Category Archives: Genetics

Genetics

Researchers Discover Genetic Underpinnings of Inherited Condition Often Misdiagnosed as Hypothyroidism – InventUM – University of Miami

By: Damian McNamara | May 31, 2024 | 6 min. read| Share Article Summary

Miami cardiologist Cintia Cupermans first-born son screened positive for congenital hypothyroidism in 2002. Her family doctor initially thought it was a false positive. Only one in about 4,000 babies are born with a malfunction of the thyroid gland that produces low levels of thyroid hormone and results in high levels of thyroid stimulating hormone (TSH).

We did some reading ourselves, Dr. Cuperman said. My husband and I are both physicians and we could tell there was something going on that we should be concerned about.

In the first few weeks, before they were referred to an endocrinologist, we were freaking out, Dr. Cuperman added.

When the couple had twins, both children had abnormal thyroid screenings, too. They underwent thyroid hormone treatment for years to avoid the associated health risks, including poor growth and neurologic and cognitive impairment.

Dr. Cupermans children are adults now and recently found out they no longer need therapy. Roy E. Weiss, M.D., Ph.D., professor and chair of the Department of Medicine at the University of Miami Miller School of Medicine, delivered the good news.

I was able to convince them and their doctors not to treat them because otherwise they would have been inappropriately treated with thyroid hormone for the rest of their lives, said Dr. Weiss, also the Rabbi Morris I. Esformes Endowed Chair in Medicine and Endocrinology and the Kathleen & Stanley Glaser Distinguished Chair of Medicine. Their thyroid tests were not consistent with the type of congenital hypothyroidism that needed treatment.

In some cases, newborns screened for congenital hypothyroidism have high TSH but have normal levels of thyroxine hormone. Dr. Cupermans children have this rare, congenital thyroid condition, known as resistance to TSH.

The important clinical implication is making the correct diagnosis, as most of these patients do not need any treatment and are misdiagnosed as hypothyroid, Dr. Weiss said. The misdiagnosis commits them to a lifetime of thyroid hormone treatment and blood tests that are not needed.

Resistance to TSH at birth has been a longstanding mystery, until now.

Dr. Weiss and fellow researchers Samuel Refetoff, M.D., from the University of Chicago Medicine, Helmut Grasberger, M.D., from the University of Michigan, and others found a genetic explanation in an unexpected place. They knew for years the genetic variants related to resistance to TSH were on chromosome 15. Recently they identified genetic changes in the non-coding region of this chromosome, a discovery published in the prestigious journal Nature Genetics.

As we better understand the function of the majority of the genome, the noncoding areas, we will learn more not only about how the thyroid functions but the genetics of other diseases. Dr. Roy Weiss

Importantly, they found how the non-coding regions resulted in the clinical syndrome. A separate team of researchers in Japan made a similar discovery regarding the molecular mechanism behind this condition and published their work in the same issue of the journal.

Their discovery may lead to finding more genetic changes and helping people with other inherited, or Mendelian, genetic conditions. Dr. Weiss and researchers identified noncoding mutations on a short tandem repeat to be the underlying cause of the condition in all affected individuals.

These mutations occur on primate-specific DNA known as the Alu retrotransposon, also found in gorillas. Previous studies have shown that some gorillas also have high-TSH thyroid tests and normal thyroid hormone, which are similar to resistance to TSH.

This is the exciting part, as we dont know how often disease is caused by the 98% of total DNA that is non-coding, Dr. Weiss said.As we better understand the function of the majority of the genome, the noncoding areas, we will learn more not only about how the thyroid functions but the genetics of other diseases.

Most of the genetic discovery took place in Dr. Refetoffs lab, before Dr. Weiss joined the Miller School faculty in 2014. At the time, he and colleagues at the University of Chicago, along with researchers at University of Washington, used the science to identify affected children and families.

One of the families was Dr. Cupermans, whom Dr. Weiss first met in 2012. Two years later, they became his patients in Miami and continue to this day.

As groundbreaking as this genetic discovery is, questions about treatment linger, Dr. Weiss said. But Dr. Cupermans sons are doing well and no longer taking thyroid hormone replacement.

They are super, super healthy, she said. They are both playing soccer in collegeyou know, thriving.

Tags: Division of Endocrinology Diabetes and Metabolism, Dr. Roy Weiss, hypothyroidism, resistance to TSH

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Researchers Discover Genetic Underpinnings of Inherited Condition Often Misdiagnosed as Hypothyroidism - InventUM - University of Miami

Genetics

Too much or too little: The impact of protein dosage on development – EurekAlert

image:

Model showing the interaction between a portion of the AFF3 protein (in white) and ubiquitin ligase (in green and gold), the protein that regulates its degradation. Amino acids mutated in KINSSHIP syndrome patients are shown as yellow atoms. The ubiquitin ligase amino acids with which they interact are depicted as colored atoms.

Credit: Nicolas Guex UNIL

New research from the University of Lausanne reveals that both the excess and the deficiency of a single protein can lead to severe intellectual deficiencies. The discovery offers critical insights for early diagnosis of a rare developmental disorder.

A team of scientists led by Alexandre Reymond, an expert in human genetics at the Center for Integrative Genomics (CIG) and professor at the Faculty of Biology and Medicine (FBM) of the University of Lausanne (UNIL), presents a major step forward in the detection of a rare genetic disease. For the first time, the authors show that both the accumulation and the deficiency of the so-called AFF3 protein are detrimental to development. The research, published in Genome Medicine, follows on from the groups 2021 discovery of the KINSSHIP syndrome, caused by mutations in the AFF3 gene and resulting in intellectual disability, an increased risk for epilepsy, kidney malformations, and bone deformation in affected children.

Discovery of the genetic cause of KINSSHIP syndrome

KINSSHIP syndrome affects about thirty individuals worldwide. As a result, there are few documented cases and understanding of the disease remains limited, making early and accurate diagnosis challenging. In our previous study we demonstrated that this pathology resulted from an abnormal accumulation of the AFF3 protein. Meanwhile, available genetic data from individuals of the general population suggested that a lack of this same protein could be similarly deleterious", explains Dr. Sissy Bassani, a postdoctoral researcher in Professor Reymond's team and the lead author of the current study.

Large genome database points researchers to a new hypothesis

The geneticists formulated their hypothesis using gnomAD, a database containing genome sequences from several hundred thousand unrelated individuals. By mining the available data for AFF3 variants, the scientists found that loss-of-function mutations in this gene are rare, indicating their likely harmful nature. This implies that this gene plays a critical role and that its loss likely has detrimental consequences for the organism. To test their hypothesis, the authors searched for individuals with only one copy of the gene, instead of the two normally present in the human genome. Collaborating with researchers from nine different countries across Europe and North America, they identified 21 patients with such an anomaly. They all showed similar but less severe symptoms than those of KINSSHIP syndrome patients.

Experiments reveal the developmental impact of AFF3 gene mutations

To demonstrate that both insufficient and excessive amounts of AFF3 are detrimental, the researchers used several different experimental systems: cells of patients, mice, and zebrafish. Artificially decreasing or increasing the protein quantity in zebrafish eggs revealed major developmental defects in the resulting fish embryos. "These results confirm that a precise amount of AFF3 is crucial for proper embryonic development and that mutations affecting its function and/or dosage cause severe malformations", concludes Prof. Reymond.

Impact for prenatal diagnostics

The authors findings are an important advancement for the diagnosis of this rare disorder, as testing for AAF3 mutations during fetal development could improve early detection of these gene defects.

Experimental study

People

Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles

30-May-2024

Annabelle Tuttle, Houda Zghal Elloumi and Chaofan Zhang are employees of GeneDx and Desiree DeMille works for ARUP Laboratories. James R. Lupski has stock ownership in 23andMe and is a paid consultant for Genome International. Claudia M.B. Carvalho provides consulting service for Ionis Pharmaceu ticals. The other authors have no competing interests to declare.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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Too much or too little: The impact of protein dosage on development - EurekAlert

Genetics

Hussman Institute Celebrates National DNA Day with Frost Science Museum – InventUM – University of Miami

More than 2,800 attendees learned about the significance of genomic research.

The day honors the 1953 discovery of the DNA double helix and the completion of the Human Genome Project in 2003. The annual eventalso invites students, educators and the community to learn about and celebrate the impact of the latest advances in genomic research.

Scientists at the Hussman Institute collaborated with Frost Science to provide hands-on experience in the genomics field to the 2,800 museum goers on National DNA day.

This is the second year in a row that we have been able to bring awareness to the community about genetics and ongoing technologies while sparking an interest in science through fun and engaging activities, said Margaret Pericak-Vance, Ph.D., director of the Hussman Institute and the Dr. John T. Macdonald Foundation Professor of Human Genetics Executive Vice Chair. This event stimulates curiosity and introduces kids to genetics, which can be a complicated topic, in a creative way that is easily accessible.

Nine interactive sessions made up the days itinerary as participants embarked on an exhilarating, DNA-based adventure. Sessions let participants create their ownstrandof DNA from candy, unravel the secrets of CRISPR genome editing and extract DNA from strawberries.

Each of our genomes tells a unique story, particularly about where we come from and how that impacts our traits and potentially our health, Dr. Griswold said. I was impressed at the level of interest of the young people at the event and their desire to know about genomics and how it will impact all our futures.

More than just an educational event, National DNA Day was a celebration of community and shared curiosity. Participants of all ages explored the wonders of genomics as the event fostered a sense of camaraderie and connection.

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Hussman Institute Celebrates National DNA Day with Frost Science Museum - InventUM - University of Miami

Genetics

International treaty agreed on handling genetics in patents – Research Professional News

World Intellectual Property Organization signs first new treaty in a decade

A global treaty has been agreed that says applicants for patents involving genetic resources, such as drugs based on a substance produced by a plant, must reveal the origins of those genetic resources.

Patent applicants will be required to disclose the country of origin or source of the genetic resources under the treaty approved by member states of the World Intellectual Property Organization (Wipo) on 24 May.

They must also disclose any basis on Indigenous knowledge.

It is the first Wipo Treaty to be agreed in more than 10 years and also the first that includes genetic resources and Indigenous knowledge.

Best possible compromise

Wipo director general Daren Tang said that the treaty made history in many ways. He said it was showing that the intellectual property system can continue to incentivise innovation while evolving in a more inclusive way, responding to the needs of all countries and their communities.

Brazilian ambassador Guilherme de Aguiar Patriota, who brought the gavel down on the agreement, called the treaty a very carefully balanced outcome.

It constitutes the best possible compromise and a carefully calibrated solution, which seeks to bridge and to balance a variety of interests, some very passionately held and assiduously expressed and defended over the course of decades, he said. Negotiations on the treaty started in 2001.

Member states cheered and applauded as the treaty was agreed on Friday last week. Wipo has 139 member countries, including the United States, China, India,Japan, Germany, France and the UK.

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International treaty agreed on handling genetics in patents - Research Professional News

Genetics

Nebraska team identifies new genetic defect impacting cattle morbidity and meat quality – Beef Magazine

Cattle have long been a cornerstone of agriculture, providing us with milk, meat, and various other products that nourish and sustain our communities. Ensuring the cattles health and optimal muscle development is vital when producing high-quality beef. However, various genetic conditions can disrupt muscle metabolism, affecting animals well-being and the quality of the meat they produce.

Researchers at the University of Nebraska Lincoln have discovered a new defect in composite cattle (Simmental, Red Angus, Gelbvieh) that often caused physical collapse when they exercised, with some calves unable to recover. This is an autosomal recessive genetic defect, which means both parents of affected calves must carry one copy of the mutation.

Herd managers at the UNL Gudmundsen Sandhills Laboratory noticed calves from one to six months old lagging behind the herd when moving between pastures. When they increased their pace, calves would collapse and remain at rest for brief periods of time. Pedigree analysis revealed a common herd bull in the sire pedigree of each affected calf. Pedigrees of the dams were unavailable, but heifers were retained as replacements within the herd and were sometimes mated to related bulls. This led to the possibility of inbreeding and suggested that a recessive genetic variant may be responsible for exercise intolerance in these calves.

The herd had undergone routine genotyping as part of the Integrated Beef Systems Initiative Genomics Infrastructure project, enabling a rapid genomic-based approach to finding the causative mutation. A genome-wide association study on 721 animals, including six affected calves, and whole-genome sequencing on two affected calves pinpointed a significant region on chromosome 29. One mutation, not previously identified in this region, waspredicted to truncate the protein product of the genePYGM(glycogen phosphorylase). Due to the expected impact of this variant on the myophosphorylase protein encoded byPYGMand the identification of a previously discoveredPYGMvariant in Charolais cattle, this variant was prioritized for follow-up studies.Next, 381 cattle, including eight affected calves, were genotyped for this variant.In every case, both parents of the affected calf were found to carry one copy of the mutation,and each affected calf had two copies, as we would expect for a recessive genetic variant.

The myophosphorylase encoded byPYGMplays a vital role in breaking down glycogen into usable energy, fueling muscles for sustained activity. Imagine coins (glycogen) collected and saved in a piggy bank (muscle). Myophosphorylase is the key that opens the piggy bank when animals need more energy. If myophosphorylase is absent or not functioning properly, the breakdown of glycogen is compromised, and the energy is not accessible, leading to difficulties in physical activity and muscle damage.

The affected calves showed a significant increase in glycogen stored in skeletal muscle, almost twice as much as the normal and carrier animals. Additionally, the affected calves had elevated creatine kinase before and after forced exercise. This is an essential enzyme that aids in energy production during muscle contraction. Elevated creatine kinase is often a sign of muscle damage or stress. The calves also experienced twitching in their hind limbs and biopsies showed visible signs of muscle damage. Despite these muscle-related issues, microscopic examination of other organs revealed no abnormalities.

The myophosphorylase protein was found in the healthy animal but noticeably missing in the affected calf. This outcome aligned with an additional test, where specific antibodies were used to identify thePYGMprotein in the muscle. The normal calf displayed a positive result with red pigmentation (Figure 1A), while the affected calves distinctly lacked thePYGMprotein (Figure 1B).

Figure 1.(A) Stain for myophosphorylase protein (red color) in a normal calf. (B) Stain for myophosphorylase protein in an affected calf.

The inability to efficiently break down glycogen not only compromises the well-being of the animals but also negatively impacts the quality of the meat they produce. Breaking down stored glycogen efficiently after an animal is harvested is crucial for making high-quality beef. In the absence of myophosphorylase, glycogen breakdown is restricted, hindering the expected decrease in pH. Consequently, the affected calves are labeled as dark-cutters, exhibiting dark-red meat that may have a purplish hue instead of the desired vibrant cherry-red color (Figure 2). This adversely influences consumer perception, shortens the products shelf life, and leads to economic losses. It is important to note that there were no significant disparities in meat quality in the animals carrying only one copy of the mutation.

Figure 2. Ribeye from an affected calf 24 hours after harvest.

Mutations in the same gene in humans result in a disease similar to what is observed in these cattle, termed McArdle disease. Individuals with McArdle disease experience muscle fatigue and weakness during physical activities, making it difficult to complete tasks requiring sustained effort. Affected individuals can live relatively normal lives by adjusting diet and exercise. However, doing the same for cattle, especially those raised for production, is less practical and achievable. Additionally, the economic benefits of managing this condition in cattle is limited due to the impact on product quality.

This recessive condition significantly affects muscle metabolism, raising concerns about animal welfare and introducing economic challenges in raising livestock. These repercussions can affect the survival of animals and, subsequently, the quality of the meat they produce at harvest. While the issue of dark-cutting beef is not new, understanding the underlying genetic factors at play is limited. This study stands out as one of the initial efforts to pinpoint a specific genetic mutation linked to this condition, paving the way for future research into the genetics of dark-cutting beef. Even though animals carrying one copy of this mutation do not show an immediate negative impact on the beef industry, it is imperative to identify them in breeding herds to prevent the production of affected calves. This comprehensive understanding is crucial for the well-being of the animals and the quality assurance of the final product.

This collaborative effort involved UNL students and faculty across disciplines including graduate student researchers Mackenzie Batt, Leila Venzor, Rachel Reith, and Nicolas Herrera, Dr. Jessica Petersen and Dr. Matt Spangler in animal breeding and genetics, Dr. Gary Sullivan in meat science, and Dr. David Steffen with the UNL Veterinary Diagnostic Center. The full paper was published inBMC Genomicsand is available at: https://link.springer.com/article/10.1186/s12864-024-10330-1#citeas.

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Nebraska team identifies new genetic defect impacting cattle morbidity and meat quality - Beef Magazine

Genetics

Exploring the wonders of molecular biology – Drug Target Review

In this episode, we explore our understanding of DNA and its implications for health outcomes. Additionally, we discuss the transition from DNA sequencing to actionable insights in medicine, contrasting genetics-driven drug discovery with traditional methods. Finally, we examine the evolving landscape of genetic technology and its potential impact on the future of medicine.

Bringing their expertise, we are thrilled to introduce Dr Matthew Nelson, Vice President, Genetics and Genomics, Deerfield Discovery and Development and CEO at Genscience and Dr Jake Rubens, President of Quotient Therapeutics and Origination Partner at Flagship Pioneering.

This podcast is in association with Molecular Devices. With its innovative life science technology, Molecular Devices makes scientific breakthroughs possible for academic, pharmaceutical, government and biotech customers. Head tomoleculardevices.comto find out more.

About the speakers

Dr Matthew Nelson

Vice President, Genetics and Genomics, Deerfield Discovery and Development and CEO at Genscience

Matthew Nelson, Ph.D., is a Vice President, Genetics and Genomics, Deerfield Discovery and Development, and joined the firm in 2019. He is also Chief Executive Officer of Deerfields affiliate, Genscience, a tech-focused company to improve integration of genetic evidence into drug discovery. Prior to joining Deerfield in 2019, Dr Nelson spent almost 15 years at GlaxoSmithKline and was most recently the Head of Genetics. Prior to GlaxoSmithKline, Dr Nelson was the Director of Biostatistics at Sequenom. He is co-author on >80 publications, including several cited >1,000 times. He began his career as an information scientist at Esperion Therapeutics. Dr Nelson was an Adjunct Associate Professor of Biostatistics at the University of North Carolina from 2010 to 2016. He holds a Ph.D. in Human Genetics and an M.A. in Statistics from the University of Michigan and obtained his B.S. in Molecular Biology from Brigham Young University.

Dr Jacob Rubens

President of Quotient Therapeutics and Origination Partner at Flagship Pioneering

Jacob is the president of Quotient and an Origination Partner at Flagship Pioneering. He is a scientist entrepreneur and leads a team that founds, builds, and grows companies based on new biotechnology.

At Flagship, Jake co-founded Sana Biotechnology and Tessera Therapeutics, and launched Kaleido Biosciences. In addition to his role at Quotient,Jake is the chief innovation officer and founding chief scientific officer at Tessera, where he led research from2018through2021. Previously, Jake was the head of innovation at Cobalt Biomedicine, where he co-invented and developed the companys Fusosome platform prior to its merger with Sana Biotechnology.

Before joining Flagship, Jake received his PhD in microbiology fromMIT, working in the Synthetic Biology Center with Professor Tim Lu with the support of aNational Science Foundation Graduate Research Fellowship. AtMIT, Jake invented gene circuits that allow engineered cells to do novel analog, digital, and hybrid computations, enabling the emerging field of intelligent cell therapies.

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Exploring the wonders of molecular biology - Drug Target Review

Genetics

30 Years After Genetic Discovery, Huntingtons Patients Still Waiting – BioSpace

Pictured: a collage of genetic indicators surrounding a patient with Huntingtons disease/ Nicole Bean for BioSpace

Its 100 percent fatal, hits patients in the prime of their lives, then gets passed down to 50 percent of the next generation. Thirty years after the discovery of the huntingtin gene, the biopharma industry is still searching for an effective treatment for Huntingtons disease.

Within the past few years, Roche and Wave Life Sciences have experienced high-profile failures in the space, and in late 2022, Triplet Therapeutics, a young startup with an approach targeting Huntingtons and other genetic diseases, closed its doors, and precision genetics medicine biotech NeuBase Therapeutics halted development of its Huntingtons program.

Symptomatic treatments exist for Huntingtons disease, which is caused by a CAG repeat in the first exon of the huntingtin (HTT) gene, but to date, no disease-modifying drug has made it across the finish line.

Rudolph Rudy Tanzi was part of the team that identified the Huntingtons gene chromosome in 1983. At the dawn of the genomic revolution, it was the first gene to be mapped to a human chromosome without any prior indication of the genes location. You had no idea what chromosome it was on, you had no idea what the protein defect was, Tanzi, now a professor of neurology at Harvard Medical School and Massachusetts General Hospital, told BioSpace. The search, which Tanzi compared to looking for 12 pieces of hay in 23 haystacks, took two years.

Instrumental to the discovery was a large group of patients in Venezuela. Huntingtons disease was evident in more than 12 families in this country, each with 10 or 11 children, Tanzi said. Once we had [those families], we tested that same DNA marker from chromosome 4, and that sealed it . . . . It was clear wed found the gene.

Ten years later, the pathogenic mutation in the huntingtin gene was identified as a CAG-repeat expansion. This mutation causes brain cells to die, leading to a host of progressive cognitive, psychiatric and movement disorders.

Theres been a lot of progress on mechanism, said Michael Hayden, CEO and founder of Prilenia Therapeutics, who was also involved in early linkage studies. Prilenia is developing treatments for Huntingtons and other neurodegenerative diseases. But . . . from the time you define mechanism to the time you have a drug can take twenty years.

Thirty years on, the search for a disease-modifying drug for Huntingtons continues.

After discovering the genetic driver for Huntingtons, researchers delved into the roles of the healthy and mutant HTT proteinsbiology that Paul Bolno, president and CEO of Wave Life Sciences, said has been interesting. We really realized that Huntingtons disease, in a lot of ways, is both a toxic gain of function and a toxic loss of function.

One challenge, Hayden told BioSpace, is that gene-silencing therapies, such as Roches tominersen, also knocked down the wildtype HTT (wtHTT) protein, which may be neuroprotective.

The pan-silencing hypothesis holds that there is a therapeutic window in which it is possible to reduce mutant HTT (mHTT) protein and concomitantly not reduce the wildtype HTT protein and keep that balance, explained Anne-Marie Li-Kwai-Cheung, Waves chief development officer, who previously led the tominersen efforts at Roche.

In a pan-silencing approach, you are succeeding, hopefully, in taking down the toxic protein, she told BioSpace. But the other half of the disease, which is a toxic loss of function, is that the wildtype [HTT] that you inevitably take out at the same time is actually really essential.

The question, Hayden posed, is would it not be better to have an allele-specific knockdown? This is the approach being taken by Wave. The companys next-generation antisense oligonucleotide (ASO) WVE-003 is designed to preferentially lower mHTT protein levels by targeting a single nucleotide polymorphism that appears on the mHTT transcript.

It is possible theres a therapeutic window, but if you can approach the problem more elegantly by being selective, that is by far the better approach in my opinion, Li-Kwai-Cheung said.

Delivery can also be a challenge, Hayden said. Intrathecal treatments, which are administered into the spinal canal, can also fail because you may not get target engagement or sufficient target engagement because you have to get from the CSF all the way deep into the center of the brain, Hayden said.

This was the case with Waves first-generation ASOs, according to the companys then chief medical officer, Michael Panzara.

Bolno believes Wave has solved this issue with WVE-003 in the form of a chemical modification to its platform. The PN chemistry weve been using . . . has really transformed what weve seen not just in terms of exposure [and] target engagement but durability, he said.

In September 2022, Wave presented data from the Phase Ib/IIa SELECT-HD trial showing a mean decrease in mHTT from baseline of 22% at 85 days. The mean reduction relative to placebo was 35% at 85 days after a single 30 mg or 60 mg. The company expects to share data from the 30 mg multi-dose cohort this quarter.

Prilenia is taking still another approach with pridopidine, a pill containing what the company describes as a highly selective and potent agonist of the sigma-1 receptor (S1R) protein, which is highly expressed in the brain and spinal cord and regulates several key processes that are commonly impaired in various neurodegenerative diseases.

Last month at the 75th American Academy of Neurology (AAN) Annual Meeting, Prilenia shared that pridopidine missed the primary endpoint, change from baseline compared to placebo at 65 weeks as measured by the Unified Huntington Disease Rating Scale-Total Functional Capacity score, in the Phase III PROOF-HD study. The drug also failed the key secondary endpoint, measured by the Composite Unified Huntingtons Disease Rating Scale.

Still, Hayden is optimistic as effects on both of these measures were reduced by the use of concomitant medications, according to the companys press release. A prespecified analysis that excluded participants taking neuroleptics and chorea medications showed clinically meaningful and nominally significant benefits with pridopidine.

When we looked then at those off of anti-dopaminergics [which includes neuroleptics], then we got a very different picture, Hayden said. In terms of total functional capacity, these patients remained stable for at least a year, and in terms of motor function and cognition, we saw improvement, he said. That was exciting because no [Huntingtons] drug had ever shown improvement in any of these functions.

Hayden additionally noted that the pridopidine is completely safe. There were no serious adverse events, and its . . . easy to take. When you look at risk-benefit, there is no risk and essentially patientsnot everybody, but many patientsderive benefit.

On the strength of these data, European regulators have encouraged Prilenia to submit a Marketing Authorization Application for approval, Hayden said, which the company plans to do by the end of July.

Its taken a long time, Hayden said, but the good news now is that Huntingtons disease has attracted the attention of pharma and biotech, big and small . . . and its recognized, sadly, that this is a disease that has been described as the worst disease known.

Li-Kwai-Cheung predicted there would be a disease-modifying therapy for Huntingtons within 5 to 10 years. Sometimes people get this feeling of like, its just futile and were not going to get there. But I dont think thats true, she said. I think all of these experiments have served a purpose to move the field forwards, and we really are on like the cusp as a field of getting a therapeutic to the market in [Huntingtons disease].

And once that happens, Weve seen in lots of different neurological spaces that that first approval really acts as an incredible catalyst and more drugs come after that as well.

Heather McKenzie is a senior editor atBioSpace. You can reach her atheather.mckenzie@biospace.com. Also follow her onLinkedIn.

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30 Years After Genetic Discovery, Huntingtons Patients Still Waiting - BioSpace

Genetics

Genetic research: possibilities and risks Exaudi – Exaudi

The Bioethics Observatory of the Catholic University of Valencia (UCV) invites an in-depth analysis of genetic research at the conference Genetic research: possibilities and risks. An approach from bioethics. This event, which will take place on July 4, 2024, at the UCV San Juan y San Vicente headquarters (18 Jorge Juan Street), will bring together experts from various fields to explore the ethical implications of scientific advances in this area.

In-person attendance at the congress requires prior registration, but the possibility of following it online will also be offered through the following link: https://youtube.com/live/.

The advancement of genetic research constitutes one of the spearheads of biomedical sciences and opens up enormous application possibilities in the fields of bioengineering, editing, and gene therapies. In parallel, with the development of these new tools, new bioethical dilemmas arise related to their fields of application, their safety and effectiveness, and regulation and control needs that urgently need to be addressed.

In our congress we propose a scientific approach to the current state of genetic research, analyzing the most recent evidence, such as that related to epigenetic processes, the therapeutic applications of the editing processes and obtaining mini human organs through bioengineering procedures, the aspects ethics of the heritability of potential changes and the need for ethical and legal regulation of related practices.

A prestigious team of expert researchers in each of these areas will provide us with updated access to this evidence that allows its bioethical assessment based on scientific rigor.

It is aimed at researchers, teachers, students and anyone with an interest in the field of Bioethics, and especially in genetics.

REGISTRATION HERE

PROGRAM

10:00. Institutional inauguration

10:15. Round Table: Epigenetics and genome editing: A scientific update

Ethics and epigenetics.

Luis Franco. Full member of the Royal Academy of Sciences of Spain and the Royal Academy of Medicine of the Valencian Community. University of Valencia.

10:45. Genome editing. Therapeutic advances and bioethical uncertainties.

Nicolas Jouve. Emeritus Professor of Genetics, former member of the Bioethics Committee of Spain.

11:15. Colloquium

Moderator:Luca Gmez Tatay. Professor of cell biology, biochemistry and bioethics. Catholic University of Valencia.

11:30. Coffee Break

12:00. Round Table: Bioengineering and gene therapy

Deciphering the potential of human mini-organs in the laboratory through ethics and bioengineering.

Nria Montserrat. ICREA research professor and principal researcher at the Institute of Bioengineering of Catalonia (IBEC).

12:30. Advances in the therapeutic application of gene editing systems based on CRISPR. Juan Roberto Rodrguez-Madoz. Researcher of the Hemato-Oncology Program. TOP. University of Navarra.

13:00. Colloquium.

Moderator:Jos Miguel Hernndez Andreu. Professor and researcher of biochemistry and molecular biology. Catholic University of Valencia.

16:15. Round Table: Ethical limits in genetic manipulation

Heritable gene editing in humans and future generations.

Vicente Bellver. Professor of Philosophy of Law at the University of Valencia. President of the Bioethics Committee of the Valencian Community.

16:45. Regulating gene editing: principles versus rules.

Federico de Montalvo. Vice Chancellor of Institutional Relations and Secretary General of the Universidad Pontificia Comillas.

17:15. Gene editing: what should really scare us?

igo De Miguel. Research Group of the Chair of Law and Human Genome of the Department of Public Law. University of the Basque Country Euskal Herriko Unibertsitatea.

17:45. Colloquium

Moderator:Mara Jos Salar. Coordinator of the Philosophy Degree. Professor at the Faculty of Economic and Social Legal Sciences of the Catholic University of Valencia.

18:00. Closure. Mr. Julio Tudela. Director of the Bioethics Observatory of the Catholic University of Valencia.

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Genetic research: possibilities and risks Exaudi - Exaudi

Genetics

Study shows effect of ‘interaction’ on epigenetic marking in… – Parkinson’s News Today

Genetic variations along with exposure to environmental factors, such as pesticides, may increase Parkinsons disease in a sex-dependent manner, a study of French farmworkers suggests.

Most cases of Parkinsons disease dont arise from a single factor, but rather a combination of a persons genes, lifestyle, and what theyre exposed to in the environment, Michael Kobor, PhD, who co-led the study from the University of British Columbia (UBC) in Canada, said in a university press release.

Studies like ours provide building blocks for investigation of personalized risk profiles for Parkinsons disease and biomarkers for earlier diagnosis, said Samantha Schaffner, PhD, a postdoctoral fellow at UBCs Edwin S.H. Leong Centre for Healthy Aging, who noted that, while its too early to know if the findings will hold true when looking at larger pools of data, in the future, [scientists] may be able to estimate someones risk level based on their sex, genetics and lifestyle, and provide tailored guidance on prevention.

The study, Genetic variation and pesticide exposure influence blood DNA methylation signatures in females with early-stage Parkinsons disease, was published in npj Parkinsons disease by Kobors team in collaboration with researchers in France.

How Parkinsons starts is unclear, but growing evidence points to how genetics and a number of environmental factors, such as breathing in or having contact with pesticides, may come together to cause the disease.

While there has been a great deal of research into each of these factors on their own, we have a limited understanding of how they interact with each other, said Kobor, a Canada research chair in social epigenetics, who is leading efforts to establish a link between genetics and pesticide exposure. Were working to bring these pieces of the puzzle together to gain a better understanding of how Parkinsons develops, whos most at risk, and how we can prevent it.

The study included 71 people with early-stage Parkinsons and 147 people without it who were enrolled with TERRE, a health database of French agricultural workers that contains a detailed history of pesticide exposure.

People exposed to pesticides used in farming are at a higher risk for developing Parkinsons and those who live or work near areas with higher levels of certain pesticides are more likely to see their symptoms get worse faster.

Here, the researchers focused on DNA methylation and how its patterns change in women versus men with Parkinsons. In DNA methylation, chemical marks on DNA can indicate whether genes are turned on or off, that is, how the information in genes is used by cells without changing the genetic code itself.

After scanning more than 42,000 regions of DNA from blood samples, the researchers found that DNA methylation linked to early-stage Parkinsons was spread across 69 regions in women and only two in men.

In women, DNA methylation mapped to genes related to cell signaling, protein production, and ion transport. In men, those epigenetic changes mapped to genes related to protein breakdown or recycling and the transport of ions within cells.

To validate their findings in women, the researchers downloaded the PEG1 (GSE111629) and SGPD (GSE145361) datasets from a public database. They found a significant match in DNA methylation between TERRE and PEG1 along with a French database called DIGPD, but not between TERRE and SGPD.

For 48 of the 69 regions targeted by DNA methylation in women, genetics alone provided the best explanation for the epigenetic changes previously attributed to Parkinsons, but pesticide exposure also contributed, especially when it interacted with genetic factors.

These findings highlight the complex interactions between genetic and environmental factors, Schaffner said. Having certain genetic variations may only increase Parkinsons disease risk in the context of an environmental exposure like pesticides, and they might have a sex-dependent effect on risk.

While this study may help lead to a more personalized approach to Parkinsons based on a persons genetic makeup, the findings should be further explored in larger study populations and in experimental systems, preferably with precise measures of exposure, the researchers said.

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