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Oral Insulin Delivery: Can the Tortoise Win the Race?

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Turtle shape compared to capsule shape
Caption: The African leopard tortoise’s shape inspired a new insulin-injecting “pill” (right). Credit: Alex Abramson

People with diabetes often must inject insulin multiple times a day to keep their blood glucose levels under control. So, I was intrigued to learn that NIH-funded bioengineers have designed a new kind of “pill” that may someday reduce the need for those uncomfortable shots. The inspiration for their design? A tortoise!

The new “pill”—actually, a swallowable device containing a tiny injection system—is shaped like the shell of an African leopard tortoise. In much the same way that the animal’s highly curved shell enables it to quickly right itself when flipped on its back, the shape of the new device is intended to help it land in the right position to inject insulin or other medicines into the stomach wall.

The hunt for a means to deliver insulin in pill form has been on ever since insulin injections first were introduced, nearly a century ago. The challenge in oral delivery of insulin and other “biologic” drugs—including therapeutic proteins, peptides, or nucleic acids—is how to get these large biomolecules through the highly acidic stomach and duodenum, where multiple powerful digestive enzymes reside, and into the bloodstream unscathed. Past efforts to address this challenge have met with only limited success.

In a study published in the journal Science, a team, led by Robert Langer at Massachusetts Institute of Technology, Cambridge, and Giovanni Traverso, Brigham and Women’s Hospital, Harvard Medical School, Boston, took a new approach to the problem by developing a tiny, ingestible injection system [1]. They call their pea-sized device SOMA, short for “self-orienting millimeter-scale applicator.”

In designing SOMA, the researchers knew they had to come up with a design that would orient the injection apparatus correctly. So they looked to the African leopard tortoise. They knew that, much like a child’s “weeble-wobble” toy, this tortoise can easily right its body if tipped over due to its low center of gravity and highly curved shell. With the shape of the tortoise shell as a starting point, the researchers used computer modeling to perfect their design. The final result features a partially hollowed-out, polymer-and-steel capsule that houses a tiny, spring-loaded needle tipped with compressed, freeze-dried insulin. There is also a dissolvable sugar disk to hold the needle in place until the time is right.

Here’s how it works: once a SOMA is swallowed and reaches the stomach, it quickly orients itself in a way that its needle-side rests against the stomach wall. After the protective sugar disk dissolves in stomach acid, the spring-loaded needle tipped with insulin is released, injecting its load of insulin into the stomach wall, from which it enters the bloodstream. Meanwhile, the spent SOMA device passes on through the digestive system.

The researchers’ tests in pigs have shown that a single SOMA can successfully deliver insulin doses of up to 3 milligrams, comparable to the amount a human with diabetes might need to inject. The tests also showed that the device’s microinjection did not damage the animals’ stomach tissue or the muscles surrounding the stomach. Because the stomach is known for being insensitive to pain, researchers expect that people receiving insulin via SOMA wouldn’t feel a thing, but much more research is needed to confirm both the safety and efficacy of the new device for human use.

Meanwhile, this fascinating work serves as a reminder that when it comes to biomedical science, inspiration sometimes can come from the most unexpected places.

Reference:

[1] An ingestible self-orienting system for oral delivery of macromolecules. Abramson A, Caffarel-Salvador E, Khang M, Dellal D, Silverstein D, Gao Y, Frederiksen MR, Vegge A, Hubálek F, Water JJ, Friderichsen AV, Fels J, Kirk RK, Cleveland C, Collins J, Tamang S, Hayward A, Landh T, Buckley ST, Roxhed N, Rahbek U, Langer R, Traverso G. Science. 2019 Feb 8;363(6427):611-615.

Links:

Diabetes (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)

Langer Lab (MIT, Cambridge)

Giovanni Traverso (Brigham and Women’s Hospital, Harvard Medical School, Boston)

NIH Support: National Institute of Biomedical Imaging and Bioengineering


Discovering a Source of Laughter in the Brain

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cingulum bundle
Illustration showing how an electrode was inserted into the cingulum bundle. Courtesy of American Society for Clinical Investigation

If laughter really is the best medicine, wouldn’t it be great if we could learn more about what goes on in the brain when we laugh? Neuroscientists recently made some major progress on this front by pinpointing a part of the brain that, when stimulated, never fails to induce smiles and laughter.

In their study conducted in three patients undergoing electrical stimulation brain mapping as part of epilepsy treatment, the NIH-funded team found that stimulation of a specific tract of neural fibers, called the cingulum bundle, triggered laughter, smiles, and a sense of calm. Not only do the findings shed new light on the biology of laughter, researchers hope they may also lead to new strategies for treating a range of conditions, including anxiety, depression, and chronic pain.

In people with epilepsy whose seizures are poorly controlled with medication, surgery to remove seizure-inducing brain tissue sometimes helps. People awaiting such surgeries must first undergo a procedure known as intracranial electroencephalography (iEEG). This involves temporarily placing 10 to 20 arrays of tiny electrodes in the brain for up to several weeks, in order to pinpoint the source of a patient’s seizures in the brain. With the patient’s permission, those electrodes can also enable physician-researchers to stimulate various regions of the patient’s brain to map their functions and make potentially new and unexpected discoveries.

In the new study, published in The Journal of Clinical Investigation, Jon T. Willie, Kelly Bijanki, and their colleagues at Emory University School of Medicine, Atlanta, looked at a 23-year-old undergoing iEEG for 8 weeks in preparation for surgery to treat her uncontrolled epilepsy [1]. One of the electrodes implanted in her brain was located within the cingulum bundle and, when that area was stimulated for research purposes, the woman experienced an uncontrollable urge to laugh. Not only was the woman given to smiles and giggles, she also reported feeling relaxed and calm.

As a further and more objective test of her mood, the researchers asked the woman to interpret the expression of faces on a computer screen as happy, sad, or neutral. Electrical stimulation to the cingulum bundle led her to see those faces as happier, a sign of a generally more positive mood. A full evaluation of her mental state also showed she was fully aware and alert.

To confirm the findings, the researchers looked to two other patients, a 40-year-old man and a 28-year-old woman, both undergoing iEEG in the course of epilepsy treatment. In those two volunteers, stimulation of the cingulum bundle also triggered laughter and reduced anxiety with otherwise normal cognition.

Willie notes that the cingulum bundle links many brain areas together. He likens it to a super highway with lots of on and off ramps. He suspects the spot they’ve uncovered lies at a key intersection, providing access to various brain networks regulating mood, emotion, and social interaction.

Previous research has shown that stimulation of other parts of the brain can also prompt patients to laugh. However, what makes stimulation of the cingulum bundle a particularly promising approach is that it not only triggers laughter, but also reduces anxiety.

The new findings suggest that stimulation of the cingulum bundle may be useful for calming patients’ anxieties during neurosurgeries in which they must remain awake. In fact, Willie’s team did so during their 23-year-old woman’s subsequent epilepsy surgery. Each time she became distressed, the stimulation provided immediate relief. Also, if traditional deep brain stimulation or less invasive means of brain stimulation can be developed and found to be safe for long-term use, they may offer new ways to treat depression, anxiety disorders, and/or chronic pain.

Meanwhile, Willie’s team is hard at work using similar approaches to map brain areas involved in other aspects of mood, including fear, sadness, and anxiety. Together with the multidisciplinary work being mounted by the NIH-led BRAIN Initiative, these kinds of studies promise to reveal functionalities of the human brain that have previously been out of reach, with profound consequences for neuroscience and human medicine.

Reference:

[1] Cingulum stimulation enhances positive affect and anxiolysis to facilitate awake craniotomy. Bijanki KR, Manns JR, Inman CS, Choi KS, Harati S, Pedersen NP, Drane DL, Waters AC, Fasano RE, Mayberg HS, Willie JT. J Clin Invest. 2018 Dec 27.

Links:

Video: Patient’s Response (Bijanki et al. The Journal of Clinical Investigation)

Epilepsy Information Page (National Institute of Neurological Disease and Stroke/NIH)

Jon T. Willie (Emory University, Atlanta, GA)

NIH Support: National Institute of Neurological Disease and Stroke; National Center for Advancing Translational Sciences


Sleep Loss Encourages Spread of Toxic Alzheimer’s Protein

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Man sleeping
Credit: iStock/bowdenimages

In addition to memory loss and confusion, many people with Alzheimer’s disease have trouble sleeping. Now an NIH-funded team of researchers has evidence that the reverse is also true: a chronic lack of sleep may worsen the disease and its associated memory loss.

The new findings center on a protein called tau, which accumulates in abnormal tangles in the brains of people with Alzheimer’s disease. In the healthy brain, active neurons naturally release some tau during waking hours, but it normally gets cleared away during sleep. Essentially, your brain has a system for taking the garbage out while you’re off in dreamland.

The latest findings in studies of mice and people further suggest that sleep deprivation upsets this balance, allowing more tau to be released, accumulate, and spread in toxic tangles within brain areas important for memory. While more study is needed, the findings suggest that regular and substantial sleep may play an unexpectedly important role in helping to delay or slow down Alzheimer’s disease.

It’s long been recognized that Alzheimer’s disease is associated with the gradual accumulation of beta-amyloid peptides and tau proteins, which form plaques and tangles that are considered hallmarks of the disease. It has only more recently become clear that, while beta-amyloid is an early sign of the disease, tau deposits track more closely with disease progression and a person’s cognitive decline.

Such findings have raised hopes among researchers including David Holtzman, Washington University School of Medicine, St. Louis, that tau-targeting treatments might slow this devastating disease. Though much of the hope has focused on developing the right drugs, some has also focused on sleep and its nightly ability to reset the brain’s metabolic harmony.

In the new study published in Science, Holtzman’s team set out to explore whether tau levels in the brain naturally are tied to the sleep-wake cycle [1]. Earlier studies had shown that tau is released in small amounts by active neurons. But when neurons are chronically activated, more tau gets released. So, do tau levels rise when we’re awake and fall during slumber?

The Holtzman team found that they do. The researchers measured tau levels in brain fluid collected from mice during their normal waking and sleeping hours. (Since mice are nocturnal, they sleep primarily during the day.) The researchers found that tau levels in brain fluid nearly double when the animals are awake. They also found that sleep deprivation caused tau levels in brain fluid to double yet again.

These findings were especially interesting because Holtzman’s team had already made a related finding in people. The team found that healthy adults forced to pull an all-nighter had a 30 percent increase on average in levels of unhealthy beta-amyloid in their cerebrospinal fluid (CSF).

The researchers went back and reanalyzed those same human samples for tau. Sure enough, the tau levels were elevated on average by about 50 percent.

Once tau begins to accumulate in brain tissue, the protein can spread from one brain area to the next along neural connections. So, Holtzman’s team wondered whether a lack of sleep over longer periods also might encourage tau to spread.

To find out, mice engineered to produce human tau fibrils in their brains were made to stay up longer than usual and get less quality sleep over several weeks. Those studies showed that, while less sleep didn’t change the original deposition of tau in the brain, it did lead to a significant increase in tau’s spread. Intriguingly, tau tangles in the animals appeared in the same brain areas affected in people with Alzheimer’s disease.

Another report by Holtzman’s team appearing early last month in Science Translational Medicine found yet another link between tau and poor sleep. That study showed that older people who had more tau tangles in their brains by PET scanning had less slow-wave, deep sleep [2].

Together, these new findings suggest that Alzheimer’s disease and sleep loss are even more intimately intertwined than had been realized. The findings suggest that good sleep habits and/or treatments designed to encourage plenty of high quality Zzzz’s might play an important role in slowing Alzheimer’s disease. On the other hand, poor sleep also might worsen the condition and serve as an early warning sign of Alzheimer’s.

For now, the findings come as an important reminder that all of us should do our best to get a good night’s rest on a regular basis. Sleep deprivation really isn’t a good way to deal with overly busy lives (I’m talking to myself here). It isn’t yet clear if better sleep habits will prevent or delay Alzheimer’s disease, but it surely can’t hurt.

References:

[1] The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Holth JK, Fritschi SK, Wang C, Pedersen NP, Cirrito JR, Mahan TE, Finn MB, Manis M, Geerling JC, Fuller PM, Lucey BP, Holtzman DM. Science. 2019 Jan 24.

[2] Reduced non-rapid eye movement sleep is associated with tau pathology in early Alzheimer’s disease. Lucey BP, McCullough A, Landsness EC, Toedebusch CD, McLeland JS, Zaza AM, Fagan AM, McCue L, Xiong C, Morris JC, Benzinger TLS, Holtzman DM. Sci Transl Med. 2019 Jan 9;11(474).

Links:

Alzheimer’s Disease and Related Dementias (National Institute on Aging/NIH)

Accelerating Medicines Partnership: Alzheimer’s Disease (NIH)

Holtzman Lab (Washington University School of Medicine, St. Louis)

NIH Support: National Institute on Aging; National Institute of Neurological Disorders and Stroke; National Center for Advancing Translational Sciences; National Cancer Institute; National Institute of Biomedical Imaging and Bioengineering


Moving Closer to a Stem Cell-Based Treatment for AMD

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In recent years, researchers have figured out how to take a person’s skin or blood cells and turn them into induced pluripotent stem cells (iPSCs) that offer tremendous potential for regenerative medicine. Still, it’s been a challenge to devise safe and effective ways to move this discovery from the lab into the clinic. That’s why I’m pleased to highlight progress toward using iPSC technology to treat a major cause of vision loss: age-related macular degeneration (AMD).

In the new work, researchers from NIH’s National Eye Institute developed iPSCs from blood-forming stem cells isolated from blood donated by people with advanced AMD [1]. Next, these iPSCs were exposed to a variety of growth factors and placed on supportive scaffold that encouraged them to develop into healthy retinal pigment epithelium (RPE) tissue, which nurtures the light-sensing cells in the eye’s retina. The researchers went on to show that their lab-grown RPE patch could be transplanted safely into animal models of AMD, preventing blindness in the animals.

This preclinical work will now serve as the foundation for a safety trial of iPSC-derived RPE transplants in 12 human volunteers who have already suffered vision loss due to the more common “dry” form of AMD, for which there is currently no approved treatment. If all goes well, the NIH-led trial may begin enrolling patients as soon as this year.

Risk factors for AMD include a combination of genetic and environmental factors, including age and smoking. Currently, more than 2 million Americans have vision-threatening AMD, with millions more having early signs of the disease [2].

AMD involves progressive damage to the macula, an area of the retina about the size of a pinhead, made up of millions of light-sensing cells that generate our sharp, central vision. Though the exact causes of AMD are unknown, RPE cells early on become inflamed and lose their ability to clear away debris from the retina. This leads to more inflammation and progressive cell death.

As RPE cells are lost during the “dry” phase of the disease, light-sensing cells in the macula also start to die and reduce central vision. In some people, abnormal, leaky blood vessels will form near the macula, called “wet” AMD, spilling fluid and blood under the retina and causing significant vision loss. “Wet” AMD has approved treatments. “Dry” AMD does not.

But, advances in iPSC technology have brought hope that it might one day be possible to shore up degenerating RPE in those with dry AMD, halting the death of light-sensing cells and vision loss. In fact, preliminary studies conducted in Japan explored ways to deliver replacement RPE to the retina [3]. Though progress was made, those studies highlighted the need for more reliable ways to produce replacement RPE from a patient’s own cells. The Japanese program also raised concerns that iPSCs derived from people with AMD might be prone to cancer-causing genomic changes.

With these challenges in mind, the NEI team led by Kapil Bharti and Ruchi Sharma have designed a more robust process to produce RPE tissue suitable for testing in people. As described in Science Translational Medicine, they’ve come up with a three-step process.

Rather than using fibroblast cells from skin as others had done, Bharti and Sharma’s team started with blood-forming stem cells from three AMD patients. They reprogrammed those cells into “banks” of iPSCs containing multiple different clones, carefully screening them to ensure that they were free of potentially cancer-causing changes.

Next, those iPSCs were exposed to a special blend of growth factors to transform them into RPE tissue. That recipe has been pursued by other groups for a while, but needed to be particularly precise for this human application. In order for the tissue to function properly in the retina, the cells must assemble into a uniform sheet, just one-cell thick, and align facing in the same direction.

So, the researchers developed a specially designed scaffold made of biodegradable polymer nanofibers. That scaffold helps to ensure that the cells orient themselves correctly, while also lending strength for surgical transplantation. By spreading a single layer of iPSC-derived RPE progenitors onto their scaffolds and treating it with just the right growth factors, the researchers showed they could produce an RPE patch ready for the clinic in about 10 weeks.

To test the viability of the RPE patch, the researchers first transplanted a tiny version (containing about 2,500 RPE cells) into the eyes of a rat with a compromised immune system, which enables human cells to survive. By 10 weeks after surgery, the human replacement tissue had integrated into the animals’ retinas with no signs of toxicity.

Next, the researchers tested a larger RPE patch (containing 70,000 cells) in pigs with an AMD-like condition. This patch is the same size the researchers ultimately would expect to use in people. Ten weeks after surgery, the RPE patch had integrated into the animals’ eyes, where it protected the light-sensing cells that are so critical for vision, preventing blindness.

These results provide encouraging evidence that the iPSC approach to treating dry AMD should be both safe and effective. But only a well-designed human clinical trial, with all the appropriate prior oversights to be sure the benefits justify the risks, will prove whether or not this bold approach might be the solution to blindness faced by millions of people in the future.

As the U.S. population ages, the number of people with advanced AMD is expected to rise. With continued progress in treatment and prevention, including iPSC technology and many other promising approaches, the hope is that more people with AMD will retain healthy vision for a lifetime.

References:

[1] Clinical-grade stem cell-derived retinal pigment epithelium patch rescues retinal degeneration in rodents and pigs. Sharma R, Khristov V, Rising A, Jha BS, Dejene R, Hotaling N, Li Y, Stoddard J, Stankewicz C, Wan Q, Zhang C, Campos MM, Miyagishima KJ, McGaughey D, Villasmil R, Mattapallil M, Stanzel B, Qian H, Wong W, Chase L, Charles S, McGill T, Miller S, Maminishkis A, Amaral J, Bharti K. Sci Transl Med. 2019 Jan 16;11(475).

[2] Age-Related Macular Degeneration, National Eye Institute.

[3] Autologous Induced Stem-Cell-Derived Retinal Cells for Macular Degeneration. Mandai M, Watanabe A, Kurimoto Y, Hirami Y, Takasu N, Ogawa S, Yamanaka S, Takahashi M, et al. N Engl J Med. 2017 Mar 16;376(11):1038-1046.

Links:

Facts About Age-Related Macular Degeneration (National Eye Institute/NIH)

Stem Cell-Based Treatment Used to Prevent Blindness in Animal Models of Retinal Degeneration (National Eye Institute/NIH)

Kapil Bharti (NEI)

NIH Support: National Eye Institute; Common Fund


For HIV, Treatment is Prevention

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U=U

For almost four decades, researchers have worked tirelessly to find a cure for the human immunodeficiency virus (HIV), which causes AIDS. There’s still more work to do, but a recent commentary published in JAMA [1] by Anthony Fauci, director of NIH’s National Institute of Allergy and Infectious Diseases, and his colleagues serves as a reminder of just how far we’ve come. Today, thanks to scientific advances, especially the development of effective antiretroviral therapy (ART), most people living with HIV can live full and productive lives. These developments have started to change how our society views HIV infection.

In their commentary, the NIH scientists describe the painstaking research that has now firmly established that people who take ART daily as prescribed, and who achieve and maintain an undetectable viral load (the amount of HIV in the blood), cannot sexually transmit the virus to others. To put it simply: Undetectable = Untransmittable (U=U).

The U=U message was introduced in 2016 by the Prevention Access Campaign, an international health equity initiative that aims to help end the HIV epidemic and HIV-related social stigma. The major breakthrough in combination ART regimens, which successfully reduced viral loads for many HIV patients, came over 20 years ago. But their importance for HIV prevention wasn’t immediately apparent.

There’d been some hints of U=U, but it was the results of the NIH-funded HIV Prevention Trials Network (HPTN) 052, published in The New England Journal of Medicine [2] in 2011, that offered the first rigorous clinical evidence. Among heterosexual couples in the randomized clinical trial, no HIV transmissions to an uninfected partner were observed when ART consistently, durably suppressed the virus in the partner living with HIV.

The data provided convincing evidence that ART not only treats HIV but also prevents the sexual transmission of HIV infection. The public health implications of what’s sometimes referred to as “treatment as prevention” were obvious and exciting. In fact, the discovery made Science’s 2011 list of top 10 Breakthroughs of the Year .

Three subsequent studies, known as PARTNER 1 and 2 and Opposites Attract, confirmed and extended the findings of the HPTN 052 study. All three showed that people with HIV taking ART, who had undetectable HIV levels in their blood, had essentially no risk of passing the virus on to their HIV-negative partners.

Of course, the success of U=U depends on people with HIV having the needed access to health care and taking their medications as prescribed every day of their lives [3]. ART works by preventing the virus from making more copies of itself. It’s important to note that achieving an undetectable viral load with treatment can take time—up to 6 months. Viral load testing should be performed on a regular basis to ensure that the virus remains at undetectable levels. If treatment is stopped, the virus typically rebounds within a matter of weeks. So, strict adherence to ART over the long term is absolutely essential.

Practically speaking, though, ART alone won’t be enough to end the spread of HIV, and other methods of HIV prevention are still needed. In fact, we’re now at a critical juncture in HIV research as work continues on preventive vaccines that could one day bring about a durable end to the pandemic.

But for now, there are more than 35 million people worldwide who are HIV positive [4]. With currently available interventions, experts have predicted that about 50 million people around the world will become HIV positive from 2015 to 2035 [5]. Work is proceeding actively on the vaccine, and also on ways to totally eradicate the virus from infected individuals (a “cure”), but that is proving to be extremely challenging.

Meanwhile, with continued advances, including improved accessibility to testing, adherence to existing medications, and use of pre-exposure prophylaxis (PrEP) in high risk individuals, the goal is to reduce greatly the number of new cases of HIV/AIDS.

References:

[1] HIV Viral Load and Transmissibility of HIV Infection: Undetectable Equals Untransmittable. Eisinger RW, Dieffenbach CW, Fauci AS. JAMA. 2019 Jan 10.

[2] Prevention of HIV-1 infection with early antiretroviral therapy. Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N, Hakim JG, Kumwenda J, Grinsztejn B, Pilotto JH, Godbole SV, Mehendale S, Chariyalertsak S, Santos BR, Mayer KH, Hoffman IF, Eshleman SH, Piwowar-Manning E, Wang L, Makhema J, Mills LA, de Bruyn G, Sanne I, Eron J, Gallant J, Havlir D, Swindells S, Ribaudo H, Elharrar V, Burns D, Taha TE, Nielsen-Saines K, Celentano D, Essex M, Fleming TR; HPTN 052 Study Team. N Engl J Med. 2011 Aug 11;365(6):493-505.

[3] HIV Treatment (U.S. Department of Health and Human Services)

[4] HIV/AIDS (World Health Organization)

[5] Effectiveness of UNAIDS targets and HIV vaccination across 127 countries. Medlock J, Pandey A, Parpia AS, Tang A, Skrip LA, Galvani AP. Proc Natl Acad Sci U S A. 2017 Apr 11;114(15):4017-4022.

Links:

HIV/AIDS (National Institute of Allergy and Infectious Diseases/NIH)

Treatment as HIV Prevention (NIAID)

Prevention Access Campaign

Anthony S. Fauci (NIAID)

HIV Prevention Trials Network (Durham, NC)


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