough time to work, Dr. Mitrani notes, typically a few weeks, to see if the overall pattern, frequency, and severity of tics has improved. And children who are being treated should continue to be monitored regularly for any changes, as tics can recur or worsen, especially when a child is excited, tired, or experiencing more stress.

Most children with tics see a natural improvement or even resolution of tics as they progress through adolescence. If there seems to be a long-standing improvement, it is appropriate to consider reducing or stopping medication, especially if the child is experiencing side effects, Dr. Mitrani notes. If tics continue and are causing distress, it is important to keep treating them.

A child going off any of these medications — alpha agonists or antipsychotics — should do so gradually, by having their dose reduced over weeks or even longer, to avoid unpleasant or dangerous side effects of sudden withdrawal.

The post Medication Treatment for Tics and Tourette’s appeared first on Child Mind Institute.

Opinion: The podcast telling the stories behind Ambien, Ozempic, EpiPens, and other game-changing drugs

Below is a lightly edited, AI-generated transcript of the “First Opinion Podcast” interview with Thomas Goetz. Be sure to sign up for the weekly “First Opinion Podcast” on Apple PodcastsSpotify, or wherever you get your podcasts. Get alerts about each new episode by signing up for the “First Opinion Podcast” newsletter. And don’t forget to sign up for the First Opinion newsletter, delivered every Sunday.

Torie Bosch: Whether it’s Ambien or Wegovy, ivermectin or fluoride, every drug in your medicine cabinet or advertised on TV has a story behind it. Not just how it came to be, but how it ends up affecting society in unexpected ways, big or small.

Read the rest…

New Low-Toxicity Transplant Method Reverses Type 1 Diabetes in Mice

Researchers at Stanford Medicine say they have developed a combination treatment method that cured or prevented type 1 diabetes in mouse models by pairing blood stem cell transplantation with pancreatic islet cell transplantation under a substantially reduced preconditioning regimen. The approach creates a mixed immune system from both donor and recipient cells, which stopped autoimmune destruction of insulin-producing cells while also producing long-term tolerance to the transplanted tissue. The findings, published in the Journal of Clinical Investigation Insight, show that reversing type 1 diabetes can be accomplished without chronic immunosuppression or the toxic conditioning via radiation or chemotherapy currently used for hematopoietic stem cell (HCT) transplantation.

“The possibility of translating these findings into humans is very exciting,” said senior author Seung K. Kim, MD, PhD, a professor of developmental biology at Stanford. “The key steps in our study—which result in animals with a hybrid immune system containing cells from both the donor and the recipient—are already being used in the clinic for other conditions. We believe this approach will be transformative for people with type 1 diabetes or other autoimmune diseases, as well as for those who need solid organ transplants.”

Type 1 diabetes is an autoimmune disease that attacks pancreatic islet cells. While islet transplantation can restore insulin production, it typically requires immunosuppressive drugs that carry risks including infection, malignancy, and organ damage. The Stanford team’s approach reduced these negative effects by inducing immune tolerance through mixed hematopoietic chimerism, a state in which donor and recipient immune cells coexist.

“Mixed hematopoietic chimerism after hematopoietic cell transplantation (HCT) can modulate the immune system and induce tolerance to allogeneic tissues,” the researchers wrote. “However, bone marrow conditioning-related toxicities preclude wider adoption of HCT for transplant allotolerance.”

The current findings by the Stanford team builds on a series of research initiatives beginning with work published in 2022, in which the researchers showed they could cure toxin-induced diabetes in mouse models using antibody-based immune conditioning combined with moderate radiation (200–300 cGy), followed by transplantation of donor-matched blood stem cells and islets. This study served as a proof of concept but used radiation at levels that are potentially toxic.

A November study published in JCI, along with the new research addressed two significant challenges for developing an effective transplantation protocol: autoimmune diabetes, in which the immune system targets islet cells, and the need to reduce conditioning toxicity. In the November study, the researchers added an immune-modulating drug used in autoimmune disease to their regimen. This change enabled the formation of a hybrid immune system that both accepted donor islets and prevented autoimmune attack. All treated mice were protected from developing diabetes, and those with already possessing the disease were cured.

To further reduce toxicity, the April study added additional agents, baricitinib, venetoclax, and an αCD47 antibody, to go with αCD117 antibody and transient T cell depletion. These agents were selected because they target distinct biological pathways involved in immune regulation and bone marrow niche clearance. Baricitinib, a JAK1/2 inhibitor, reduces inflammatory signaling and supports donor cell engraftment. Venetoclax promotes apoptosis of specific immune cells, and αCD47 disrupts a signaling pathway that normally protects cells from clearance, which helped in the removal of host stem cells to make space for donor cells.

“We systematically tested baricitinib (JAK1/2 inhibitor), venetoclax (Bcl2 inhibitor), and αCD47 antibody, agents in current clinical use, and quantified hematopoietic chimerism after HCT,” the researchers wrote. “Combined with αCD117 antibody, transient T cell depletion, and just 10 centigray (cGy) total body irradiation (TBI), these agents enabled durable mixed chimerism and matching allo-islet tolerance, to cure diabetes without evidence of [graft-versus-host disease].”

This new combination allowed researchers to reduce radiation exposure to 10 cGy, a fraction of the levels used in conventional bone marrow transplantation. Mice treated using this regimen showed stable engraftment of donor cells, maintained fertility, and experienced no graft-versus-host disease. They also remained insulin-independent for the duration of the study.

The findings provide a potential pathway toward clinical adoption, which could be speedier than usual since many of the agents used for this approach are already approved or under evaluation in humans.

Work at Stanford will continue in this area and will focus on testing the reduced-intensity regimen in autoimmune diabetes models, refining conditioning strategies, and exploring alternative sources of islet cells, including those derived from stem cells.

If successfully, translated to the clinic, this treatment regimen could reduce or eliminate the need for lifelong insulin therapy, while expanding the use of transplantation-based therapies across a wider set of patients.

The post New Low-Toxicity Transplant Method Reverses Type 1 Diabetes in Mice appeared first on Inside Precision Medicine.