Category Archives: Gene Medicine

Its perhaps ironic then that ORourke, in sharing the story behind the research, is among those currently thinking aloud about the pros and cons of engineering dramatically longer lives.

The researcher said firmly, Theres a discussion around anti-aging therapeutics that society needs to have.

Scientists have known for more than a decade now that several genetic and biochemical pathways can either extend or shorten a persons life. The long answer to why the genome evolved this way is complex, ORourke said. The short answer resides in reproduction.

Nature cares about organisms becoming healthy reproductive adults, she said. But once we have produced as many babies as we are capable of, nature doesnt care about our health.

Should our muscles atrophy, or remain firm and tight? We can obviously improve our muscle tone by exercise, for example. But at some juncture, instructions meant to optimize development and survival earlier in life begin to tell the body to slow down. Obsolescence is in our genetic programming.

In that regard, our bodies are complex communication networks. The inputs and middle links in aging communication were identified prior to the UVA research. And acting on that accumulated knowledge, previous scientists indeed figured out ways to slow down, and even reverse, aging in animals such as lab mice.

But one reason you may not have heard about all the developments has been the ugly tradeoffs: compromised immunity, cancer.

The problem with playing around with many of the input and middle-link genes is that as they are such important players in the cell and control so many things it is very hard or even impossible to find a condition in which you can only get the good effects of changing their activities, ORourke explained.

In her attempt to solve this problem, ORourke assembled a Hoos-who of UVA scientists.

The team that yielded the revelatory research was led by biology graduate student Abbas Ghaddar and postdoctoral fellow Vinod Mony, with the contributions of graduate students Swarup Mishra, Elisa Enriquez-Hesles and Mary Kate Horak; undergraduate students Samuel Berhanu, Emma Harrison, James C. Johnson and Aaroh Patel; and aging expert Jeffrey S. Smith, a professor of biochemistry and molecular genetics.

Traditionally, worms have been associated with death. In science, however, worms in particular, roundworms have been responsible for some major health breakthroughs, winning Nobel Prizes in physiology and medicine (along with their scientists).

The type of roundworm ORourke and company used wasnt the parasitic type sometimes found in our pets, but rather C. elegans, which grows to about a millimeter long and is clear-bodied. As the first multicellular organism to have had its entire genome sequenced, the roundworm is transparent in more than one way. The creepy-crawly may seem far removed from us humans, but its chemical pathways are remarkably analogous.

Using the worm as a key model for this research, the team sought to decipher what happens at the end of those previously mentioned communication chains that control aging (as opposed to the inputs or middle links).

Specifically, ORourke wanted to find the molecular players most responsible for aging, which are those that break or repair cells, and by extension, tissues and organs. The thought was that by being at the end of the communication chain, playing around with the genes might mean fewer unwanted effects.

They set out by looking at biologys natural process of cellular cleanup and repair, called autophagy. The command to renew cells has long been thought to underlie longevity.

Autophagy is a process that clears the unwanted and recycles parts of the cells, ORourke said. When cell components go bad, they need to be disposed of. To this end, autophagy breaks them down to use the parts to make new cell components.

So autophagy was the main anti-aging candidate, in particular because we had already defined that the mid-link gene we were studying acted as a switch to turn autophagy on when animals were fasting, a dietary intervention that extends lifespan.

If their hypothesis was correct and autophagy was promoting longevity, then by stopping it, animals would not live longer.

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Thanks to UVA Research, You Might Live to 120. But Can Society ... - UVA Today

Why do humans have disease if they went through millions of years of evolution? Its a question Steven Gazal, PhD, assistant professor of population and public health sciences at the Keck School of Medicine of USC, hopes to answer.

Gazal is part of an international team of researchers who have become the first to precisely identify base pairs of the human genome that remained consistent over millions of years of mammalian evolution, and which play a crucial role in human disease. Thefindings werepublishedin a specialZoonomiaedition ofScience.

Gazal and his team analyzed the genomes of 240 mammals, including humans, zooming in with unprecedented resolution to compare DNA. They were able to identify base pairs that were constrained meaning they remained generally consistent across mammal species over the course of evolution. Individuals born with mutations on these genes may not have been as successful within their species or were otherwise not likely to pass down the genetic variation. We were able to identify where gene mutations are not tolerated in evolution, and we demonstrated that these mutations are significant when it comes to disease, explains Gazal.

The team found that3.3% of bases in the human genome are"significantly constrained,"including 57.6% of the coding bases that determine amino acid position, meaningthese bases had unusually few variants across species in the dataset. The most constrained base pairs in mammals were over seven times more likely to be causal forhuman disease and complex trait, and over 11 times more likely when researchers looked at the most constrained base pairs in primates alone.

Thedataset wasprovided bytheZoonomiaconsortium, whichaccording to the project website, "is applying advances inDNA sequencingtechnologies to understand how genomes generate the tremendous wealth of animaldiversity.Gazalgives credit to Zoonomia for making this type of data available to researchers and anticipates it will be widely used by human geneticists. Its a cheap resource togenerate, as opposed to datasets generated in human genetic studies, says Gazal.

His teams findings are a significant step forward, as Gazal notes, "we do not understand 99% of the human genome, so it is fundamental to understand which part has been constrained by evolution and is likely to have an impact on human phenotypes. Their discoveries and methods could become crucial tools for further research.

The next step for Gazal and his team is to repeat the process with a primate-only dataset. By restricting the subjects, they hope to focus on functions of DNA that appeared more recently in human evolution. We expect this to be even more useful in determining information on human disease, says Gazal.

Meta-analysis

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Leveraging base-pair mammalian constraint to understand genetic variation and human disease

28-Apr-2023

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USC researcher uses mammal DNA to zoom into the human ... - EurekAlert

There is no complete genetic explanation for why humans live longer than mice or why tortoises can live for a century. Looking for answers in long-lived animals genomes is tempting for researchers who want to figure out which genes extend lifespan.

I want to live as long as possible, said Stephen Treaster, a postdoctoral researcher at Boston Childrens Hospital. I want to see what technology and society looks like in 1000 years, ideallyhe said. Treaster used rockfish as an unlikely organism to explore the possibilities for longevity and uncovered two new pathways that appear connected to lifespan. He and his colleagues published their results in Science Advances(1).

For aging studies, researchers mostly use short-lived animals like mice, which live about three years, or Drosophila and Caenorhabditis elegans, which live for months or days (24). To make them live 10, 15, 20 percent longer, it doesn't necessarily apply to our end of the aging spectrum, said Treaster. Evolution has already solved the aging problem. There are individual species that can live hundreds and hundreds of years. My approach is to look at these exceptionally long-lived models.

Lifespan arises in different species from a complex network of genes and environmental interactions. Because of that complexity, it is difficult to look at the genetics of many model organisms and say for certain which genes contribute to that organisms lifespan. Fortunately, a natural evolutionary experiment on longevity exists. Rockfish are a family of common marine fish with worldwide distribution. Some species of rockfish live as little as 10 years while others can reach ages of 200 years or more. Since the rockfish clade emerged a relatively recent eight million years ago, there hasnt been time for rockfish to develop much genetic diversity.

The wide variety of lifespans in rockfish make them an interesting model for aging research.

credit: NOAA's National Ocean Service

The rockfishs nascent lineage is an analysts advantage. The wide variety of lifespans that different rockfish lineages exhibit can easily be pinned to genetic differences. Just as important, rockfish lifespans do not correlate with environmental conditions such as temperature or water depth, the kind of confounding effects that might make a genetic link to longevity in other animals less clear.

By analyzing genes related to aging that seemed to be evolutionarily selected across a variety of different rockfish species with varying lifespans, Treaster identified two different genetic pathways that seem to have evolved along with changes in lifespan.

The first pathway controls insulin signaling. Scientists know that insulin signaling affects aging and metabolism from past studies in other model organisms. On one hand, this is kind of a boring result, said Treaster. On the other hand, however, the fact that insulin signaling reappeared when analyzing rockfish seems to confirm the groups approach.

It was extremely clever analysis. It's not an easy analysis to do because the genomes of these [fish] are not well described.-Stephen Austad, University of Alabama

The other less well-known pathway they found is in the flavonoid signaling network. The flavonoid pathway is made up of proteins with activity modulated by flavonoid molecules, which are three-ring and 15-carbon structures common in plants (5).

None of the previous mouse or fly studies have pointed to the flavonoid network, said Steven Austad, an evolutionary biologist and aging researcher at the University of Alabama at Birmingham who was not involved in the study. It was extremely clever analysis. It's not an easy analysis to do because the genomes of these [fish] are not well described.

While Treaster is excited about identifying a possible new genetic link to lifespan, he emphasized that how exactly flavonoid pathway genes affect lifespan is not known. The next step is to play with these genes from rockfish to see if we can extend longevity in a conventional model. We're doing that right now. We are targeting these genes in zebrafish to see if we can extend lifespan, said Treaster. If that work confirms that flavonoids do directly alter lifespan, then Treaster hopes that scientists interested in aging-related diseases may explore the pathway for potential drug targets.

Austad isnt certain that identifying these genetic pathways to aging in fish will result in druggable targets in humans. He doubts that the insulin pathway, which has a demonstrated connection to longevity in flies and roundworms, can be connected to human lifespan. The evidence that that's a major player in human aging is relatively sparse, he said, noting that there havent been any human centenarians with identified novel mutations in the insulin signaling pathway.

Nevertheless, the publication gave him hope. This flavonoid network it's really a new thing and deserves investigation, he said.

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New genetic pathways involved in aging - Drug Discovery News

Article from Cloud-based Medicine Studio A national authoritative medical organization for rare diseases will be established, and the second list of rare diseases will be updated  Marketscreener.com

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Article from Cloud-based Medicine Studio A national authoritative medical organization for rare diseases will be established, and the second list of...

Low- and middle-income countries (LMICs) can and should play a leading role in dictating the future of the worlds most advanced healthcare technologies, according to the World Economic Forums Accelerating Global Access to Gene Therapies: Case Studies from Low- and Middle-Income Countries white paper.

Gene therapy is at the forefront of modern medicine. By making precise changes to the human genome, these sophisticated technologies can potentially lead to one-time lifelong cures for infectious and non-communicable diseases (e.g. HIV, sickle cell disease) that affect tens of millions of people around the globe, most of whom live in LMICs. However, too often the benefits of advanced healthcare technologies remain restricted to high-income countries (HICs), a reality that could happen to gene therapies.

The narrative that new healthcare technologies are unsuitable for LMICs is a long-standing rationale for excluding a majority of the world from the benefits of modern medicine. Without concerted efforts to build gene therapy capacity in LMICs, the global health divide will continue to widen.

The gene therapy industry is in its infancy, but early clinical successes and substantial funding have generated enormous momentum. This is an ideal moment for LMICs to enter the global market, prioritizing the needs of communities carrying the highest disease burdens.

We asked five clinical researchers from LMICs, who are all co-authors on the recent white paper, what innovations on the ground and changes at policy-level need to happen for gene therapy to make a real impact on global health.

Dr. Cissy Kityo Mutuluza, Executive Director, Joint Clinical Research Centre, Uganda

Although gene therapy has the potential to treat or even cure life-limiting diseases and infections, the full impact will only be realized if we deliver it for the benefit of all people, instead of fueling more health inequity between and within countries.

An essential first step towards maximizing the global impact of gene therapies is to build research and development (R&D) capacity in LMICs. Current gene therapy R&D has mainly excluded LMICs, instead centering pre-clinical and clinical work in HICs. Gene therapy R&D needs to be performed in regions where target diseases are prevalent to ensure that these therapies are safe and effective for those populations. Manufacturing technologies and healthcare infrastructure, which are the cost drivers for gene therapy products in HICs, need to be replaced with innovative and simplified platforms and workflows that bring down costs and are functional and cost-effective within LMIC health systems.

As for policy and regulation, individual countries must establish gene therapy frameworks that enable R&D. The construction of such frameworks should be guided by recommendations from the World Health Organization, emphasizing safety, effectiveness and ethics.

A critical component in effective global health interventions is community outreach. Treatment acceptability is essential for future clinical trials, thus it is important for scientists and clinicians to be clear about the risks and benefits of gene therapies. Communication and education activities should be made accessible to a broad range of stakeholders. Gene therapy and gene editing technologies are complex and it can be difficult for the public to understand their possible benefits or side effects. However, patient and public support is critical for the successful adoption of any new technology.

Professor Johnny Mahlangu, University of the Witwatersrand, South Africa

The ongoing COVID-19 pandemic is accelerating innovation, implementation and acceptance of molecular therapeutics (e.g. mRNA vaccines) globally. As a result, there is escalating interest in developing molecular interventions for many other conditions, such as gene therapies for genetic diseases. Strategically leveraging infrastructure that is being developed for molecular therapeutics will be critical in manufacturing, testing, and delivering gene therapies across diverse settings. Three critical areas of consideration include:

The application of precision medicine to save and improve lives relies on good-quality, easily-accessible data on everything from our DNA to lifestyle and environmental factors. The opposite to a one-size-fits-all healthcare system, it has vast, untapped potential to transform the treatment and prediction of rare diseasesand disease in general.

But there is no global governance framework for such data and no common data portal. This is a problem that contributes to the premature deaths of hundreds of millions of rare-disease patients worldwide.

The World Economic Forums Breaking Barriers to Health Data Governance initiative is focused on creating, testing and growing a framework to support effective and responsible access across borders to sensitive health data for the treatment and diagnosis of rare diseases.

The data will be shared via a federated data system: a decentralized approach that allows different institutions to access each others data without that data ever leaving the organization it originated from. This is done via an application programming interface and strikes a balance between simply pooling data (posing security concerns) and limiting access completely.

The project is a collaboration between entities in the UK (Genomics England), Australia (Australian Genomics Health Alliance), Canada (Genomics4RD), and the US (Intermountain Healthcare).

Professor Vikram Mathews, Christian Medical College, Vellore, India

Gene therapy is on course to revolutionize medical care for several conditions. The hope is that gene therapy will be a one-time curative therapeutic intervention for diseases ranging from inherited hemoglobinopathies, such as sickle cell disease and thalassemia, to acquired diseases such as HIV.

A primary challenge limiting access to these life-saving therapies is their astronomical costs, making them inaccessible even in developed countries where most gene therapies have originated. Due to economic challenges, there is often a mismatch between regions in the world where development and clinical research happens versus regions in the world where the incidence of the disease target is the highest. Classic examples of these are sickle cell disease and HIV with the highest incidence rates in Africa.

Moving the manufacturing of gene therapy products to local regions and point of care settings (within hospitals) are strategies that can both significantly reduce the cost of these products and improve accessibility. Additionally, current gene therapy approaches use expensive ex vivo procedures that require removal of a patients cells from their body. Instead, researchers must develop novel in vivo methods that simplify the procedure to a single injection directly into the patient, saving time and money.

Professor Julie Makani, Muhimbili University of Health and Allied Sciences, Tanzania

In order for gene therapy to have an impact on global health, changes in innovation and policy must occur at several levels: individual, institutional, national, continental and global.

At the individual level, patients and personnel are the primary focal points. Taking a patient-centered approach will ensure that the community is involved in research and will have a say in receiving a particular health intervention when it is available. For personnel working in areas pertinent to gene therapy including healthcare, research and education, there is a need to increase knowledge and to change perspectives regarding the advancements and achievements made within the field of gene therapy.

At the national, continental and global levels, genomic research is catalyzed by strategic partnerships and often occur in Centers of Excellence (CoE). Many countries in Africa have established CoEs in academic settings, which integrate health and science programmes. These innovative environments help maximize resources (physical and human) and provide settings that facilitate research and translation of research findings to health interventions to be done contemporaneously, in the appropriate population and geographical region.

At the policy-level, investments in global health and research in gene therapy must change. This can be done in three ways: direct investment to institutions in Africa; increase in the level of investment through funding partnerships; and recognition that the duration of investment needs to be longer than the normal funding cycles of three to five years.

Professor Suradej Hongeng, Mahidol University, Thailand

Gene therapy has received global attention over the last few years, recognition that continues to grow with each new clinical success. The field is constantly evolving, with disruptive innovation across public and private sectors. However, access to these life-saving treatments remain restricted due to a number of technical and policy challenges.

First, researchers must continue to develop cost-effective ways to administer gene therapies into patients, an area of R&D where the private sector can play an important role. Yet many LMICs have weak ecosystems to support the emergence of new companies or entice collaborations with multinational companies. Stronger private sector involvement will be critical for penetration into emerging markets.

Second, the unique nature of these personalized treatments makes them difficult to regulate within traditional frameworks, meaning that agencies must update current policies and regulations. As regulation evolves, it must also converge with the frameworks of other countries. This will make it easier for companies to navigate regulations and interact with agencies when performing clinical trials or bringing a therapy to multiple markets.

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Gene therapy can make a real impact on global health but we need equitable access, say experts - World Economic Forum

From left: Editas CMO Baisong Mei and CEO Gilmore O'Neill/courtesy of Editas Medicine

CRISPR gene editing leader Editas Medicineoften makes biotech headlines for its therapies for sickle cell and retinal diseases. Less often does it make the news for its preclinical cancer pipeline which could be why the company is reportedly considering a sale of these assets.

Editas is in "advanced discussions" regarding the sale of its preclinical oncology lineup, according to reporting from Endpoints News. When asked to confirm the rumors, Cristi Barnett, VP & head of corporate communications at Editas told BioSpace,We have long shared our plans to pursue development and commercialization opportunities through partnerships, specifically with oncology and our iNK program.

Barnett added that with a new leadership team onboard, Editas undertook a strategic review to inform opportunities.

Investors seemed to agree with the notion as Editas stock rose4.2% following the report.

Editas has given its C-Suite a makeover this year. In April, the company appointed genetic medicine veteran Gilmore ONeill as president and CEO.

ONeill wasted no time in bringing on board Sanofi veteran Baisong Mei to serve as the companys new chief medical officer. Mei has deep experience in the hemophilia space at both Sanofi and Bayer. He replaced Lisa Michaels, who was terminated by the company in February.

Editas presented data on one of its oncology assets, EDIT-202, last week at the European Society of Gene and Cell Therapy 29th Annual Meeting in Edinburgh, Scotland. EDIT-202 is a gene-edited iPSC-derived NK cell therapy that maintains prolonged persistence, high cytotoxicity and enhanced in vivo control of solid tumors, according to Editas.

Currently, there is no change to our program or plans. EDIT-202is advancing toward IND-enabling studies, Barnett said. She added that Editas will share additional updates on this program later this year including additional preclinical data at an upcoming medical meeting.

Also at ESGCT, Editas presented preclinical data from another program, EDIT-103, which is being developed to treat rhodopsin-associated autosomal dominant retinitis pigmentosa (RHO-adRP), a progressive type of retinal degeneration.

In a non-human primate model, the therapy demonstrated nearly 100% knockout of the endogenous RHO gene. Additionally, the replacement RHO gene produced over 30% of normal RHO protein levels in the treated area of subretinal injection, the company reported.

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Editas Rumored to be in Advanced Discussions around Potential Sale of Oncology Assets - BioSpace