PTC Wins First FDA Nod for Direct-to-Brain Gene Therapy, Targets Ultrarare Disease

 

The FDA has followed in the footsteps of its European counterparts and granted accelerated approval to PTC Therapeutics’ gene therapy Kebilidi for AADC deficiency. It is the first approved gene therapy to be delivered directly to the brain.

The FDA on Wednesday signed off on PTC Therapeutics’ gene therapy eladocagene exuparvovec-tneq for the treatment of aromatic L-amino acid decarboxylase deficiency. The treatment will be marketed under the brand name Kebilidi.

With only around 350 cases reported in the literature, aromatic L-amino acid decarboxylase (AADC) deficiency is an ultrarare genetic disease characterized by severe disability that begins during the first few months of life, ultimately leading to death. Patients with AADC deficiency suffer from severe physical, mental and behavioral symptoms, made worse by seizure-like crisis episodes.

AADC deficiency is caused by mutations in the DDC gene, which under healthy circumstances encodes for the AADC enzyme that plays a role in the production of dopamine and serotonin in neurons. In patients with AADC deficiency, the protein has lower activity, leading to the signature developmental delays and abnormalities that mark the disease.

Kebilidi is a recombinant AAV-based gene therapy that works by delivering a functional copy of the DDC gene to cells in a brain region called the putamen. That makes it the first FDA-approved gene therapy to be delivered directly to the brain, according to a note to investors from William Blair. According to PTC’s announcement, Kebilidi is indicated for children and adults across “the full spectrum of disease severity”—a relatively broader label than what it was granted in the EU and U.K., where it is marketed as Upstaza and is approved for use in children aged 18 months and above.

Wednesday’s approval was granted under the FDA’s accelerated pathway. PTC will need to validate Kebilidi’s clinical benefit in a confirmatory trial to keep the therapy on the market.

The FDA’s verdict was supported by data from an open-label, single-arm study that enrolled 13 patients with severe AADC deficiency. Gross motor development milestones at 48 weeks were assessed in 12 patients. According to Kebilidi’s label, 67% of study participants hit a new gross motor milestone at this time point, including three who achieved full head control and two who were able to sit with or without assistance. Meanwhile, none of the 43 untreated patients were able to achieve such milestones by a median age of 7.2 years.

With Kebilidi’s approval, PTC “has once again pioneered a new approach to treating highly morbid neurologic diseases,” CEO Matthew Klein said in a statement. Launch preparations for Kebilidi in the U.S. are “well underway,” the biotech noted in announcement, adding that it had already identified centers of excellence and surgeons to administer the therapy.

“We view the approval of Kebilidi in the U.S. favorably for PTC and think the FDA approval of the first gene therapy that is administered directly to the brain is a positive for the broader gene therapy space, particularly those pursuing similar routes of administration,” William Blair said in its note.

PTC is also developing a phenylketonuria therapy, sepiapterin, the regulatory submission for which was filed in the third quarter, according to the company’s business report last week. A target action date has been set for July 29, 2025.

https://www.biospace.com/fda/ptc-wins-first-fda-nod-for-direct-to-brain-gene-therapy-targets-ultrarare-disease

Merck Hops Onto PD-1/VEGF Train, Committing up to $3B Plus in LaNova Deal

 

Despite recent enthusiasm around the PD-1/VEGF space, BMO Capital Markets analyst Evan Seigerman noted that Merck’s pact with LaNova Medicines is more “conservativism” on the pharma’s part, rather than confirmatory of recent data in the drug class.

Merck announced a licensing deal Thursday with Shanghai-based LaNova Medicines to advance a next-generation cancer therapy that could help the pharma maintain its frontrunner status in oncology—even as its blockbuster PD-1 inhibitor Keytruda (pembrolizumab) begins to face biosimilar competition in the coming years.

Under the terms of agreement, Merck will pay $588 million upfront for the exclusive global right to develop, manufacture and commercialize LaNova’s investigational bispecific antibody LM-299. The Chinese biotech will also be eligible to receive up to $2.7 billion in technology transfer, development, regulatory and commercialization milestones across several oncology indications.

Merck and LaNova expect to close the transaction by the end of the year, pending antitrust approvals and other customary conditions.

LM-299, the centerpiece of Thursday’s agreement, is a bispecific antibody that belongs to a new but rapidly emerging class of cancer therapies. It is currently being assessed in a Phase I study in China for solid tumors, though the partners have yet to reveal what specific cancer types they plan to target. The investigational treatment works by combining the PD-1 and VEGF pathways, which theoretically would allow it to restore the immune system’s cancer-killing activity while simultaneously preventing tumors from forming new blood vessels.

Biopharma has begun to see the potential of this mechanism of action, with more and more companies upping their investments in the drug class.

This shift was highlighted in September 2024 when Summit Therapeutics and development partner Akeso, also headquartered in China, announced that their investigational PD-1/VEGF-A bispecific ivonescimab outperformed Keytruda in advanced non-small cell lung cancer. Patients treated with ivonescimab saw a nearly 50% drop in the risk of disease progression or death versus Keytruda—a strongly significant effect with p-value lower than 0.0001.

At the time, Summit CEO Maky Zanganeh said these findings point to the potential of ivonescimab “to be the next generation in PD-1 directed immunotherapy.”

BioNTech is also coming after Keytruda’s throne, putting down $800 million upfront on Wednesday to acquire China-based Biotheus and its anti-PD-L1/VEGF-A bispecific antibody BNT327/PM8002. The acquisition agreement also includes up to $150 million in certain milestone payments. BioNTech CEO Ugur Sahin said he believes the candidate “has the potential to set a new standard of care in multiple oncology indications, surpassing traditional checkpoint inhibitors.”

Analysts, however, do not seem to be convinced just yet. In response to Summit’s data drop in September, BMO Capital Markets’ Evan Seigerman wrote in a note that despite the promising results, ivonescimab is “not yet the Keytruda slayer.”

Seigerman again took a measured note on Thursday, calling the LaNova deal a “conservative acquisition for Merck, rather than confirmatory of the data we have seen from other players.” Merck maintains its “best-in-class” status in the PD-1 space, “with a wall of clinical data and a rapidly advancing pipeline of other modalities” targeting the pathway, Seigerman said. LM-299 “simply adds another arrow to Merck’s arsenal.”

Guggenheim Partners’ Vamil Divan echoed Seigerman’s cautious optimism about the PD-1/VEGF space, writing in a Thursday note that “we await overall survival data from PD-1/VEGF bispecifics in a broader, more geographically diverse population.” Still, “it makes sense for Merck to be proactive in working to address this potential threat.”

https://www.biospace.com/business/merck-hops-onto-pd-1-vegf-train-committing-up-to-3b-plus-in-lanova-deal

Russian Nuclear Weapons Are Keeping NATO Troops Out Of Ukraine: Top Admiral

 by Kyle Anzalone via The Libertarian Institute,

A top NATO military official said that NATO forces would have deployed to Ukraine to drive Russian soldiers from the country if Russia did not have nuclear weapons. 

Chair of the NATO Military Committee, Dutch Admiral Rob Bauer, explained to the International Institute for Strategic Studies’ Prague Defense Summit in the Czech Republic that Russia’s nuclear weapons are deterring a NATO deployment to Ukraine.

"I am absolutely sure if the Russians did not have nuclear weapons, we would have been in Ukraine, kicking them out," he stated. 

Bauer said the challenge for the West is finding where Russia’s redlines on nuclear use are, noting that Washington mistakenly miscalculated that sending tanks and F-16s to Ukraine were the Kremlin’s redlines. 

Admiral Bauer was discussing the difference between the Ukraine conflict and other NATO wars such as the Afghanistan occupation. He stated the main difference between Moscow and Kabul is Russia’s nuclear stockpile.

In Afghanistan, American and NATO forces quickly forced the Taliban from Kabul in 2001. Then, the Western alliance engaged in a two-decade nation-building project while the Taliban fought using insurgent tactics. 

The top NATO official went on to say the Afghan War was not of strategic importance. "Afghanistan was never of strategic importance. If we’re really honest Afghanistan was not of strategic importance."

He continued, "We spent 20 years there and we did a lot of things and people lost their lives but if you ask the question, ‘was it of strategic importance?’ In Afghanistan, the answer is no."

Bauer argued that Ukraine is strategically important to NATO because the bloc is defending the "rules-based international order." While the alliance has denounced Moscow for invading Ukraine, it has been silent as its core member has lavished Israel with arms as it conducts a genocide in Gaza and invades Lebanon.

* * *

Watch Adm. Rob Bauer's full remarks below in "Sustaining the Long War: Money, Manpower and Public Support":

https://www.zerohedge.com/geopolitical/russian-nuclear-weapons-are-keeping-nato-troops-out-ukraine-top-admiral

Hochul’s cynical flip-flop on congestion pricing proves she wants to scam New Yorkers’ pockets dry

 With Election Day in the rearview mirror, we are seeing the political cynicism of Gov. Hochul in full bloom. 

Back in June, Governor Hochul surprised the political world, the media and New Yorkers when she “indefinitely paused” her congestion-pricing plan. 

She cited economic concerns raised by the business community and commuters, which was true, but her real motive is she thought it would hurt Democrats in the elections. 

Now, without a blush of embarrassment, she plans to bring it back.

New York voters are being scammed once again. 

New Yorkers have a narrow window to stand up and speak out against this underhanded war on cars and elitist plan that will negatively impact our commuters and small businesses — and not improve the environment but simply shift traffic and pollution to working-class and mostly minority communities. 

We’ve introduced bipartisan legislation, filed federal lawsuits and stoked public outrage to reverse course.

If the governor won’t listen to the will of two-thirds of New York City residents who resoundingly said they don’t want congestion pricing, we’ll work with incoming President Trump to terminate this scam. 

The stakes are high, and if we don’t act now, we’ll all pay the price. 

Republican Rep. Nicole Malliotakis represents Staten Island and part of southern Brooklyn.

https://nypost.com/2024/11/13/opinion/hochuls-cynical-flip-flop-on-congestion-pricing-proves-she-wants-to-scam-new-yorkers-pockets-dry/

Key influenza-severity risk factor found hiding in plain sight on our antibodies

 Viruses are the fastest-evolving biological entity on Earth. This fact explains why we need flu shots every year: Seasonal influenza perennially outwits the immunity we've acquired from previous vaccinations or infections.

Some new strains are rougher than others. The 1918 flu pandemic killed 50 million people and infected one-fifth of the world's population. Influenza pandemics also occurred in 1957, 1968 and 2009.

"Influenza remains an incredibly dangerous risk to global health," said Taia Wang, MD, Ph.D., associate professor of infectious diseases and of microbiology and immunology.

A team led by Wang has found that the relative abundance of a certain kind of sugar molecule in our antibodies—the specialized proteins our immune systems cook up to block viruses and other microbes from entering our cells and replicating profusely once inside—plays an outsized role in whether we become mildly ill rather than severely ill from a flu infection.

They've also figured out why, and they've demonstrated, in mice, how to head off severe flu symptoms regardless of which strain is on the march. That would come in handy in the event of the next large-scale flu outbreak—and it may apply to other infectious diseases.

The findings, described in a study published in Immunity, may even help explain why older people are more susceptible to severe flu and many other diseases, infectious or otherwise.

Wang, a faculty member in Stanford Medicine's Institute for Immunity, Transplantation and Infection, is the study's senior author. Lead authors of the study are basic life research scientist Saborni Chakraborty, Ph.D.; postdoctoral scholar Bowie Cheng, Ph.D.; graduate student Desmond Edwards; and former graduate student Joseph Gonzalez, Ph.D.

Inflammation over replication

Sitting on the surface of some of our immune cells is a receptor called CD209, which the study showed can dial down inflammation in response to a flu infection. Wang and her associates were able to kick that anti-inflammatory receptor into gear by fiddling with the composition of antibodies.

This didn't stop the virus from getting into lung cells and making copies of itself while inside the cells it invaded. But it didn't have to.

Viruses furiously self-replicating inside our lung cells are not a good thing, obviously. But fatal cases of influenza infection are usually caused by an overwhelming inflammatory response to the infection, which exacerbates lung damage and prevents gas exchange, rather than by the virus alone, Wang said.

"We've discovered a new way to protect against severe influenza by shutting down this follow-on inflammation, regardless of ongoing viral replication," she said.

The experimental inflammation-lowering technique isn't limited to a single flu strain.

The antibody molecules circulating in our blood and known to immunologists as IgG (the acronym stands for "immunoglobin G") are roughly Y-shaped. The Y's horns are customized to cling to specific surface features of particular pathogens, and if the fit is snug enough and ties up the right part of the invading pathogen, prevent it from getting into cells.

The stalk of an antibody's Y-shaped structure is oblivious to whatever the horns are binding to. That stalk's job is to tell the rest of the immune system what to do. It can have differing affinities for various immune cells. It can also exert different effects on whichever immune cells it makes contact with, depending on the chemistry of a couple of long, bifurcated chains attached to its surface.

These chains' links are made of sugar—granted, not the kind you'd find in a candy store. To carbohydrate scientists, the term "sugar" refers to nearly a dozen distinct but chemically similar substances our own bodies produce. Most of these sugars have names few of us have ever heard of. Sewn into or stapled onto larger molecules, they provide structural support, stability or signaling capability.

As many as four molecules of a particular sugar called sialic acid may get snapped into place as final links on an IgG molecule's branching sugar chains. How many actually do can make a big difference.

Enter the alveolar macrophage

Wang's study began by characterizing antibodies from people who did or did not become very sick after infection by H1N1, a common seasonal influenza subtype. The only significant difference the scientists observed between those who became mildly ill and those who were hospitalized was in the amount of sialic acid on infected individuals' antibodies. High levels correlated with mild symptoms; sicker patients' antibodies sported fewer sialic acid links.

Wang and her colleagues explored further, using bioengineered mice whose cells expressed human receptors for antibodies.

"We gave the mice human antibodies differing only in their sialic acid content," Wang said. Then the mice received what would ordinarily be a lethal dose of either of two very different seasonal influenza virus subtypes.

The sialic acid-rich antibodies, but not the others, protected the animals from both types of flu, evidently due to markedly reduced lung inflammation.

"The reduced inflammation led to better oxygen and carbon dioxide exchange," Wang said. "The lungs could keep doing their job."

The difference in sialic acid abundance had no effect on the virus's ability to replicate inside infected lung cells.

The scientists found that the high- and low-sialic acid antibodies were binding to entirely different receptors on the surfaces of immune cells called alveolar macrophages. These fierce sentinel cells, among other things, patrol the alveoli—the tiny, delicate air sacs studding the surfaces of our lungs, through which oxygen from the air we breathe and carbon dioxide, a respiration byproduct, are exchanged.

When alveolar macrophages spy a pathogen, they gobble it up. They also signal the immune system to send in more troops. Usually that influx of additional immune cells is enough to quell the microbial invasion.

But sometimes, ironically, the surplus of fired-up immune cells and the noxious substances they squirt out—the essence of inflammation—do more harm than good: They not only expunge virally infected cells but tear up healthy ones, too. That may cause even more inflammation.

Antibodies usually bind to pro-inflammatory receptors on alveolar macrophages, spurring downstream inflammatory activity. But higher levels of sialic acid on an antibody's stalk, the scientists proved, induce the antibody to bind to CD209 instead, shifting alveolar macrophages' mood to anti-inflammatory.

"CD209 has been shown to be anti-inflammatory in autoimmunity," Wang said. "But it's never before been implicated in calming our immune response to an infectious disease."

Analyses of alveolar macrophages' gene-activation levels showed that the same set of genes whose activity levels differed in flu-infected mice receiving high- versus low-sialic acid antibodies could be used to divide influenza patients into "mild" and "severe" categories.

Many of these genes are associated with mounting an inflammatory response. In particular, sialic acid-rich antibodies' binding to CD209 shut down activity of a famous inflammatory sparkplug called NF-kappa-B.

Who needs horns?

An antibody's horns can bind to only one, or at most, an extremely narrow range of pathogens. Yet, sialic acid-rich antibodies' beneficial dialing down of disease severity wasn't limited to a single flu strain. Nor did their benefits come from any clearing of the virus. It was purely the anti-inflammatory response that was reducing disease severity.

Wang said, "We wondered: Does this protection we see against highly different influenza-virus subtypes require the whole antibody? Are its horns even necessary? Or might the stalk alone be enough to protect against flu severity?"

Fortunately, just such high-sialic acid antibody stalks are available, as they're under active clinical investigation for treating autoimmune disorders, which are also inflammatory in character. These stalks proved effective in preventing severe symptoms in flu-infected mice.

Wang's team is doing longitudinal studies in humans to see if sialic acid-enriched antibody stalks can predict risk of disease progression in influenza patients.

The findings' applications may extend beyond influenza, or lung infections in general, to numerous infectious diseases and even to a broad range of inflammatory conditions, she said.

"Age is the major factor differentiating people whose antibodies characteristically have high versus low sialic acid content," Wang said.

The age-associated decline in sialic acid's abundance in people's antibodies may account in part for the observed high incidence of chronic low-level inflammation in older people, predisposing them to conditions ranging from heart trouble and strokes to Alzheimer's and Parkinson's disease to cancer and many other aging-associated diseases.

Wang is a consultant for Nuvig Therapeutics Inc., which is testing antibody stalks for treating autoimmunity, and provided these reagents for use in this study.

Researchers from the University of California, San Diego; Nuvig Therapeutics Inc.; the University of Colorado; National Jewish Health; Washington University School of Medicine; the National Institutes of Health; and the Howard Hughes Medical Institute contributed to the work.

More information: Saborni Chakraborty et al. Sialylated IgG induces the transcription factor REST in alveolar macrophage to protect against lung inflammation and severe influenza disease, Immunity (2024). DOI: 10.1016/j.immuni.2024.10.002. www.cell.com/immunity/fulltext … 1074-7613(24)00482-5

https://medicalxpress.com/news/2024-11-key-influenza-severity-factor-plain.html

Over 800 m adults living with diabetes with more than half not receiving treatment

 The total number of adults living with either type 1 or type 2 diabetes in the world has surpassed 800 million—over four times the total number in 1990, according to findings from a global analysis published ahead of World Diabetes Day in The Lancet. Additionally, 445 million adults aged 30 years and older with diabetes (59%) did not receive treatment in 2022, three and a half times the number in 1990.

Of the 828 million adults with diabetes in 2022, over a quarter (212 million) lived in India with another 148 million in China, followed by the U.S. (42 million), Pakistan (36 million), Indonesia (25 million) and Brazil (22 million).

The study was unable to separate type 1 and type 2 diabetes in adults. However, previous evidence suggests that the vast majority of cases of diabetes in adults are type 2.

Senior author Professor Majid Ezzati, of Imperial College London, said, "Our study highlights widening global inequalities in diabetes, with treatment rates stagnating in many low- and middle-income countries where numbers of adults with diabetes are drastically increasing.

"This is especially concerning as people with diabetes tend to be younger in low-income countries and, in the absence of effective treatment, are at risk of life-long complications—including amputation, heart disease, kidney damage or vision loss—or in some cases, premature death."

A global study with global data

The new study, conducted by the NCD Risk Factor Collaboration (NCD-RisC), in collaboration with the World Health Organization (WHO), is the first global analysis of trends in both diabetes rates and treatment which includes all countries. Researchers used data from over 140 million people aged 18 years or older from more than 1,000 studies in populations of different countries.

The authors used statistical tools to bring all the data across different years, ages and countries together, and estimate diabetes rates and treatment in a way that enables comparisons across countries.

Diabetes was defined as having a fasting plasma glucose (FPG) of 7.0 mmol/L or higher, having a glycated hemoglobin (HbA1c) of 6.5% or higher (two commonly used diagnostic criteria options for diabetes according to modern guidelines) or taking medication for diabetes. Treatment was defined as taking medication for diabetes.

Most previous studies looking at diabetes rates relied on high FPG as a single measure of diabetes and did not account for people who have high HbA1c, leading to likely underestimates of rates especially in south Asia, where using FPG alone misses more cases of diabetes than in other regions.

Global rates of diabetes doubled over the last two decades

From 1990 to 2022, global diabetes rates doubled in both men (6.8% in 1990 to 14.3% in 2022) and women (6.9% to 13.9%). With the additional impact of population growth and aging, this equates to an estimated 828 million adults with diabetes in 2022, an increase of approximately 630 million people from 1990, when roughly 198 million adults were estimated to have the disease.

The changes in diabetes rates from 1990 to 2022 varied drastically across different countries with mostly LMICs experiencing the largest increases (e.g. the diabetes rate among women in Pakistan rose from 9.0% in 1990 to 30.9% in 2022, the largest increase across all countries).

While some higher-income countries, such as Japan, Canada and some countries in western Europe (e.g. France, Spain and Denmark), saw no change or even a small decrease in diabetes rate over the last two decades.

Substantial global variations in diabetes rates in 2022

The countries with the lowest rates of diabetes in 2022 were in western Europe and east Africa for both sexes, and in Japan and Canada for women. For example, diabetes rates in 2022 were as low as 2-4% for women in France, Denmark, Spain, Switzerland, and Sweden, and 3–5% for men in Denmark, France, Uganda, Kenya, Malawi, Spain, and Rwanda.

By contrast, countries with the highest rates, where 25% or more of the population had diabetes for both men and women, were the Pacific island nations and those located in the Caribbean and the Middle East and North Africa, as well as Pakistan and Malaysia. Among high-income industrialized nations, diabetes rates in 2022 were highest in the U.S. (11.4% among women and 13.6% among men).

An important driver of the rise in type 2 diabetes rates, and its variation across countries, is obesity and poor diets. Diabetes rate was either already high or increased more in some of the regions where obesity was or became prevalent between 1990 to 2022, compared to many high-income countries, especially those in the Pacific and western Europe, where, in general, obesity and diabetes rates did not rise or rose by a relatively small amount.

"Given the disabling and potentially fatal consequences of diabetes, preventing diabetes through healthy diet and exercise is essential for better health throughout the world," said Dr. Ranjit Mohan Anjana, Madras Diabetes Research Foundation, India.

"Our findings highlight the need to see more ambitious policies, especially in lower-income regions of the world, that restrict unhealthy foods, make healthy foods affordable and improve opportunities to exercise through measures such as subsidies for healthy foods and free healthy school meals, as well as promoting safe places for walking and exercising, including free entrance to public parks and fitness centers."

Widening global inequalities in diabetes treatment

Three out of five (59%) of adults aged 30 years and older with diabetes, a total of 445 million, were not receiving medication for diabetes in 2022, three and half times the number in 1990 (129 million).

Since 1990, some countries, including many in central and western Europe, Latin America and East Asia and the Pacific, as well as Canada and South Korea have seen vast improvements in treatment rates for diabetes, resulting in more than 55% of people with diabetes in these countries receiving treatment in 2022. The highest treatment rates were estimated in Belgium, at 86% for women and 77% for men.

However, for many LMICs, diabetes treatment coverage has stayed low and changed little over the previous two decades, with over 90% of people with diabetes not receiving treatment in some countries in both 1990 and 2022.

As a result of these trends, the gap between the countries with the highest and lowest treatment coverage for diabetes has widened since 1990 to 2022; from 56 to 78 percentage points in women and from 43 to 71 percentage points in men.

"Our findings suggest there is an increasing share of people with diabetes, especially with untreated diabetes, living in low- and middle-income countries. In 2022, only 5-10% of adults with diabetes in some sub-Saharan African countries received treatment for diabetes, leaving a huge number at risk of serious health complications," said Professor Jean Claude Mbanya, University of Yaoundé 1, Cameroon.

He continues, "Most people with untreated diabetes will not have received a diagnosis, therefore increasing detection of diabetes must be an urgent priority in countries with low levels of treatment.

"Better diagnosis of diabetes requires innovations such as workplace and community screening programs, extended or flexible health care hours to enable people to visit outside of standard working hours, integration with screening and care for diseases like HIV/AIDS and TB which have well-established programs, and the use of trusted community health care providers."

In 2022, almost one third (133 million, 30%) of the 445 million adults aged 30 years or older with untreated diabetes lived in India, more than 50% greater than the next largest number which was in China (78 million) because treatment coverage was higher in China (45% for women and 41% for men) than in India (28% for women and 29% for men).

Similarly, Pakistan (24 million) and Indonesia (18 million), the next two countries with the largest number of untreated diabetes, surpassed the U.S. (13 million), which had higher treatment coverage (65% for women and 67% for men).

The authors acknowledge some limitations to their study, including that most survey data did not separate type 1 and type 2 diabetes in adults. Additionally, some countries where estimates were provided on diabetes rates and treatment had very little, or in some cases, no data and their estimates were informed to a stronger degree by data from other countries.

The study included two measures for diabetes: FPG and HbA1c. In studies that did not measure HbA1c, the prevalence of elevated HbA1c was predicted based on the relationship between HbA1c, FPG and other predictors in studies that had measured both, which increased the uncertainty of the study estimates.

More information: Worldwide trends in diabetes prevalence and treatment from 1990 to 2022: a pooled analysis of 1108 populationrepresentative studies with 141 million participants, The Lancet (2024). DOI: 10.1016/S0140-6736(24)02317-1. www.thelancet.com/journals/lan … (24)02317-1/fulltext

https://medicalxpress.com/news/2024-11-million-adults-diabetes-treatment-global.html

Human vision restored by stem cell replacement

 Researchers led by Osaka University in Japan have conducted the first human trial using induced pluripotent stem-cell-derived corneal epithelium to treat limbal stem cell deficiency, offering a potential new avenue for restoring vision.

Limbal stem cell deficiency (LSCD) is a severe ocular condition where the loss of functioning adult stem cells at the cornea's edge leads to vision impairment due to the invasion of fibrotic conjunctival tissue over the cornea. Limbal stem cells normally perform repair functions by differentiating into corneal epithelium. Without them, the integrity and transparency of the corneal surface becomes compromised, leading to fibrotic tissue buildup, and ultimately, vision loss.

Traditional treatments often involve grafts from the patient's healthy eye or donors, but these methods carry risks like immunological rejection, or require the removal of healthy tissue.

In a study titled "Induced pluripotent stem-cell-derived corneal epithelium for transplant surgery: a single-arm, open-label, first-in-human interventional study in Japan," published in The Lancet, researchers conducted transplants of pluripotent stem cell (iPSC)-derived corneal epithelial sheets (iCEPS) as a potential treatment for LSCD.

Four patients with LSCD participated in the study. After removing any fibrotic tissue, the team transplanted allogeneic iCEPS onto the affected eyes. All surgeries were performed without human leukocyte antigen (HLA) matching. Half the patients received low-dose cyclosporine (typically used to mitigate organ rejection after a transplant), while the other half received no immunosuppressive agents beyond corticosteroids.

Two years of monitoring revealed no severe adverse events. Minor adverse events were managed effectively and without lasting effects.

All four patients experienced significant improvements in vision. Disease stages advanced to less severe classifications in three patients. One patient, with a more severe underlying condition, initially improved to a less severe stage by 32 weeks, but later regressed to baseline after one year. Quality-of-life assessments aligned with visual improvements, with three of the four patients reporting enhanced scores.

Overall, the study demonstrated that iCEPS transplantation not only stabilizes the corneal surface but also restores functional vision, significantly enhancing the daily lives of patients with limbal stem cell deficiency. Beneficial outcomes were more pronounced in patients who received low-dose cyclosporine, suggesting that non-use might have triggered subclinical immunological rejection.

The iCEPS were cultivated using a method that replicates aspects of natural eye development to produce functional corneal cells. This technique not only ensures the structural integrity of the grafts but also reduces immunogenicity, potentially eliminating the need for HLA matching and extensive immunosuppression typically required in traditional grafts.

The successful result is a major therapeutic advancement, building on earlier successes in regenerative medicine while overcoming the limitations of existing LSCD surgical treatments. The Osaka team plans to initiate a larger multicenter clinical trial to further validate the findings and explore the broader applicability of iCEPS transplantation.

More information: Takeshi Soma et al, Induced pluripotent stem-cell-derived corneal epithelium for transplant surgery: a single-arm, open-label, first-in-human interventional study in Japan, The Lancet (2024). DOI: 10.1016/S0140-6736(24)01764-1

https://medicalxpress.com/news/2024-11-human-vision-stem-cell-regenerative.html