Category Archives: Human Genetics

Solvin Zankl / NPL / Minden Pictures

Experiments with fruit flies have enabled researchers to assess the biological impacts of dozens of rare genetic mutations found in autistic people, a new study finds.

We are using fruit flies as living test tubes to study which genetic variants identified in autism spectrum disorder patients have functional consequences, says co-lead investigator Shinya Yamamoto, assistant professor of molecular and human genetics at Baylor College of Medicine and an investigator at the Jan and Dan Duncan Neurological Research Institute at Texas Childrens Hospital in Houston, Texas.

The work focused on one kind of genetic alteration that occurs more often in autistic people than in non-autistic people and is especially challenging for scientists to understand: missense mutations, in which a swap of a single DNA letter alters one amino acid in a protein.

Whereas some autism-linked genetic anomalies will clearly greatly modify the workings of genes and their resulting proteins, missense mutations are more like misspellings that are less clear whether they matter or not, says co-lead investigator Michael Wangler, assistant professor of molecular and human genetics at Baylor and an investigator at Texas Childrens. These missense changes could be noise, or they could be important for autism spectrum disorder.

Understanding the roles played by genetic variants of unknown significance is one of the biggest problems in medical genomics and a daily challenge for our clinical colleagues, says Annette Schenck, chair and professor of translational genomics of neurodevelopmental disorders at Radboud University Medical Center in Nijmegen, the Netherlands, who did not participate in this work. The new study is spot-on, addressing this problem in an impressive scale, she says.

The scientists engineered 79 autism-linked variants most of which are missense variants into the equivalent genes in fruit flies, or Drosophila. The variants came from the Simons Simplex Collection, a repository of genetic data from families with one autistic child. (The dataset is funded by the Simons Foundation, Spectrums parent organization.)

The researchers discovered that 30 of these changes had significant consequences for the flies, such as a reduction in courtship behaviors; greater or lesser amounts of grooming; smaller eyes; and smaller, crumpled, serrated, blistered or absent wings.

The fly is an excellent tool for understanding genes, Wangler says. We can use tissues like the wing or eye to find how the genetic mechanisms work, and then see how those mechanisms might be at work in autism spectrum disorder.

By using the online matchmaking software GeneMatcher and examining human genetics databases and clinical genome-sequencing data, the researchers found an additional 13 unrelated people with and without autism traits who carry rare variants in one of the genes linked to disruptive effects in fruit flies: GLRA2, which helps control the chemical messenger glycine in the brain. These people show a spectrum of neurodevelopmental conditions, such as autism, epilepsy, developmental delay, intellectual disability, microcephaly (a small head) and nystagmus (involuntarily moving eyes).

A mutation seen in one of the people likely stopped GLRA2 from functioning in fruit flies and may have reduced communication between neurons, the researchers found. Another persons mutation triggered the formation of dark nodules in the bodies of the insects, possibly the result of an immune reaction, and may have increased communication between neurons.

Of the 30 mutations that had disruptive effects on fruit flies, computer models previously predicted that 4 would not prove damaging and that 9 would have only moderate effects, which shows the importance of performing experiments at the bench to study the functional consequence of missense variants, Yamamoto says. We hope that some of our data can be used by researchers who are developing these bioinformatic tools so their performance can be improved.

The scientists detailed their findings March 15 in the journal Cell Reports.

One interesting finding was the unpredictability of some of their results, says Lawrence Reiter, professor of neurology at the University of Tennessee Health Science Center in Memphis, who did not take part in this research. For example, some variants led to a loss of function of their genes in the eye but a gain of function of those genes in the wing, he notes. In other words, not all genetic variants are necessarily acting the same in all tissue types.

The scientists cautioned that although these 30 mutations did have strong consequences in fruit flies, we are not trying to claim that all 30 of these variants cause autism spectrum disorder, Yamamoto says. Previous research estimated that 13 percent of the spontaneous, or de novo, missense variants identified in autistic people in the Simons Simplex Collection contribute to an autism diagnosis. We show that GLRA2 is one such promising gene, based on matchmaking and additional functional studies, but additional work is required to validate the other candidate genes and variants from our study.

The strategy could help researchers investigate other human mutations of unknown significance, Reiter says. They have barely scratched the surface of what is possible even for the Simons Simplex Collection, he adds, targeting only about 11 percent of the fly counterparts to de novo mutations in that database. This process, while still being streamlined, could be used for any large collection of human variants suspected of causing genetic disease.

Cite this article: https://doi.org/10.53053/EDJW6706

See original here:
Fruit flies help reveal effects of autism-linked mutations | Spectrum - Spectrum

New technologies are filling in gaps in the human genome and opening major areas for discovery. UAB researchers explain the pros and cons and how they are using long reads at UAB.

Zechen Chong, Ph.D. (left), has developed a tool called Inspector that improves whole-genome assembly in long-read sequencing. Robert Kimberly, M.D. (right), is using long-read sequencing in partnership with Chong and HudsonAlpha to study structural variations in the genomes of patients with lupus.Accurately mapping genetic variation between people is crucial to uncovering the causes of rare diseases and the increased susceptibility to a range of conditions within population groups. Until last summer, a surprisingly large proportion of the human genome remained uncharted, partially due to limitations of short-read sequencing. A new software program developed by University of Alabama at Birmingham researchers helps map out the human genome by improving the accuracy of long-read genomic sequencing.

The standard next-generation genome sequencing used today, including the vast majority of research and clinical sequencing at UAB, is done on machines that work via short reads. The preparation process chops up the deoxyribonucleic acid in a sample into strands roughly 150 base pairs long, or less, and the sequencing machine reads the base pairs found on each strand. Software then assembles the tiny chunks into a complete picture. The process works fine for much of the genome. But for regions with long stretches of repeated bases such as the sequence GAGAGA repeated a few thousand times or small insertions or deletions, it is difficult or impossible to determine the proper order from short reads alone.

Long reads can generate more accurate assemblies than short-read technologies, especially when there is no reference genome to check against or in repetitive sections of the genome and regions with complex genetic rearrangements, said Zechen Chong, Ph.D., assistant professor in the UAB Marnix E. Heersink School of Medicine Department of Genetics. The downside of long-read sequencing is higher error rates and a lack of effective tools for accurately evaluating assembly results.

The high error rates are why Chongs labs Inspector software for assembling long-read de novo genomes, described in a November 2021 article in the journal Genome Biology, is generating attention in the field and was celebrated as one of Heersinks Featured Discoveries in February 2022. Inspector largely reduces assembly errors and thereby improves the assembly quality, according to Chong.

Robert Kimberly, M.D., director of the UAB Center for Clinical and Translational Science, says Chongs work is an important step forward in the sequencing field. Kimberlys lab, which has a major focus on lupus research, is working with Chong and with HudsonAlpha Institute for Biotechnology in Huntsville, Alabama, to use long-read sequencing to study structural variations in patients with lupus. This is the same category of work that has been done using genome-wide association studies for more than a decade, Kimberly points out.

The difference is those studies are focused necessarily, because of the nature of the technology on changes in individual bases of nucleic acids, Kimberly said. Long-read sequencing gives you a much better understanding of structural variations insertions, deletions and duplications of genetic material on a given chromosome. The larger read length gives you more real estate on the chromosome. Structural variation in relationship to disease phenotypes is a major area for discovery.

Generating long reads is one thing. Analyzing them is another problem entirely, and one where Chongs Inspector tool shines.

In evaluations reported in the Genome Biology paper, Inspector outperformed two other long-read assembly evaluators on a simulated genome task. Chong and his team have uploaded the source code for Inspector to GitHub to allow open access, and they have addressed dozens of questions regarding usage of Inspector from users through GitHub and email, Chong said.

A major challenge for reference-based analysis is distinguishing true variations from assembly errors, Chong said. Inspector is the first tool to facilitate the discovery of long-read assembly errors, including both small- and large-scale errors. Accurate assembly results are the basis for variant discovery, genome annotation and subsequent functional discoveries. It improves whole-genome assembly by identifying and correcting assembly errors and is not affected by genetic variants.

Read more about Chongs lab and Inspector here.

See the rest here:
Researchers pioneering long-read sequencing studies explain why long reads matter - University of Alabama at Birmingham

April 13, 2022

In genomic studies, researchers examine the DNA of a population to understand the influence of genetics on health and disease. Though genomic studies have been common for more than a decade, most participants in these studies have been of European descent.

Dr. Lindsay Fernndez-Rhodes

Dr. Misa Graff

A new study led by Lindsay Fernndez-Rhodes, PhD, assistant professor of biobehavioral health at Penn State and 2016 doctoral graduate of the UNC Gillings School of Global Public Health, and Mariaelisa Graff, PhD, associate professor of epidemiology at the Gillings School, has shown that increasing the diversity of genomic samples can improve researchers ability to identify important genetic markers for health conditions.

One of the goals of conducting genomic studies is to develop precision medicine, which is the delivery of the exact treatment or medication that a person needs exactly when they need it.

Precision medicine is a great idea, but it only works if we study the full diversity of the populations that we may see in the clinic, Fernndez-Rhodes explained. We cannot treat people with precision if we do not have the relevant data. Previous large-scale genomic studies have largely overlooked Hispanic/Latino people. Since the United States is becoming increasingly diverse, our ability to provide appropriate medical treatment will suffer if the gaps in our genomic data are not addressed.

Fernndez-Rhodes and Graff were joined by more than 100 researchers from around the world to form the Hispanic/Latino Anthropometry Consortium. The consortium pools research expertise and genetic data on people of Hispanic/Latino ethnicity in order to bolster the diversity in genomic studies.

Dr. Kari North

Our consortium fills a major research gap in genomic studies. Inclusion of individuals of diverse ancestral backgrounds is imperative, both from the perspective of scientific necessity and equity, said Kari E. North, PhD, professor of epidemiology at the Gillings School, one of the consortiums multiple principal investigators, and co-author of this research. By embracing diversity, we are discovering novel genomic associations and moving the field forward.

In anew article in Human Genetics and Genomics Advances, Fernndez-Rhodes and Graff led the examination of genomic data from more than 70,000 Hispanic/Latino individuals. The data were compiled from 18 smaller studies and combined with two other consortia to bring the total sample to over 470,000 adults. To date, the article is the largest published genomic study of body measures in Hispanic/Latino individuals.

The researchers identified regions of the genome that are associated with three body measurements: body mass index (BMI), height, and waste-to-hip ratio. BMI, a ratio of weight to height, is the most common assessment of obesity used by physicians. Waist-to-hip ratio indicates where on their bodies people are carrying excess weight.

Consortium researchers identified 42 previously unidentified regions of the human genome related to BMI, height and waist-to-hip ratio. These traits have been examined in previous genomic studies, but the unique ancestry and experiences of Hispanic/Latino people made the regions easier to identify using the consortiums combined data.

The newly identified regions of the genome may help scientists understand how people grow, develop and perhaps most importantly for human health develop obesity. Significantly, the regions appear to be relevant to the health and development of all people, regardless of their ancestry. The researchers say that the results indicate a widespread need to build larger, more diverse data sources.

There is a very large gap between who is experiencing obesity and who is being included in genomic studies. The consortium is working to close one part of that gap. Hopefully, this is the first step of many toward increased diversity in genomic studies, said Fernndez-Rhodes. Researchers need to ensure that all people are represented in our scientific knowledge base. We need to harness the power of diversity to uncover the genes that pattern human health and disease.

Read the original release from Penn State.

Contact the UNC Gillings School of Global Public Health communications team at sphcomm@unc.edu.

Link:
Greater diversity in genetic studies helps researchers uncover new insights - UNC Gillings School of Global Public Health

This article was originally published here

Philos Trans R Soc Lond B Biol Sci. 2022 Jun 6;377(1852):20200427. doi: 10.1098/rstb.2020.0427. Epub 2022 Apr 18.

ABSTRACT

The Apportionment of Human Diversity stands as a noteworthy intervention, both for the field of human population genetics as well as in the annals of public communication of science. Despite the widespread uptake of Lewontins conclusion that racial classification is of virtually no genetic or taxonomic significance, the biomedical research community continues to grapple with whether and how best to account for race in its work. Nowhere is this struggle more apparent than in the latest attempts to translate genetic associations with complex disease risk to clinical use in the form of polygenic risk scores, or PRS. In this perspective piece, we trace current challenges surrounding the appropriate development and clinical application of PRS in diverse patient cohorts to ongoing difficulties deciding which facets of population structure matter, and for what reasons, to human health. Despite numerous analytical innovations, there are reasons that emerge from Lewontins work to remain sceptical that accounting for population structure in the context of polygenic risk estimation will allow us to more effectively identify and intervene on the significant health disparities which plague marginalized populations around the world. This article is part of the theme issue Celebrating 50 years since Lewontins apportionment of human diversity.

PMID:35430888 | DOI:10.1098/rstb.2020.0427

See the original post here:
Polygenic risk, population structure and ongoing difficulties with race in human genetics - DocWire News

The further back in time you go, the vaguer and more fragmented the fossil record of our ancestors becomes. Hominins, the branch of our family tree that separated itself from the other great apes, are believed to have ventured out of their place of origin in sub-Saharan Africa as early as two million years ago. Members of the now extinct species Homo erectus may have been the worlds first pioneers, followed, 1.5 million years later, by Homo heidelbergensis, a possible ancestor of the Neanderthals.

These hominins got a head start over our own species, Homo sapiens. Fossils from Israel and Greece suggest that their initial attempt to leave Africa happened between 210,000 and 177,000 years ago. This wave of migration ended in failure, with Homo sapiens populations in Eurasia being replaced by Neanderthal communities. Evidence for the interaction and interbreeding between these groups can be found in the DNA of non-African modern humans, less than 4% of which comes from Neanderthals.

Members of Homo sapiens did not spread across the corners of the globe in a single, uninterrupted migratory movement. Ancient humans undertook dozens of voyages during the prehistoric period, the majority of which were unsuccessful. Sometimes migratory populations were unable to take root in new regions. At other times, they simply packed their things and returned to Africa. A study from last year showed that archaic humans spent almost half a millennium moving in and out of the Arabian Peninsula following changes in the global climate.

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Because early migration out of Africa was so inconsistent, we are left with a poor understanding of how ancient humans traveled to and settled across continents. The routes they may have taken to get to Europe, Asia, and the Americas continue to spark fierce debate among researchers, and every few months, a new study places the prevailing argument in a fresh perspective. Recently, geologists from Imperial College London used cosmogenic nuclide exposure dating to rule out the Clovis First hypothesis, which argued humans entered North America via an ice-free corridor in what is modern-day Canada.

Another enduring question of early migration is the way in which our species came to populate Eurasia between 50 and 35 thousand years ago. A group of archaeologists and geneticists from Italy, Germany, and Estonia analyzed paleolithic DNA to better understand the relationships between different migratory groups. Their findings, published in Genome Biology and Evolution, suggest that Homo sapiens settled in a yet to be located population hub before the broader colonization of Eurasia, which was characterized by multiple events of expansion and local extinction.

Fossil evidence shows that archaic humans successfully colonized Eurasia as early as 70 thousand years ago. However, genetic analysis of these fossils reveals eastern and western Eurasian people only began to diverge genetically around 45 to 40 thousand years ago. Many articles have been written to explain what happened during this time gap. The simplest explanation is that eastern and western Eurasian people spent at least 15 thousand years living together at a central population hub before parting ways.

Unfortunately, this explanation does not hold up. In 2021, researchers sequenced genomes from a handful of paleolithic individuals recovered from Bulgarias Bacho Kiro cave. The individuals, who lived around 45 thousand years ago, were genetically closer to modern-day East Asians than modern-day Europeans, indicating eastern and western Eurasian populations already diverged once before. The genome of a particularly old paleolithic woman found on Czech Republics Zlat K mountain, meanwhile, differed from both western and eastern Eurasian people.

This is where the article published in Genome Biology and Evolution comes in. An enhanced understanding of the population dynamics during the broader colonization of Eurasia is critical to explain the shaping of current H. sapiens genetic diversity out of Africa, its authors explain, and to understand if cultural change documented in the archaeological record can be attributed to population movements, human interactions, convergence or any intermediate mechanism of biocultural exchange.

To better understand the role that the aforementioned hub might have played in early migration patterns, the researchers assembled an overview of all the available genomes from archaic humans in Eurasia. They then used genetics software called qpGraph to plot the relationships between individual genomes based on similarities and differences in their DNA. The resulting family tree posits the woman from Zlat K the oldest Homo sapiens genome ever sequenced as basal to all subsequent splits within Eurasia.

qpGraph could have processed the data into a number of possible family trees, some of which do not place the woman from Zlat K at its base. The researchers chose this particular family tree because its organization matched the spatiotemporal distribution of material cultural evidence at a cross continental scale. In other words, the relationships depicted in the tree also correspond with similarities between materials such as tools and technology, which, much like DNA, ultimately share common origin.

The story told by the articles family tree goes as follows: The woman from Zlat K belonged to an early yet unsuccessful expansion into Eurasia that must have taken place sometime before 45 thousand years ago. Genetically, the woman bears little resemblance to modern-day Europeans or East Asians. Because she is the only representative from this migration wave that we have thus far managed to find, it is difficult to say how large this wave was, what parts of Eurasia it reached, or how long it lasted.

Then, around 45 kya, study co-author Leonardo Vallini said in a statement, a new expansion emanated from the Hub and colonized a wide area spanning from Europe to East Asia and Oceania. The fate of these colonists varied from region to region. While those in Asia who survived became the ancestors of people inhabiting that part of the world today, their European cousins were less fortunate. As evidenced by the bodies from Bulgarias Bacho Kiro, settlers of this region gradually vanished.

Finally, says co-author Luca Pagani, one last expansion occurred sometime earlier than 38 kya and re-colonized Europe from the same population Hub, whose location is yet to be clarified. Genetic analysis shows that the representatives of the second migration wave occasionally interacted with the survivors of the previous one. However, explains Pagani, extensive and generalized admixture between the two waves only took place in Siberia where it gave rise to a peculiar ancestry known as Ancestral North Eurasian, which eventually contributed to the ancestry of Native Americans.

In the article, Vallini and Pagani refer to their family tree as a scaffold that elegantly accommodates available information on the most likely associated cultural assemblies for the most representative ancient human remains available to date. At the same time, they recognize that their study took on an extremely broad perspective and that more precise research is necessary to test their hypothesis on the branching and adaptation of local populations. Still, their explanation is more comprehensive than the overly simplistic narrative they started out with.

Subsequent studies, the article concludes, should also strive to uncover the location of the fabled population hub that Vallini and Pagani reference but never locate. DNA can only reveal a persons lineage, not their precise whereabouts and movements. The authors list North Africa and West Asia as plausible locations for the hub, but stress that we need older genomes to know for certain.

Continue reading here:
Mysterious "population hub" spawned ancient human migration - Big Think

The disease took Noemi Flemings elderly mother slowly, the first hints in repeated anecdotes or phrases. Then misplaced keys and bills. Then, Fleming caught her mother walking outside in the middle of the night, looking for the newspaper.

Mama, its 1 oclock in the morning, Fleming would tell her. The newspaper doesnt get here until 8.

On HoustonChronicle.com: Alzheimers diagnoses are increasing in Harris County. This tour aims to educate caregivers and public.

Flemings mother died at 91 in their hometown of Rio Grande City after a two-decade battle with Alzheimers, a brain disorder that slowly destroys memory and thinking skills. The familys story is a familiar one in Starr County, a mostly rural, heavily Hispanic county of about 65,000 on the Texas-Mexico border, where about 26 percent of Medicare beneficiaries have been diagnosed with Alzheimers and related dementias. That rate is the second highest among all U.S. counties, according to Medicare data.

The Starr County figures underline a recent push in the Rio Grande Valley to better understand how and why the disease disproportionately affects Hispanics, who along with Black people are traditionally underrepresented in Alzheimers research. The countys first private clinical research site, El Faro Health & Therapeutics Center, recently opened in Rio Grande City, and federal funds were awarded last month to the University of Texas Rio Grande Valley to investigate a wide spectrum of underlying causes.

The efforts are still in the early stages, but eventually, the researchers hope to identify ways to diagnose and treat the disease more effectively.

One of the problems, because theres no real cure, is that a lot of the focus has just been trying to prepare families for what lies ahead, and making sure families have things in order, said Dr. James Falcon, the primary investigator at El Faro.

Fleming, 69, jumped at the opportunity to join the first Alzheimers study at El Faro.

The research would help develop inexpensive tests to detect amyloid plaques, or sticky clumps of protein that build up around brain cells and disrupt brain activity.

In addition to watching her mothers decline, Fleming had worked as a nurse for more than 30 years at Starr County Memorial Hospital. She understood the value of learning her diagnosis early and potentially helping others do the same. And she could easily drive to the three required appointments.

Im glad they did it in Starr County, Fleming said. Because (usually) when it comes to clinical trials, youd probably have to go to a larger city.

On HoustonChronicle.com:New ruling clouds future of Alzheimers drug Houston doctor had seen promise with

Studies from the National Institutes of Health have linked underrepresentation to the lack of research efforts within minority communities. Other barriers include a mistrust of the predominantly white research establishment and inadequate education about the purpose of the research. Studies also cite medical staffing that does not represent participants culture, and eligibility criteria that disproportionately excludes minorities.

The El Faro clinic was created as an antidote to those issues, said John Dwyer, president of the Global Alzheimers Platform Foundation, an advocacy group that opened the clinic in partnership with James Falcon and his father, Dr. Antonio Falcon. The elder Falcon, a longtime family practitioner, grew up in Rio Grande City.

There is an appropriate and profound effort toward making sure that all clinical trials represent the population more broadly afflicted with disease, said Dwyer, pointing to one common estimate: Black people are twice as likely to be diagnosed with Alzheimers compared with white people, and Hispanics are 1.5 times as likely.

Dwyer said the study is still in the recruiting phase. The group is aiming for at least 20 percent of participants to be either Black or Hispanic.

When Fleming enrolled in the El Faro study, she was not surprised to learn her community was disproportionately affected by Alzheimers. She frequently saw patients with the disease in the hospital. But she always wondered why it affected some people and not others.

At El Faro, a series of tests revealed that she faced a low risk of Alzheimers. Her mothers siblings did not have Alzheimers, yet Fleming remembers at least one of her mothers relatives hospitalized with dementia a general term for a loss of thinking abilities severe enough to affect daily life.

New research may lead to possible answers.

A large-scale study published April 4 by the UK Dementia Research Institute found 42 genes that can serve as pathways for Alzheimers development, providing compelling evidence that inflammation and the immune system play a role in the disease.

Lifestyle factors such as smoking, exercise and diet influence our development of Alzheimers, and acting to address these now is a positive way of reducing risk ourselves, according to a statement from study co-author Julie Williams, center director at the UK Dementia Research Institute at Cardiff University. However, 60 to 80 percent of disease risk is based on our genetics and therefore we must continue to seek out the biological causes and develop much-needed treatments for the millions of people affected worldwide.

On HoustonChronicle.com: The disturbing link between veterans and Alzheimer's, and what Houston experts are doing to fix it

Dr. Gladys Maestre, director of the Rio Grande Valley Alzheimers Disease Resource Center for Minority Aging Research, has several theories for the high prevalence of Alzheimers in Starr County and the surrounding area.

Social isolation or chronic stress related to a heavy presence of border patrol might contribute, she said. It also could be related to the high number of uninsured residents about 35 percent in Starr County alone coupled with the low number of nonprofit health centers, she said.

Maestre, who also serves as a professor of neuroscience and human genetics at the University of Texas Rio Grande Valley, is working toward gathering 2,500 seniors with Alzheimers to participate in a study funded by a $2.9 million National Institute on Aging grant.

She will investigate a wide range of risk factors through in-person interviews and special technology, such as facial recognition software and memory tests using virtual reality. She is starting her work in Brownsville.

Hopefully we can learn from that, and we can get to Zapata and to Starr counties, she said.

For Antonio Falcon, clearer answers cannot come soon enough.

After more than four decades caring for patients in the city where he grew up, he became used to telling Alzheimers patients and their families the difficult truth: He did not have any medications that treated the disease itself, only those that can prolong comfort and independence. Deterioration was inevitable.

So when the Food and Drug Administration last year granted accelerated approval of Aduhelm, a monoclonal antibody drug designed to slow the onset of the disease by targeting amyloid plaques, he was ecstatic. It was the first drug approved to treat Alzheimers in 18 years, and the only one designed to treat the underlying cause.

It was a huge door that opened for us, he said. All of a sudden we were at the forefront of possibly getting medications for our patients.

Doubt quickly surrounded the drug. Questions lingered about its benefits, and some patients reported serious brain swelling or bleeding. Public health officials strongly advised to limit its use.

On HoustonChronicle.com: UTHealth administers first dose of controversial Alzheimer's drug in Texas

The FDA is investigating its own approval of the drug. And last week, the Centers for Medicare and Medicaid Services dramatically limited coverage of Aduhelm, all but ensuring Alzheimers patients in Starr County would not access the medication, which is estimated to cost around $28,000 for a year of treatment.

The decision was applauded by Alzheimers experts who continue to urge caution around its use. Both Antonio and James Falcon remain disappointed the agency did not open up access to more vulnerable groups.

But they are hopeful for three new monoclonal antibodies therapies currently in clinical trials. In the immediate future, they are focused on drawing more interest to the El Faro study.

People are developing (Alzheimers-related dementia) as we speak, and its not going to stop, Antonio Falcon said. Thats a one way street for them at this point.

julian.gill@chron.com

Originally posted here:
Texas county has the 2nd highest Alzheimer's rate in the US. Why? - Houston Chronicle

The disease took Noemi Flemings elderly mother slowly, the first hints in repeated anecdotes or phrases. Then misplaced keys and bills. Then, Fleming caught her mother walking outside in the middle of the night, looking for the newspaper.

Mama, its 1 oclock in the morning, Fleming would tell her. The newspaper doesnt get here until 8.

On HoustonChronicle.com: Alzheimers diagnoses are increasing in Harris County. This tour aims to educate caregivers and public.

Flemings mother died at 91 in their hometown of Rio Grande City after a two-decade battle with Alzheimers, a brain disorder that slowly destroys memory and thinking skills. The familys story is a familiar one in Starr County, a mostly rural, heavily Hispanic county of about 65,000 on the Texas-Mexico border, where about 26 percent of Medicare beneficiaries have been diagnosed with Alzheimers and related dementias. That rate is the second highest among all U.S. counties, according to Medicare data.

The Starr County figures underline a recent push in the Rio Grande Valley to better understand how and why the disease disproportionately affects Hispanics, who along with Black people are traditionally underrepresented in Alzheimers research. The countys first private clinical research site, El Faro Health & Therapeutics Center, recently opened in Rio Grande City, and federal funds were awarded last month to the University of Texas Rio Grande Valley to investigate a wide spectrum of underlying causes.

The efforts are still in the early stages, but eventually, the researchers hope to identify ways to diagnose and treat the disease more effectively.

One of the problems, because theres no real cure, is that a lot of the focus has just been trying to prepare families for what lies ahead, and making sure families have things in order, said Dr. James Falcon, the primary investigator at El Faro.

Fleming, 69, jumped at the opportunity to join the first Alzheimers study at El Faro.

The research would help develop inexpensive tests to detect amyloid plaques, or sticky clumps of protein that build up around brain cells and disrupt brain activity.

In addition to watching her mothers decline, Fleming had worked as a nurse for more than 30 years at Starr County Memorial Hospital. She understood the value of learning her diagnosis early and potentially helping others do the same. And she could easily drive to the three required appointments.

Im glad they did it in Starr County, Fleming said. Because (usually) when it comes to clinical trials, youd probably have to go to a larger city.

On HoustonChronicle.com:New ruling clouds future of Alzheimers drug Houston doctor had seen promise with

Studies from the National Institutes of Health have linked underrepresentation to the lack of research efforts within minority communities. Other barriers include a mistrust of the predominantly white research establishment and inadequate education about the purpose of the research. Studies also cite medical staffing that does not represent participants culture, and eligibility criteria that disproportionately excludes minorities.

The El Faro clinic was created as an antidote to those issues, said John Dwyer, president of the Global Alzheimers Platform Foundation, an advocacy group that opened the clinic in partnership with James Falcon and his father, Dr. Antonio Falcon. The elder Falcon, a longtime family practitioner, grew up in Rio Grande City.

There is an appropriate and profound effort toward making sure that all clinical trials represent the population more broadly afflicted with disease, said Dwyer, pointing to one common estimate: Black people are twice as likely to be diagnosed with Alzheimers compared with white people, and Hispanics are 1.5 times as likely.

Dwyer said the study is still in the recruiting phase. The group is aiming for at least 20 percent of participants to be either Black or Hispanic.

When Fleming enrolled in the El Faro study, she was not surprised to learn her community was disproportionately affected by Alzheimers. She frequently saw patients with the disease in the hospital. But she always wondered why it affected some people and not others.

At El Faro, a series of tests revealed that she faced a low risk of Alzheimers. Her mothers siblings did not have Alzheimers, yet Fleming remembers at least one of her mothers relatives hospitalized with dementia a general term for a loss of thinking abilities severe enough to affect daily life.

New research may lead to possible answers.

A large-scale study published April 4 by the UK Dementia Research Institute found 42 genes that can serve as pathways for Alzheimers development, providing compelling evidence that inflammation and the immune system play a role in the disease.

Lifestyle factors such as smoking, exercise and diet influence our development of Alzheimers, and acting to address these now is a positive way of reducing risk ourselves, according to a statement from study co-author Julie Williams, center director at the UK Dementia Research Institute at Cardiff University. However, 60 to 80 percent of disease risk is based on our genetics and therefore we must continue to seek out the biological causes and develop much-needed treatments for the millions of people affected worldwide.

On HoustonChronicle.com: The disturbing link between veterans and Alzheimer's, and what Houston experts are doing to fix it

Dr. Gladys Maestre, director of the Rio Grande Valley Alzheimers Disease Resource Center for Minority Aging Research, has several theories for the high prevalence of Alzheimers in Starr County and the surrounding area.

Social isolation or chronic stress related to a heavy presence of border patrol might contribute, she said. It also could be related to the high number of uninsured residents about 35 percent in Starr County alone coupled with the low number of nonprofit health centers, she said.

Maestre, who also serves as a professor of neuroscience and human genetics at the University of Texas Rio Grande Valley, is working toward gathering 2,500 seniors with Alzheimers to participate in a study funded by a $2.9 million National Institute on Aging grant.

She will investigate a wide range of risk factors through in-person interviews and special technology, such as facial recognition software and memory tests using virtual reality. She is starting her work in Brownsville.

Hopefully we can learn from that, and we can get to Zapata and to Starr counties, she said.

For Antonio Falcon, clearer answers cannot come soon enough.

After more than four decades caring for patients in the city where he grew up, he became used to telling Alzheimers patients and their families the difficult truth: He did not have any medications that treated the disease itself, only those that can prolong comfort and independence. Deterioration was inevitable.

So when the Food and Drug Administration last year granted accelerated approval of Aduhelm, a monoclonal antibody drug designed to slow the onset of the disease by targeting amyloid plaques, he was ecstatic. It was the first drug approved to treat Alzheimers in 18 years, and the only one designed to treat the underlying cause.

It was a huge door that opened for us, he said. All of a sudden we were at the forefront of possibly getting medications for our patients.

Doubt quickly surrounded the drug. Questions lingered about its benefits, and some patients reported serious brain swelling or bleeding. Public health officials strongly advised to limit its use.

On HoustonChronicle.com: UTHealth administers first dose of controversial Alzheimer's drug in Texas

The FDA is investigating its own approval of the drug. And last week, the Centers for Medicare and Medicaid Services dramatically limited coverage of Aduhelm, all but ensuring Alzheimers patients in Starr County would not access the medication, which is estimated to cost around $28,000 for a year of treatment.

The decision was applauded by Alzheimers experts who continue to urge caution around its use. Both Antonio and James Falcon remain disappointed the agency did not open up access to more vulnerable groups.

But they are hopeful for three new monoclonal antibodies therapies currently in clinical trials. In the immediate future, they are focused on drawing more interest to the El Faro study.

People are developing (Alzheimers-related dementia) as we speak, and its not going to stop, Antonio Falcon said. Thats a one way street for them at this point.

julian.gill@chron.com

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This Texas county mysteriously has the 2nd highest Alzheimer's rate in the US, and no one knows why - Houston Chronicle

Human ex vivo data demonstrate the promise of Pathios' 'Macrophage Conditioning' approach in reversing the immunosuppressive polarization of macrophages brought about by an acidic microenvironment

Preclinical study results show the ability of GPR65 inhibition to inhibit tumor growth and increase infiltration of key effector cell populations

OXFORD, United Kingdom, April 12, 2022 /PRNewswire/ -- Pathios Therapeutics Limited ("Pathios"), a biotech company focused on the development of first-in-class therapies for cancer, today announced that new data on PTT-3213, the company's orally bioavailable, potent and selective GPR65 inhibitor, were reported in a podium presentation at the American Association for Cancer Research (AACR) Annual Meeting 2022. Presented findings from human genetic and ex vivo human cellular studies demonstrated that GPR65, a pH-sensing, G protein-coupled receptor, serves as a critical innate immune checkpoint in the human tumor microenvironment. Furthermore, data showed that inhibition of GPR65 with PTT-3213 resulted in significantly reduced tumor growth in the MC38 mouse syngeneic cancer model. The AACR conference is being held April 8-13, 2022 in New Orleans, Louisiana.

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Stuart Hughes, Ph.D., Pathios' chief executive officer, delivered the podium presentation as part of the conference's "Cancer Biology and Tumor Immunity" mini-symposium. The key findings presented included:

In response to acidic pH, human macrophages undergo profound alterations in gene expression that render them indistinguishable from a typical immunosuppressive tumor associated macrophage. Pathios' small molecule GPR65 inhibitors are able to fully counteract this polarization and re-establish an anti-tumorigenic phenotype.

In vivo studies in the MC38 colon cancer syngeneic mouse model demonstrated that once weekly oral dosing with PTT-32131 provided equivalent efficacy to dosing twice weekly with a murine anti-PD-1 antibody.

The combination of PTT-3213 and anti-PD-1 therapy provided greater efficacy than either agent gave alone in the MC38 colon cancer syngeneic mouse model.

Inhibition of GPR65 by PTT-3213 was associated with significant increases in tumor-infiltrating CD8+ T cells and natural killer T (NKT) cells, both cell types with critical tumor cell killing capabilities. There was a clear correlation between the increased infiltration of these cells and decreased tumor volume across combination groups.

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"These are powerful findings as they firmly demonstrate the substantial clinical promise of GPR65 inhibition as a novel immuno-oncology strategy in a range of solid cancers. Importantly, these data further validate our long-held view that low pH acting on GPR65 is a critical innate immune checkpoint and the key determinant of immunosuppressive myeloid cells in the tumor microenvironment," commented Dr. Hughes. "As highlighted during our AACR presentation, we have now assembled a robust collection of data on the associations between the human genetics of GPR65 and cancer outcomes, including ex vivo studies in human cells. Additionally, we have now shown that weekly dosing of a small molecule GPR65 inhibitor is able to provide equivalent efficacy to anti-PD-1. We look forward to continuing research into this novel immuno-oncology target as we build on this data and complete further candidate nomination studies through 2022."

About Acidity in the Tumor Microenvironment The acidic tumor microenvironment, inherent to many cancers, causes a profound immunosuppression of infiltrating immune cells. This environment disarms the anti-cancer immune response and negates the effectiveness of current immunotherapies. This is particularly evident in tumor associated macrophages (TAM), where acidity is sensed by the cell-surface receptor GPR65, leading to an induction of the transcriptional repressor ICER (inducible cAMP early repressor) and the widespread suppression of a host of pro-inflammatory mediators and anti-tumorigenic genes.

About Pathios Therapeutics Launched in 2017, Pathios is a drug discovery and development company focused on translating innovative science into new medicines. Pathios was founded by a team of experienced biotech and pharmaceutical industry professionals, entrepreneurs and clinicians. The company is focused on developing small-molecule inhibitors of the pH-sensing G protein-coupled receptor GPR65 to target immunosuppressive macrophages in advanced cancers. To date, Pathios has secured a total of US$33M in Series A funding from the leading venture capital firms, Canaan Partners and Brandon Capital. Pathios is headquartered at the Innovation Centre on Milton Park, a key science precinct south of Oxford, UK. For more information, please visit http://www.pathios.com.

1. PTT-3213 co-dosed with the CYP inhibitor 1-ABT to prolong compound exposure

Contacts

Pathios Therapeutics Stuart Hughes, Chief Executive Officer, +44 1865 292 039 info@pathios.com

Tim Brons Vida Strategic Partners (media) 646-319-8981 tbrons@vidasp.com

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Pathios Therapeutics Highlights Role of GPR65 as Critical Innate Immune Checkpoint in the Human Tumor Microenvironment and Reports Anti-Tumor Activity...

Patrice Abela first knew something was wrong when his eldest daughter was learning to walk and her feet left trails of blood behind her, yet she showed no sign of distress.

She was soon diagnosed with congenital insensitivity to pain (CIP), an extremely rare and dangerous genetic disorder that dooms sufferers to a lifetime of hurting themselves in ways they cannot feel.

Abela, a 55-year-old software developer in the southern French city of Toulouse, then watched in horror as his youngest daughter was revealed to have the same condition.

Now aged 12 and 13, the two girls spend around three months of every year in hospital.

When they take a shower, they perceive hot and cold, but if it burns, they dont feel anything, said the father of four.

Due to repeated infections, my eldest daughter lost the first joint of each of her fingers.

She also had to have a toe amputated.

Repeated knee injuries have left both girls only able to move around using crutches or a wheelchair.

Abela said they may not feel physical pain, but lamented their intense psychological pain.

Aiming to raise awareness about the disease and challenge the scientific community, Abela plans to run the equivalent of 90 marathons in fewer than four months.

He started on April 12 (2022), following the route of this years Tour de France from Copenhagen to Paris.

A life without pain might sound like a dream come true, but the reality is more like a nightmare.

There are only a few thousand known cases of the condition worldwide.

The low number is believed to be partly due to sufferers often not living into adulthood.

Pain plays a major physiological role in protecting us from the dangers of our environment, said Dr Didier Bouhassira from the centre for pain evaluation and treatment at Ambroise-Pare hospital in Paris, France.

In the most extreme cases, babies will mutilate their tongue or fingers while teething, he said.

Then comes a lot of accidents, burns, walking on fractured limbs which heal badly, he said.

They have to be taught what is innate in others: to protect themselves.

But when there are no warning signs, danger lurks everywhere.

Appendicitis, which announces itself in others via symptoms like pain and fever, can fester into a devastating general infection of the abdomen.

Blindness can also occur because the eye must always be kept moist and the nervous system controls these processes via the so- called blink reflex, said Professor Dr Ingo Kurth of Germanys Institute of Human Genetics.

CIP was first recognised in the 1930s, and numerous studies have since identified a genetic mutation that blocks a persons ability to feel pain.

We have now learned that there are more than 20 genetic causes of congenital or progressive insensitivity to pain, Prof Kurth shared.

There is no cure and no real drug breakthroughs have been made so far, he added.

But our understanding of the molecular causes of CIP continues to reveal new targets, and based on this, hopefully new therapies will be developed in the coming years.

There are also hopes that studying how CIP works could lead to the development of a new kind of painkiller, prompting huge interest from pharmaceutical giants seeking a fresh product in the billion-dollar industry of pain relief.

In this way, the unlucky few with CIP could contribute to the creation of a treatment that would help everyone in the world -- except themselves. AFP Relaxnews

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Being unable to feel pain is not a good thing - The Star Online

By Brandon Diep, Apr. 12, 2022

What would you change about yourself? Would you change your eye color, hair type, height or the sound of your voice? Maybe you want to become smarter? Funnier? Imagine you could. With human genetic engineering, all the physical and mental traits you desire could become a reality. The only question is: is it morally right?

I believe gene editing or engineering should only be used to cure illnesses and diseases. Designer babies, the ability to change the superficial features of a child, are unethical and should not be conducted. Humans should not change the physical and mental characteristics of their children, but love them as they are.

Human genetic engineering is already possible, and it will soon change the way we think of childbirth and human health. Using a technology called CRISPR, also known as Clustered Regularly Interspaced Short Palindrome Repeats, which is defined by Live Science as, a powerful tool for editing genomes, meaning it allows researchers to easily alter DNA sequences and modify gene function, humans will then have the ability to aesthetically edit the genetic characteristics of an unborn child.

This technology holds unimaginable possibilities. As reported by Tides, a social charity foundation, a person can give a fertility clinic a checklist of characteristics and features they want for their child, scientists then use CRISPR to edit the genes of an embryo accordingly, implant the embryo into the mother for pregnancyand finally, the designer baby is born.

Gene editing was developed for the eradication of diseases and curing of cancer, but it can also be used for creating the child of your dreams. The science is unbelievable and is already being used in controversial ways.

On Nov. 25, 2018, the impossible became possible. A biophysics researcher from China, He Jiankui, shocked the world with the first gene-edited humans. He revealed that he had altered embryos for seven couples during fertility treatmentswith one resulting pregnancy. He was trying to bestow a trait that few people naturally have an ability to resist future infection of HIV, the AIDS virus, according to Associated Press.

Babies Lulu and Nana were the results of Hes gene-editing experiment. Born from an HIV-positive father and HIV-negative mother, the twins are now resistant from contracting the illness their father has. Controversy soon followed the researcher. He is scrutinized by the public for conducting the experiment in secret. Some praised him and called He, the rogue scientist, Chinas Dr. Frankenstein, and a mad genius, as written in the South China Morning Post. The Peoples Court of Shenzhen disagreed with his work, they sentenced him to three years of imprisonment and held him financially responsible for any future genetic complications that might occur in the babies lives. He may have had the best intentions, but he crossed the line of regulated science.

Although Lulu and Nana are the first of many genetically engineered human experiments, gene editing has shown its benefits. The tool has unveiled great opportunities in correcting the course of unfair diseases placed in humans. However, the regulation of gene editing should be a high priority.

The ethics of designer babies needs to be debated. I believe gene editing could negatively affect our future if it is used to aesthetically change children. U.S. News found in 2021 that there are companies offering parents the means of selecting better embryos, although in the form of superficial features has yet to be done. There are some who may use genetic engineering virtuously to prevent hereditary diseases while there are others who may abuse gene editing to design their child with the best attributes. I think it is likely that people will create humans with perfect symmetrical faces and ideal physiques for sports. A child will unfortunately grow up to think that their physical features are what creates their success. These exploitative fantasies could be manipulated into actuality.

Gene editing might also cause major repercussions for religion. There may be some who will find gene editing of a persons exterior to be a defiance against Gods creation. A few branches of Judaism prohibits members from trimming their hair because their body belongs to God and therefore they cannot alter it. I do believe there is a higher being and even though I dont practice this rule, I understand the sentiment. Like many religions, I hold the strong belief that one should not change themselves outwardly but inwardly. Changing the body of a healthy child before they are born is disrespectful toward their creator and their lineage.

Parents considering changing their children to look different from them is also flawed. The traits inherited from previous generations should not be seen as ugly or a mistake. This mindset will only further indoctrinate artificiality and self-hatred into future generations. We all hold a part of our parents within ourselves, we cannot let that go. If we change these genetics, then we are changing something special that connects us with our family. Your genetic material is inherited from hundreds to thousands of previous generations. Genetically modifying it for a superficial reason would counter all of the meaning and history behind that from your ancestors. The gifts of our familys pasts remind us of who were from.

The future reaps the consequences of today. Gene editing is still in its infancy. Going forth with designer babies may give birth to abominable effects on our descendants. One enhancement to the length of our arms could inadvertently mutate the body in a harmful way unknowingly passed down the generations. The harm would only be discovered after it is too late. It is too risky to change the genetic makeup of the most precious thing in life: ourselves.

What needs to be changed is our mentality. Our different eye colors, curly or straight hair, tall or short limbs arent what make us. The power to change these superficial features will not help. As humans, we should not change our children to conform to body standards, but instead, change body standards to conform to us. When you can stop caring about vain appearances, it is only then that we can start caring about what matters. Whats important are the things youve done and the things you are going to do. You arent your body, a shell your soul was born in. You are only who you think you are.

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Designer future: Human intervention is crossing the line of creation - The Poly Post