Engineering the Microbiome to Cure Disease

Calendar August 8, 2022 | Posted by admin

Residing within the human gut are trillions of bacteria and other microorganisms that can impact a variety of chronic human ailments, including obesity, type 2 diabetes, atherosclerosis, cancer, non-alcoholic fatty liver disease and inflammatory bowel disease. Numerous diseases are associated with imbalance or dysfunction in gut microbiome. Even in diseases that don’t involve the microbiome, gut microflora provide an important point of access that allows modification of many physiological systems.

Modifying to remedy, perhaps even cure these conditions, has generated substantial interest, leading to the development of live bacterial therapeutics (LBTs). One idea behind LBTs is to engineer bacterial hosts, or chassis, to produce therapeutics able to repair or restore healthy microbial function and diversity.

Existing efforts have primarily focused on using probiotic bacterial strains from the Bacteroides or Lactobacillus families or Escherichia coli that have been used for decades in the lab. However, these efforts have largely fallen short because engineered bacteria introduced into the gut generally do not survive what is fundamentally a hostile environment.

The inability to engraft or even survive in the gut requires frequent re-administration of these bacterial strains and often produces inconsistent effects or no effect at all. The phenomenon is perhaps most apparent in individuals who take probiotics, where these beneficial bacteria are unable to compete with the individual’s native microorganisms and largely disappear quickly.

“The lack of engraftment severely limits the use of LBTs for chronic conditions for curative effect or to study specific functions in the gut microbiome,” said Amir Zarrinpar, MD, PhD, assistant professor of medicine at UC San Diego School of Medicine and a gastroenterologist at UC San Diego Health. “Published human trials using engineered LBTs have demonstrated safety, but still need to demonstrate reversal of disease. We believe this may be due to problems with colonization.”

In a proof-of-concept study, published in the August 4, 2022, online issue of Cell , Zarrinpar and colleagues at University of California San Diego School of Medicine report overcoming that hurdle by employing native bacteria in mice as the chassis for delivering transgenes capable of inducing persistent and potentially even curative therapeutic changes in the gut and reversing disease pathologies. Using this method, the group found they can provide long-term therapy in a mouse model of type 2 diabetes.

Source: https://health.ucsd.edu/

Category Categories: Uncategorized  |  Tag Tags: , , , , , , , , , , , , , , , ,

How to Protect Neurons and Encourage Their Growth

Calendar December 17, 2020 | Posted by admin

Many neurodegenerative conditions, from glaucoma to Alzheimer’s disease, are characterized by injury to axons — the long, slender projections that conduct electrical impulses from one nerve cell to another, facilitating cellular communications. Injury to axons often leads to neuronal impairment and cell death.

Researchers know that inhibiting an enzyme called dual leucine zipper kinase (DLK) appears to robustly protect neurons in a wide range of neurodegenerative diseases models, but DLK also inhibits axonal regeneration. Until now, there have been no effective methods to modify genes to improve both the long-term survival of neurons and promote regeneration.

In a paper published December 14, 2020 in PNAS, a multi-university team led by researchers at University of California San Diego School of Medicine and Shiley Eye Institute at UC San Diego Health identified another family of enzymes called germinal cell kinase four kinases (GCK-IV kinases) whose inhibition is robustly neuroprotective, while also permitting axon regeneration, making it an attractive therapeutic approach for treating at some neurodegenerative diseases.

Example of retinal ganglion cells with axons and dendrites in the retina of a healthy eye.

“We basically figured out that there are a set of genes that, when inhibited, allow optic nerve cells to survive and regenerate,” said senior author Derek Welsbie, MD, PhD, associate professor of ophthalmology in the Viterbi Family Department of Ophthalmology at Shiley Eye Institute.

“Prior to this work, the field knew how to get these cells to survive, but not regenerate. Conversely, there are ways to promote regeneration, but then the survival was rather modest. Of course, for a successful strategy of vision restoration, you need both and this is a step in that direction.”

Source: https://ucsdnews.ucsd.edu/

Category Categories: Uncategorized  |  Tag Tags: , , , , , , , , , , , ,

How To Implant Neural Stem Cell Grafts To Cure Spinal Cord Injuries

Calendar August 11, 2020 | Posted by admin

Researchers at the University of California San Diego School of Medicine have successfully implanted grafts of neural stem cells straight into spinal cord injuries in mice and documented their functionality in mimicking the animals’ existing neuronal network after growing and filling the place of injury, a new study reports.

This stem cell breakthrough might be what patients who are living with spinal cord injury are waiting for. According to the press release, nearly 18,000 people in the U.S. suffer from spinal cord injury and 294,000 people live with it. Whether it is a permanent paralysis or diminished physical function, researchers were trying their hand at restoring these lost functions using stem cells lately. In order to solve this, the researchers used recent technology and were able to stimulate and record the activity of neuron populations with light rather than electricity, enabling them to see the connections.

They saw that graft neurons acted like the neural networks of the normal spinal cord even when there was an absence of direct stimulation. To further the research, the team stimulated regenerating exons from the mice’s brain and found that “some of the same spontaneously active clusters of graft neurons responded robustly.” This meant that these networks receive functional synaptic connections from inputs that typically cause movement, also being activated by light touch and pinches.

 “We knew that damaged host axons grew extensively into (injury sites), and that graft neurons, in turn, extended large numbers of axons into the spinal cord, but we had no idea what kind of activity was actually occurring inside the graft itself,” stated the study’s first author Steven Ceto.

What they didn’t know, however, was whether if host and graft axons were making functional connections.  “We showed that we could turn on spinal cord neurons below the injury site by stimulating graft axons extending into these areas. Putting all these results together, it turns out that neural stem cell grafts have a remarkable ability to self-assemble into spinal cord-like neural networks that functionally integrate with the host nervous system. After years of speculation and inference, we showed directly that each of the building blocks of a neuronal relay across spinal cord injury are in fact functional,” explained Ceto,

The team is now working to further enhance the functional connectivity of stem cell grafts and trying to move their stem cell graft approach into clinical trials. According to the researchers, a therapy might be achieved within a decade.

The study was published in Cell Stem Cell.

Source: https://www.cell.com/
AND
https://interestingengineering.com/

Category Categories: Uncategorized  |  Tag Tags: , , , , , , ,

CRISPR-Cas9 gene editing could ‘turn off’ HIV virus

Calendar October 1, 2019 | Posted by admin

HIV treatment has come a long way over the years, due in large part to antiretroviral drugs that stop the HIV virus from replicating in the body. This gives the immune system a chance to repair itself and stop further damage. Thanks to these amazing advances, HIV is no longer the death sentence that it was in previous decades. However, antiretrovirals only keep HIV at bay for as long as they’re taken. Defaulting on the drugs means that the HIV virus comes back. Even worse, it can cause patients to build up resistance to the antiretrovirals so that they do not work so effectively in the future. In other words, there’s still room for improvement when it comes to treatment. Fortunately, researchers from the University of California — San Diego School of Medicine are poised to provide help, courtesy of a new genetic-sequencing approach that could possibly provide a “kill switch” to clear out dormant HIV reservoirs inside cells.

“The most exciting part of this discovery has not been seen before,” Tariq Rana, professor of pediatrics and genetics at UC San Diego School of Medicine, said in a statement. “By genetically modifying a long non-coding RNA, we prevent HIV recurrence in T cells and microglia upon cessation of antiretroviral treatment, suggesting that we have a potential therapeutic target to eradicate HIV and AIDS.”

The work is based on the discovery of a recently emerged gene that appears to regulate HIV replication in immune cells, including macrophages, microglia, and T cells. The team refers to this as HIV-1 Enchanced LncRNA (HEAL), and it is elevated in people with HIV. By using CRISPR-Cas9 gene editing, their work suggests that it could stop HIV from recurring in the event that antiretroviral treatment is stopped.

“This has the potential for [being a] cure but, [we’ll] have to wait for animal studies,” Rana told Digital Trends. As for the next steps, Rana said that future studies “will determine if turning this regulator HEAL off can remove viral reservoirs, which are the key source for viral rebound when therapies are discontinued.” A paper describing the work was recently published in the journal mBio.

Source: https://mbio.asm.org/
AND
https://www.digitaltrends.com/

Category Categories: Uncategorized  |  Tag Tags: , , , , , , , , , , , , ,

Eye Test Reveals How Likely Is A Person To Develop Alzheimer’s

Calendar September 19, 2019 | Posted by admin

Alzheimer’s disease (AD) begins to alter and damage the brain years — even decades — before symptoms appear, making early identification of AD risk paramount to slowing its progression.

In a new study published online in the September 9, 2019 issue of the Neurobiology of Aging , scientists at University of California San Diego School of Medicine say that, with further developments, measuring how quickly a person’s pupil dilates while they are taking cognitive tests may be a low-cost, low-invasive method to aid in screening individuals at increased genetic risk for AD before cognitive decline begins.

In recent years, researchers investigating the pathology of AD have primarily directed their attention at two causative or contributory factors: the accumulation of protein plaques in the brain called amyloid-beta and tangles of a protein called tau. Both have been linked to damaging and killing neurons, resulting in progressive cognitive dysfunction.

The new study focuses on pupillary responses which are driven by the locus coeruleus (LC), a cluster of neurons in the brainstem involved in regulating arousal and also modulating cognitive function. Tau is the earliest occurring known biomarker for AD; it first appears in the LC; and it is more strongly associated with cognition than amyloid-beta. The study was led by first author William S. Kremen, PhD, and senior author Carol E. Franz, PhD, both professors of psychiatry and co-directors of the Center for Behavior Genetics of Aging at UC San Diego School of Medicine.

The LC drives pupillary response — the changing diameter of the eyes’ pupils — during cognitive tasks. (Pupils get bigger the more difficult the brain task.) In previously published work, the researchers had reported that adults with mild cognitive impairment, often a precursor to AD, displayed greater pupil dilation and cognitive effort than cognitively normal individuals, even if both groups produced equivalent results. Critically, in the latest paper, the scientists link pupillary dilation responses with identified AD risk genes.

face of an elderly man

How quickly a person’s pupils dilate while doing mental tasks may be an indicator of increased genetic risk for Alzheimer’s disease.

“Given the evidence linking pupillary responses, LC and tau and the association between pupillary response and AD polygenic risk scores (an aggregate accounting of factors to determine an individual’s inherited AD risk), these results are proof-of-concept that measuring pupillary response during cognitive tasks could be another screening tool to detect Alzheimer’s before symptom appear,” said Kremen.

Source: https://health.ucsd.edu/

Category Categories: Uncategorized  |  Tag Tags: , , , , , , , , , , , , , , ,