Category Archives: Genome

CAMBRIDGE, Mass., Oct. 21, 2021 (GLOBE NEWSWIRE) -- Intellia Therapeutics, Inc. (NASDAQ:NTLA), a leading clinical-stage genome editing company focused on developing curative therapeutics using CRISPR/Cas9 technology both in vivo and ex vivo, announced today that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation to NTLA-2001 for the treatment of transthyretin (ATTR) amyloidosis. This investigational therapy is the first CRISPR therapy to be administered systemically to edit a disease-causing gene inside the human body. NTLA-2001 has the potential to be the first single-dose treatment for ATTR amyloidosis as it may be able to halt and reverse the devastating complications of this disease. ATTR amyloidosis is a rare condition that can impact a number of organs and tissues within the body through the accumulation of misfolded transthyretin (TTR) protein deposits.

Orphan drug designation underscores the FDAs recognition of NTLA-2001s potential promise as a single-dose, novel therapy for the treatment of ATTR amyloidosis, said Intellia President and Chief Executive Officer John Leonard, M.D. At Intellia, we are committed to advancing our modular genome editing platform to develop potentially curative treatment options for life-threatening diseases, and we look forward to working with the ATTR amyloidosis community and the FDA to bring a much-needed treatment option to patients.

NTLA-2001 is currently being studied in a Phase 1 trial in adults with hereditary ATTR amyloidosis with polyneuropathy (ATTRv-PN). In June 2021, Intellia and its collaborator Regeneron announced positive interim clinical results from the first two cohorts of this study. These results, which were published in the New England Journal of Medicine, represented the first-ever clinical data supporting the safety and efficacy of in vivo CRISPR genome editing in humans.

The FDA's Orphan Drug Designation program provides orphan status to drugs defined as those intended for the treatment, diagnosis or prevention of rare diseases that affect fewer than 200,000 people in the United States. Orphan drug designation qualifies the sponsor of the drug for certain development incentives, including tax credits for qualified clinical testing, prescription drug user fee exemptions and seven-year marketing exclusivity upon FDA approval. The decision by the FDA follows a March 2021 decision by the European Commission (EC) to also grant NTLA-2001 orphan drug designation for the treatment of ATTR amyloidosis.

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About Transthyretin (ATTR) Amyloidosis Transthyretin amyloidosis, or ATTR amyloidosis, is a rare, progressive and fatal disease. Hereditary ATTR (ATTRv) amyloidosis occurs when a person is born with mutations in the TTR gene, which causes the liver to produce structurally abnormal transthyretin (TTR) protein with a propensity to misfold. These damaged proteins build up as amyloid deposits in the body, causing serious complications in multiple tissues, including the heart, nerves and digestive system. ATTRv amyloidosis predominantly manifests as polyneuropathy (ATTRv-PN), which can lead to nerve damage, or cardiomyopathy (ATTRv-CM), which can lead to heart failure. Some individuals without any genetic mutation produce non-mutated, or wild-type TTR proteins that become unstable over time, misfolding and aggregating in disease-causing amyloid deposits. This condition, called wild-type ATTR (ATTRwt) amyloidosis, primarily affects the heart.

About NTLA-2001Based on Nobel Prize-winning CRISPR/Cas9 technology, NTLA-2001 could potentially be the first curative treatment for ATTR amyloidosis. NTLA-2001 is the first investigational CRISPR therapy candidate to be administered systemically, or intravenously, to edit genes inside the human body. Intellias proprietary non-viral platform deploys lipid nanoparticles to deliver to the liver a two-part genome editing system: guide RNA specific to the disease-causing gene and messenger RNA that encodes the Cas9 enzyme, which carries out the precision editing. Robust preclinical data, showing deep and long-lasting transthyretin (TTR) reduction following in vivo inactivation of the target gene, supports NTLA-2001s potential as a single-administration therapeutic. Interim Phase 1 clinical data released in June 2021 confirm substantial, dose-dependent reduction of TTR protein following a single dose of NTLA-2001. Intellia leads development and commercialization of NTLA-2001 as part of a multi-target discovery, development and commercialization collaboration with Regeneron.

About Intellia TherapeuticsIntellia Therapeutics, a leading clinical-stage genome editing company, is developing novel, potentially curative therapeutics using CRISPR/Cas9 technology. To fully realize the transformative potential of CRISPR/Cas9, Intellia is pursuing two primary approaches. The companys in vivo programs use intravenously administered CRISPR as the therapy, in which proprietary delivery technology enables highly precise editing of disease-causing genes directly within specific target tissues. Intellias ex vivo programs use CRISPR to create the therapy by using engineered human cells to treat cancer and autoimmune diseases. Intellias deep scientific, technical and clinical development experience, along with its robust intellectual property portfolio, have enabled the company to take a leadership role in harnessing the full potential of CRISPR/Cas9 to create new classes of genetic medicine. Learn more at intelliatx.com. Follow us on Twitter @intelliatweets.

Forward-Looking StatementsThis press release contains forward-looking statements of Intellia Therapeutics, Inc. (Intellia or the Company) within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements include, but are not limited to, express or implied statements regarding Intellias beliefs and expectations regarding its: being able to complete clinical studies for NTLA-2001 for the treatment of transthyretin (ATTR) amyloidosis pursuant to its clinical trial applications (CTA), including submitting additional regulatory applications in other countries; ability to demonstrate effectiveness of NTLA-2001 in treating or reversing ATTR amyloidosis in patients; advancement and expansion of its CRISPR/Cas9 technology to develop human therapeutic products, as well as its ability to maintain and expand its related intellectual property portfolio; expectations of the potential impact of the coronavirus disease 2019 pandemic on strategy, future operations and timing of its clinical trials or IND submissions; ability to optimize the impact of its collaborations on its development programs, including but not limited to its collaborations with Regeneron, including its co-development programs for ATTR amyloidosis; and statements regarding the timing of regulatory filings regarding its development programs.

Any forward-looking statements in this press release are based on managements current expectations and beliefs of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to: risks related to Intellias ability to protect and maintain its intellectual property position; risks related to Intellias relationship with third parties, including its licensors and licensees; risks related to the ability of its licensors to protect and maintain their intellectual property position; uncertainties related to the authorization, initiation and conduct of studies and other development requirements for its product candidates; the risk that any one or more of Intellias product candidates will not be successfully developed and commercialized; the risk that the results of preclinical studies or clinical studies will not be predictive of future results in connection with future studies; and the risk that Intellias collaborations with Regeneron or its other collaborations will not continue or will not be successful. For a discussion of these and other risks and uncertainties, and other important factors, any of which could cause Intellias actual results to differ from those contained in the forward-looking statements, see the section entitled Risk Factors in Intellias most recent annual report on Form 10-K as well as discussions of potential risks, uncertainties, and other important factors in Intellias other filings with the Securities and Exchange Commission (SEC). All information in this press release is as of the date of the release, and Intellia undertakes no duty to update this information unless required by law.

Intellia Contacts:

Investors:Ian KarpSenior Vice President, Investor Relations and Corporate Communications+1-857-449-4175ian.karp@intelliatx.com

Lina LiDirector, Investor Relations+1-857-706-1612lina.li@intelliatx.com

Media:Lisa QuTen Bridge Communications+1-678-662-9166media@intelliatx.com lqu@tenbridgecommunications.com

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Intellia Therapeutics Receives U.S. FDA Orphan Drug Designation for NTLA-2001, an Investigational CRISPR Therapy for the Treatment of Transthyretin...

For most of human history, the cause of infant mortality was a mystery. Modern medicine has solved large parts of that riddle for us, thanks in no small part to technologies like genetic screening and ambitious research like the Human Genome Project. Today, sick babies are routinely screened for a bevy of congenital conditions using whole genome sequencing and soon, their healthy counterparts might be as well.

In September 2021, Genomics England, the U.K.'s premier genomics research organization, announced its intention to move forward with a pilot program that would use whole genome sequencing to screen for hundreds of genetic diseases in 200,000 otherwise healthy-seeming newborns. The initiative (called the Newborn Genomics Progamme) was received favorably by the U.K. public following an open dialogue sponsored U.K. Research and Innovation's Sciencewise program. However, the announcement sparked controversy in the scientific community.

The debate boils down to this: How helpful is genome sequencing for babies? And, on a more existential note, if everyone knows their full genetic history, how do we prevent society from going full Gattaca?

The Human Genome Project, which began in 1990, was officially deemed complete in 2003 (though technically the final 8 percent of our DNA wasn't fully sequenced until earlier in 2021).

A genome is a map of an organism's entire genetic code, one that includes every gene, active or not. While the human genome gets a lot of attention, it's not the only genome that scientists have sequenced. To date, we have full genomic data for more than 350 species of plants, more than 250 animals, and a whole bunch of microorganisms, including the SARS-CoV-2 virus.

Both our understanding of genomics and genomic sequencing technology have come a long way since the 1990s. Though it took 13 (ahem, 31) years to sequence the first human genome, today scientists can reliably sequence one person's genome in around 24 hours, and for substantially less money. "Since the end of the Human Genome Project, the cost of sequencing DNA has gone down a million-fold," says Dr. Eric Green, director of the National Human Genome Research Institute in the U.S.

Genomes including our human ones are incredibly valuable scientific tools, because they allow researchers to study how different genes interact, and they provide a baseline against which to compare bits of an individual's DNA, or even their entire personal genome.

So with that in mind, what are the potential benefits to infant genome sequencing?

Having a newborn's complete genomic information can enable doctors to catch and treat certain genetic conditions right away for example, children born with severe combined immunodeficiency (SCID). The disease, which suppresses immune function by way of multiple white blood cell mutations, was once considered a death sentence. But infant genetic testing has rendered SCID, while still serious, treatable.

In fact, infants in the U.S. and the U.K. are already routinely screened for a number of genetic conditions using a small blood sample and some basic DNA amplification. Babies who develop complications after a couple of weeks receive a more thorough battery of genetic tests, including whole genome sequencing. Which leads proponents of infant genome sequencing to wonder: Why shouldn't doctors just go ahead and do a comprehensive check from the start?

"It's really odd that we still do this for just three or four dozen diseases," says Green, "when we could detect literally thousands of diseases if we did it at birth."

In addition, he points out, having a full genome scan on hand could prove useful to people later in life; he envisions a world in which primary care physicians can tailor each patient's health care regimen to suit their genomic needs. And while there are still a lot of unknowns when it comes to making gene-based diagnoses, having more data will ultimately help fill in the gaps. "We need to give those physicians the tools," Green says.

Not everyone is sold on across-the-board infant genome sequencing, however. "I'm not a fan," says Dr. David Curtis, a geneticist specializing in psychiatric conditions at University College London.

Imagine knowing from the moment you were born how you were most likely going to die. One of the potential issues with genomic screening, Curtis says, is exactly that: A patient might uncover an incurable condition that won't affect them until later in life.

Take Huntington's disease, for example. This rare neurodegenerative condition, which causes tremors, cognitive difficulties and seizures, doesn't typically rear its head until a person is in their 40s. However, it is easily detectable by genomic screening from birth. To date, there is no effective treatment or cure for Huntington's.

Some folks might prefer to know what's in the cards for them upfront; but for others, such knowledge constitute a living nightmare. Not to mention the issue of privacy all of that data has to be secured in a large national database, and as recent ransomware events have shown, no database is completely hack-proof. In Curtis's view, the sticking point is consent. "A lot of it is actually applicable, you know, to 18-year-olds," he says, "Not to newborns."

Another consent issue is linked to the nature of DNA itself. Since our DNA is inherited from our parents, all humans essentially carry two genomes with them: one from their mother, and one from their father. In turn, each parent shares a genome with their parents, and so on. Factor in other relatives, like brother, sisters, uncles, cousins, etc. and things quickly get messy. After all, even if the baby in question is fine putting their genetic data into a national database, their grandparents might not be so keen on it.

"So," says Curtis, "it is a bit of a big deal."

Ultimately, though, universal genome testing might be less a question of if, and more a question of when. With Genomics England's Newborn Genomics Programme (and others like it) receiving an increasing amount of public and governmental support, it seems likely that whole genome sequencing will become standard practice at some point in the not-too-distant future.

"It'll be a grand experiment," Green says.

Read more:
Should We Sequence the Genome of Every Baby? - HowStuffWorks

An international team of researchers, led by scientists at University of California San Diego and Shiley Eye Institute at UC San Diego Health, has broadened and deepened understanding of how inherited retinal dystrophies (IRDs) affect different populations of people and, in the process, have identified new gene variants that may cause the diseases.

The findings published in the October 18, 2021 issue of PLOS Genetics.

IRDs are a group of diseases, from retinitis pigmentosa to choroideremia, that result in progressive vision loss, even blindness. Each IRD is caused by at least one gene mutation, though mutations in the same gene may lead to different IRD diagnoses.

IRDs are rare, but they affect individuals of all ages, progressing at different rates, even within families afflicted with the same disease. Specific diagnosis depends on finding the genetic causative mutations.

The U.S. Food and Drug Administration has approved gene therapy for treating one form of IRD involving the gene RPE65, but for other IRDs caused by mutations in more than 280 different genes, there are no cures or treatments proven to slow disease progression.

The researchers conducted whole-genome sequences (WGS) of 409 persons from 108 unrelated family lineages, each with a previously diagnosed IRD. WGS is a process of determining the entirety, or near-entirety, of the DNA sequence of an individual. It provides a comprehensive portrait of the persons entire genome, including mutations and variants, which can be used for broad comparative purposes.

Study participants were recruited from three different geographic regions: Mexico, Pakistan and European Americans living in the United States. Genomic analyses were conducted from blood samples taken from all participants, which revealed causative variants in 62 of the 108 lineages. A total of 94 gene variants were found in the 62 families: 52 variants had previously been identified as causative and 42 had not. Surprisingly, more than half of the new variants were not listed in the Genome Aggregation Database, an international compilation of genomic data.

Overall, causative variants were detected in 63 percent of Mexican participants, 60 percent of Pakistani, and 48 percent of European American.

The study also identified a large proportion of new IRD causative mutations specific to the populations studied and revealed the types of mutations contributing to inherited retinal dystrophies. Approximately 13 percent of the families displayed atypical or unexpected changes in the genome. Five of the family lineages had mutations in more than one gene in all affected individuals; one family carried mutations in different genes in different affected members and a de novo mutation was found in one patient that was not present in both parents.

An additional 8 percent of families had large changes in the structure of their genome causing the inherited retinal disease and the initial clinical diagnosis in four families was re-classified based on their genotype.

The authors said the new findings boost understanding of the distribution of IRD causative mutations in these three diverse populations, which will further understanding of disease variation and presentation. That, in turn, will help design more efficient genetic testing strategies and therapies applicable to global populations.

The research team was led by Radha Ayyagari, PhD, professor of ophthalmology and pathology, and Kelly A. Frazer, PhD, professor of pediatrics and director of the Institute for Genomic Medicine, both at UC San Diego School of Medicine; and S. Amer Riazuddin, PhD, associate professor of ophthalmology at John Hopkins University, in collaboration with institutions in India, Mexico, Canada, Brazil, Pakistan and the United States.

Co-authors include: Pooja Biswas, UC San Diego and REVA University, India; Adda L. Villanueva, Retina and Genomics Institute, Mexico and Hpital Maisonneuve Rosemont, Canada; Angel Soto-Hermida, Hiroko Matsui, Shyamanga Borooah, Berzhan Kumarov, Bonnie Huang, John Suk, Jason Zhao, Sindhu Devalaraja, Andrew Huynh, Akhila Alapati and Qais Zawaydeh, UC San Diego; Jacque L. Duncan, UCSF; Gabriele Richard, GeneDx; Shahid Yar Khan, Johns Hopkins University School of Medicine; Kari Branham, Naheed W. Khan and John R Heckenlively, University of Michigan; Benjamin Bakall, University of Arizona; Jeffrey L. Goldberg, Byers Eye Institute; Luis Gabriel, Genetics and Ophthalmology, Genelabor, Brazil; Pongali B Raghavendra, REVA University and Manipal University, Brazil India; Richard G Weleber, Oregon Health & Science University; J. Fielding Hejtmancik, National Institutes of Health; Sheikh Riazuddin, University of Punjab and Allama Iqbal Medical College, Pakistan; and Paul A. Sieving, National Eye Institute and UC Davis.

Funding for this research came, in part, from the National Institutes of Health (grants EY031663, EY13198, EY21237, EY002162 and P30EY022589) the Foundation Fighting Blindness; Research to Prevent Blindness; The Claire Giannini Foundation; The L.L. Hillblom Foundation and That Man May See, Inc.

Link:
Genomic Study Revealing Among Diverse Populations with Inherited Retinal Disease - UC San Diego Health

image:ALRs are essential for the patients response to radiation and chemotherapy: A schematic depiction of how by impeding the repair of DNA breaks, ALRs enhance the killing effects of radiation and chemotherapy. Schematic prepared by Hui Jiang and Nelson Gekara. view more

Credit: Schematic prepared by Hui Jiang and Nelson Gekara.

Researchers at Stockholm University have identified key genetic factors important for the efficacy of radiation and chemotherapy. These proteins called AIM2-like receptors (ALRs) are possible biomarkers for predicting the patients response to treatment and could be targeted to achieve optimal outcome radiation and chemotherapy.

Radiation and chemotherapy are not only the most common treatments for cancer but also essential preparative procedures for bone marrow transplantation. These treatments are however highly unspecific and often cause severe harm to the patients. The outcomes of radiation and chemotherapy varies from individual to individual, mostly due to inherent genetic differences in patients. This makes it difficult to prescribe an optimal patientspecific dose. Hence, the fixeddose prescribed for the majority is limited because of the severe toxicity witnessed in a minority of individuals when higher doses are used. The molecular determinants of patient response to radiation and chemotherapy remain unclear. Understanding these is key for optimal individualized treatments and is required for the development of therapies against tissue injury caused by these treatments, explains Dr. Nelson Gekara, Stockholm University, the senior investigator of the study published in Advanced Science.

The bone marrow is the most radiosensitive tissue and bone marrow failure is the major cause of suffering and death upon exposure to irradiation.

When we exposed mice deficient in ALRs to a high dose of irradiation, we found that such mice were resistant, and their bone marrows were less affected compared the control mice. We also found that cancer cells deficient in ALRs were resistant but when genetically engineered to express ALRs, such cells became sensitive to the killing effect of irradiation and chemotherapy. Notably, our analysis of cancer patient data revealed that patients with lower levels of ALRs had poorer survival following chemotherapy, describes Dr. Hui Jiang a research engineer at Stockholm University and the first author of the study.

ALRs were originally identified as proteins that become highly expressed under inflammatory conditions, such as during viral infections. Until now ALRs were thought to act as innate immune receptors that detect the presence of foreign or misplaced DNA inside cells and initiate inflammation. Here, the authors found that the ability of ALRs to potentiate the effects of radiation and chemotherapy is independent of their classical function in innate immune activation.

The most toxic effect of radiation or chemotherapy is linked to their ability to damage the genome. DNA damage often results in cell death, or if incorrectly repaired, causes genetic alterations that may lead to cancer or hereditary disorders. The authors found that when exposed to irradiation or chemotherapy, mouse and human cells deficient in ALRs repair DNA breaks faster, indicating that ALRs are inhibitors of DNA repair hence accelerate the killing effects of radiation and chemotherapy.

How do the ALRs inhibit the repair of the genome? The estimated length of DNA in a single mammalian cell is about 2 meters. In order to accommodate it within the nucleus of an average size of 6 m, DNA is folded and densely packed within the chromatin. However, when the genome incurs damage, the chromatin undergoes decompaction to allow DNA repair factors to be recruited to damaged sites.

We show that ALRs are in fact chromatin-bound proteins and that by virtue of their ability to undergo self-self interaction, these proteins hinder chromatin decompaction vital for the efficient repair of DNA breaks, explains Dr. Jiang.

The discovery of ALRs as key drivers of host response to radiation and chemotherapy is significant and could lead to more optimized treatment. For example, devising safe means to modulate the expression of ALRs would be one way of manipulating the patients response to achieve the desired therapeutic effects of radiation and chemotherapy. Further, determining the expression level of these proteins could be used to predict how the patients are likely to respond and therefore help in adjusting the treatment to suit the specific patient, concludes Dr. Gekara.

About the study:Nuclear AIM2-Like Receptors Drive Genotoxic Tissue Injury by Inhibiting DNA Repair by Hui Jiang, Patrycja Swacha, and Nelson O. Gekara was published in Advanced Science, October 2021, DOI: 10.1002/advs.202102534

For more information, please contactNelson Gekara, Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University. Phone: +46 8-16 41 89, e-mail: nelson.gekara@su.se

Experimental study

Animals

Nuclear AIM2-Like Receptors Drive Genotoxic Tissue Injury by Inhibiting DNA Repair

18-Oct-2021

The authors declare no conflict of interest.

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The DNA sensors ALRs regulate genome repair and are targets for improve radiation and chemotherapy - EurekAlert

LEXINGTON, Mass., Oct. 18, 2021 /PRNewswire/ --LogicBio Therapeutics, Inc.(Nasdaq:LOGC), a clinical-stage genetic medicine company, today announced clinical trial results demonstrating the first-ever in vivo genome editing in children. Early data from the company's Phase 1/2 SUNRISE clinical trial showed measurable levels of albumin-2A, a technology-related biomarker indicating site-specific gene insertion and protein expression. The SUNRISE trial is evaluating the safety, tolerability and preliminary efficacy of LB-001, the company's investigational, single-administration genome editing therapy, in pediatric patients with methylmalonic acidemia (MMA).

These results follow a recommendation from the independent Data Safety Monitoring Board (DSMB) overseeing the SUNRISE trial to continue the study without modification. The DSMB's recommendation was based on an evaluation of the safety data from the first two patients enrolled in the trial. Per the FDA-cleared protocol, albumin-2A detection together with the DSMB continuation recommendation enables LogicBio to begin enrolling two patients in the higher dose (1 x 1014 vg/kg) cohort (with ages ranging three to twelve years old) and two patients in the lower age (six months to two years old) cohort at the lower dose (5 x 1013 vg/kg) of LB-001.

"We are very excited to have achieved this significant milestone in the field of genetic medicine," said Fred Chereau, president and chief executive officer of LogicBio. "These early data indicate that we can precisely edit hepatocytes in vivo to treat a genetic liver disease with a single intravenous infusion using our proprietary GeneRide technology. Today's announcement is a demonstration that homologous recombination genome editing without the use of nucleases is a potential alternative to genome editing technologies in development that use nucleases, such as CRISPR. The ability to insert the correct version of a gene in a cell's genome without nucleases is an important step to unlocking the potential of GeneRide to treat a larger number of genetic diseases."

SUNRISE is a first-in-human, open-label, multi-center, Phase 1/2 clinical trial designed to assess the safety and tolerability of a single intravenous infusion of LB-001 in pediatric patients with MMA. LB-001 is designed to non-disruptively insert a corrective copy of the MMUT gene into the albumin locus to drive lifelong therapeutic levels of MMUT expression in the liver. LB-001 is based on the company's proprietary GeneRide technology, which uses homologous recombination, a natural DNA repair process, to enable precise editing of the genome without the need for exogenous nucleases and promoters that have been associated with an increased risk of immune response and cancer.

"MMA is a rare, life-threatening genetic disorder for which there are no treatments addressing the underlying cause of the disease. By demonstrating for the first time ever that in vivo, nuclease-free genome editing in pediatric patients is achievable, we are one step closer to bringing a safe and effective genetic medicine to children suffering from MMA and, potentially, other early onset genetic diseases where early intervention is critical to achieve optimal health outcomes," said Daniel Gruskin, MD, chief medical officer of LogicBio. "I would like to thank the patients, their families and the investigators who are participating in this landmark trial. We look forward to continuing to progress the clinical study to better understand the biochemical and clinical effect of this genome editing therapy."

The Company remains on track to present additional interim data by the end of 2021.

About the SUNRISE Trial

The SUNRISE trial is an open-label, multi-center, Phase 1/2 clinical trial designed to assess the safety and tolerability of a single intravenous infusion of LB-001 in pediatric patients with methylmalonic acidemia (MMA) characterized by methylmalonyl-CoA mutase gene (MMUT) mutations. Seven leading centers in the United States and one in Saudi Arabia are expected to participate in the trial. With the aim of evaluating LB-001 at an early age, the SUNRISE trial initially enrolled 3-12 year old patients and, following a recommendation from the trial's independent Data Safety Monitoring Board and detection of a biomarker indicating site-specific gene insertion, is permitted to enroll infants as young as 6 months old. The SUNRISE trial is designed to enroll up to 8 patients and evaluate a single administration of LB-001 at two dose levels.

About LB-001

LB-001 is an investigational, first-in-class, single-administration, genome editing therapy for early intervention in methylmalonic acidemia (MMA) using LogicBio's proprietary GeneRide drug development platform. GeneRide technology utilizes a natural DNA repair process called homologous recombination that enables precise editing of the genome without the need for exogenous nucleases and promoters that have been associated with an increased risk of immune response and cancer. LB-001 is designed to non-disruptively insert a corrective copy of the methylmalonyl-CoA mutase (MMUT) gene into the albumin locus to drive lifelong therapeutic levels of MMUT expression in the liver, the main site of MMUT expression and activity. LB-001 is delivered to hepatocytes intravenously via liver-targeted, engineered recombinant adeno-associated virus vector (rAAV-LK03). Preclinical studies found that LB-001 was safe and demonstrated transduction of hepatocytes, site-specific genomic integration, and transgene expression. LB-001corrected hepatocytes in a mouse model of MMA demonstrated preferential survival and expansion (selective advantage), thus contributing to a progressive increase in hepatic MMUT expression over time. LB-001 resulted in improved growth, metabolic stability, and survival in MMA mice. TheU.S. Food and Drug Administration(FDA) granted fast track designation, rare pediatric disease designation and orphan drug designation for LB-001 for the treatment of MMA. In addition, theEuropean Medicines Agency(EMA) granted orphan drug designation for LB-001 for the treatment of MMA.

About Methylmalonic Acidemia (MMA)

Methylmalonic acidemia (MMA) is a rare and life-threatening genetic disorder affecting approximately 1 in 50,000 newborns in the United States. In the most common form of MMA, a mutation in a gene called methylmalonyl-CoA mutase (MMUT) prevents the body from properly processing certain fats and proteins. As a result, toxic metabolites accumulate in the liver, in muscle tissue and in the brain. Symptoms include vomiting, lethargy, seizures, developmental delays and organ damage. There is no approved medical therapy addressing the underlying cause of the disease. To manage the symptoms, patients go on a severely restrictive, low-protein, high-calorie diet, often through a feeding tube. Even with aggressive management, these patients often experience life-threatening metabolic crises that can require recurrent hospitalizations and cause permanent neurocognitive damage. Because of this risk for irreversible damage, early intervention is critical and newborns are screened for MMA in every state in the United States.

AboutLogicBio Therapeutics

LogicBio Therapeuticsis a clinical-stage genetic medicine company pioneering genome editing and gene delivery platforms to address rare and serious diseases from infancy through adulthood. The Company's genome editing platform, GeneRide, is a new approach to precise gene insertion harnessing a cell's natural DNA repair process potentially leading to durable therapeutic protein expression levels. The Company's gene delivery platform, sAAVy, is an adeno-associated virus (AAV) capsid engineering platform designed to optimize gene delivery for treatments in a broad range of indications and tissues. The Company is based inLexington, MA.For more information, visitwww.logicbio.com, which does not form a part of this release.

Forward-Looking Statements

Statements in this press release regarding LogicBio's strategy, plans, prospects, expectations, beliefs, intentions and goals are forward-looking statements within the meaning of the U.S. Private Securities Litigation Reform Act of 1995, as amended, including but not limited to statements regarding early clinical results and the significance and interpretation thereof; homologous recombination genome editing without the use of nucleases as a potential alternative to genome editing technologies in development that use nucleases, such as CRISPR; the potential of the GeneRide platform, including the potential for genetic medicines based on the platform to be treatment options for genetic diseases; progressing the SUNRISE trial; the expected timing of announcing additional interim clinical data in the SUNRISE trial; the potential benefits of LB-001; and the sites expected to participate in the SUNRISE trial. The terms "demonstrating," "indicate," "look forward," "on track," "potential" and similar references are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Each forward-looking statement is subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied in such statement, including the risk that existing preclinical and clinical data, including early clinical data from a trial, may not be predictive of the results of ongoing or later clinical trials; the risk that clinical trials may not be successful or may be discontinued or delayed for any reason; the potential direct or indirect impact of the COVID-19 pandemic on our business, operations, and the markets and communities in which we and our partners, collaborators and vendors operate; manufacturing risks; risks associated with management and key personnel changes and transitional periods; the actual funding required to develop and commercialize product candidates, including for safety, tolerability, enrollment, manufacturing or economic reasons; the timing and content of decisions made by regulatory authorities; the actual time it takes to initiate and complete preclinical and clinical studies; the competitive landscape; changes in the economic and financial conditions of LogicBio; and LogicBio's ability to obtain, maintain and enforce patent and other intellectual property protection for LB-001 and any other product candidates. Other risks and uncertainties include those identified under the heading "Risk Factors" in LogicBio's Annual Report on Form 10-K for the year ended December 31, 2020 and other filings that LogicBio may make with the U.S. Securities and Exchange Commission in the future. These forward-looking statements (except as otherwise noted) speak only as of the date of this press release, and LogicBio does not undertake, and specifically disclaims, any obligation to update any forward-looking statements contained in this press release.

Investor Contacts:

Laurence Watts Gilmartin Group (619) 916-7620 [emailprotected]

Stephen Jasper Gilmartin Group (858) 525-2047 [emailprotected]

Media Contacts:

Jenna Urban Berry & Company Public Relations W: 212-253-8881 C: 203-218-9180 [emailprotected]

Bill Berry Berry & Company Public Relations W: 212-253-8881 C: 917-846-3862 [emailprotected]

SOURCE LogicBio Therapeutics, Inc.

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LogicBio Therapeutics Announces Early Clinical Trial Results Demonstrating First-Ever In Vivo Genome Editing in Children - PRNewswire

NEW YORK, Oct. 19, 2021 (GLOBE NEWSWIRE) -- Cellectis S.A. (NASDAQ: CLLS EURONEXT GROWTH: ALCLS) (the Company), a gene-editing company with clinical-stage immuno-oncology programs using allogeneic chimeric antigen receptor (CAR)-T cells and gene therapy programs for genetic diseases, in collaboration with Professor Toni Cathomen, scientific director at the Center for Chronic Immunodeficiency Medical Center at the University of Freiburg, Germany, will present two oral presentations at the European Society of Gene and Cell Therapy (ESGCT) Congress to be held virtually from October 19-22, 2021.

Professor Cathomens team at University of Freiburg will be presenting encouraging pre-clinical data that supports further evaluation of Cellectis .HEAL platform, an innovative gene therapy platform that uses a genome editing approach based on TALEN , for two product candidates targeting primary immunodeficiencies: RAG1 for Severe Combined Immunodeficiency (SCID) and STAT3 for Hyper IgE syndrome.

The data accepted for presentation at ESGCT reflects our ongoing commitment to finding new ways to treat and potentially provide a cure to patients that have failed to respond to standard therapies. Utilizing Cellectis TALEN technology, which we believe to be the most precise, versatile, and effective gene editing tool currently available, we demonstrate our potential to precisely correct RAG1 and STAT3 deficient genes and restore functionalities of the gene. These new milestones bring us one step closer to our goal of unlocking the full potential of our gene editing platform and bringing new therapies to patients with unmet medical needs. said Philippe Duchateau, Ph.D, Chief Scientific Officer of Cellectis.

Last May, during Cellectis Innovation Days, the Company revealed its new .HEAL platform, a novel hematopoietic stem cell gene therapy that aims to address debilitating genetic diseases. .HEAL leverages the power of TALEN gene editing technology to perform genome surgery, resulting in highly efficient and precise gene inactivation, insertion, and correction in hematopoietic stem cells (HSCs). Cellectis has announced ongoing programs targeting sickle cell disease, lysosomal storage disorders and primary immunodeficiencies.

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Presentations details

Data presentation on preclinical development of a TALEN based genome editing therapy for RAG1 deficiency

Newborns with RAG1 SCID have extremely low levels of B and T cells and a severe risk of recurrent, life-threatening infections. RAG1 is an essential enzyme specifically and temporarily expressed in the early development of T and B cells, making traditional gene therapy approaches to treat the disease challenging due to the need for tight and precise spatio-temporal expression control.

Previous attempts to treat the RAG1 deficiency via conventional gene therapy have produced unsatisfactory results.

These results highlight the need for tight spatio-temporal control of RAG1 expression as key for functional restoration and the use of a gene editing tool.

Using Cellectis TALEN technology and .HEAL, Professor Cathomen engineered HSCs with a corrected copy of RAG1 that replaced the existing, mutated copy of RAG1. The precise replacement of the mutated gene enabled the corrected RAG1 gene to be expressed at its natural timing and stage of cell development.

30% of gene correction was achieved within the long-term HSC population.

The presentation titled Preclinical development of a TALEN based genome editing therapy for RAG1 deficiency will be made on October 21 (9-11AM CET) by Manuel Rhiel, Ph.D University of Freiburg, and can be found on the ESGCT website.

Presentation Details:

Data presentation on a preclinical development of a TALEN based genome editing in T-cells for the treatment of Hyper-IgE- Syndrome

Hyper IgE syndrome is a rare primary immunodeficiency disease that clinically manifests as skin inflammation and recurrent skin and lung infections. Mutations in the transcription factor STAT3 have been associated with Hyper IgE. Alternative splicing gives rise to two STAT3 isoforms, STAT3 and STAT3 that display distinct functions.

The / ratio needs to be tightly regulated, which represents a major challenge for traditional gene therapy approaches.

Cellectis has developed a strategy applicable in HSCs and T-cells to insert a corrected version of the STAT3 gene into the patients genome to restore its functionality.

In T-cells isolated from patients, 60% integration was achieved. More importantly, the / isoforms ratio was restored.

The presentation titled Preclinical development of a TALEN based genome editing in T cells for the treatment of Hyper-IgE-Syndrome' will be made on October 20 (9-11AM CET) by Viviane Dettmer, Ph.D, University of Freiburg, and can be found on the ESGCT website.

About Cellectis Cellectis is a gene editing company, developing first of its kind therapeutic products. Cellectis utilizes an allogeneic approach for CAR-T immunotherapies in oncology, pioneering the concept of off-the-shelf and ready-to-use gene-edited CAR T-cells to treat cancer patients, and a platform to make therapeutic gene editing in hemopoietic stem cells for various diseases. As a clinical-stage biopharmaceutical company with over 21 years of expertise in gene editing, Cellectis is developing life-changing product candidates utilizing TALEN, its gene editing technology, and PulseAgile, its pioneering electroporation system to harness the power of the immune system in order to treat diseases with unmet medical needs. As part of its commitment to a cure, Cellectis remains dedicated to its goal of providing lifesaving UCART product candidates for multiple cancers including acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia (B-ALL) and multiple myeloma (MM). .HEAL is a new platform focusing on hemopoietic stem cells to treat blood disorders, immunodeficiencies and lysosomial storage diseases. Cellectis headquarters are in Paris, France, with locations in New York, New York and Raleigh, North Carolina. Cellectis is listed on the Nasdaq Global Market (ticker: CLLS) and on Euronext Growth (ticker: ALCLS).

For more information, visit http://www.cellectis.com Follow Cellectis on social media: @cellectis, LinkedIn and YouTube.

For further information, please contact:

Media contacts: Margaret Gandolfo, Senior Manager, Communications, +1 (646) 628 0300 Pascalyne Wilson, Director, Communications, +33776991433, media@cellectis.com

Investor Relation contact: Eric Dutang, Chief Financial Officer, +1 (646) 630 1748, investor@cellectis.com

Forward-looking Statements

This presentation contains forward-looking statements within the meaning of applicable securities laws, including the Private Securities Litigation Reform Act of 1995. Forward-looking statements may be identified by words such as at this time, anticipate, believe, expect, on track, plan, scheduled, and will, or the negative of these and similar expressions. These forward-looking statements, which are based on our managements current expectations and assumptions and on information currently available to management, include statements about our research and development projects and priorities, our pre-clinical project development efforts and the timing of our presentation of data. These forward-looking statements are made in light of information currently available to us and are subject to numerous risks and uncertainties, including with respect to the numerous risks associated with biopharmaceutical product candidate development as well as the duration and severity of the COVID-19 pandemic and governmental and regulatory measures implemented in response to the evolving situation. With respect to our cash runway, our operating plans, including product development plans, may change as a result of various factors, including factors currently unknown to us. Furthermore, many other important factors, including those described in our Annual Report on Form 20-F and the financial report (including the management report) for the year ended December 31, 2020 and subsequent filings Cellectis makes with the Securities Exchange Commission from time to time, as well as other known and unknown risks and uncertainties may adversely affect such forward-looking statements and cause our actual results, performance or achievements to be materially different from those expressed or implied by the forward-looking statements. Except as required by law, we assume no obligation to update these forward-looking statements publicly, or to update the reasons why actual results could differ materially from those anticipated in the forward-looking statements, even if new information becomes available in the future.

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Cellectis Presents Initial Preclinical Data on Two Novel Gene Therapies for Patients with RAG1 Severe Combined Immunodeficiency (SCID) and Hyper IgE...

This article has been sponsored by Intel.

Every successful startup or business begins with an idea that has the potential to inspire and create impact. But aside from the eureka moment, the idea alone cannot drive the impact it aims. Understandably, it takes countless days, months or even years of work to translate it into something substantial.

In addition to the big idea, the methodology involved to create a tangible product is what sets the stage for progress. And, in this situation technology becomes a prominent enabler.

Time and again through numerous startup success stories, we have been reminded of the transformational power of technology. When leveraged in the optimal way, it can bridge the gap between availability and accessibility with an efficiency like no other.

In this sphere, Intel has been facilitating this change as a pioneer in disruptive technologies. From its AI-driven technology solutions that are employed in a variety of sectors like security, education and healthcare to its mentorship program called Intel Startup Program, the company has been paving the way for tech startups and businesses who are about to change the world for the better.

Intels technical assistance, mentorship and high-impact collaboration with the industry, academia and government, has helped several companies/individuals realise their maximum potential and here are some of those:

Motivated to help a friend, Jagadish K Mahendran and his team designed a unique AI-powered voice-activated visual assistance system that could bridge the gap of accessibility and help the visually impaired perceive the world around them efficiently.

Equipped with OpenCVs Artificial Intelligence Kit with Depth (OAK-D) and powered by Intel, this innovation comes in a backpack that helps the wearer effectively navigate and detect common accessibility challenges like, changing elevations, traffic signs, moving objects, crosswalks, etc.

The backpack comes with a host computing unit that looks like a laptop, a Luxonis OAK-D spatial AI camera and a pocket-size battery pack with a capacity to power the device for at least 8 hours. The wearer can easily navigate with the help of this interactive device by connecting it with a pair of Bluetooth-enabled earphones. Through voice commands and responses, the system continuously guides the wearer through the journey.

This innovation can potentially help more than 285 million visually-impaired individuals across the globe.

The technology exists, we are only limited by the imagination of the developer community. Its incredible to see a developer take Intels AI technology to the edge and quickly build a solution to make their friends life easier, says Hema Chamraj, director, Technology Advocacy and AI4Good at Intel.

Dr Tinku Acharya started Videonetics in 2008, with a vision to create a homegrown Unified Video Computing platform that can revolutionise security and surveillance across the globe. Today, almost 12 years later, this company has used the same technology to aid in securing public health and safety during the pandemic.

To do so, their technologists developed SAJAG, an innovative video analytics-based Pandemic Management Suite that enables 247 monitoring of cities, hotspots, IT parks, office complexes, educational institutions, hospitals, etc. Operating in collaboration with several private and public stakeholders, SAJAG monitors a vast array of COVID relevant parameters and ensures the detection of anomalies with accuracy.

From ensuring compliance with all the government lockdown guidelines to monitoring social distancing to maintaining law and order it has played a pivotal role in helping authorities tackle the pandemic, says Avinash Trivedi, VP Business Development of Videonetics.

An ISV (Independent Software Vendor) partner of Intel, Videonetics has been leveraging technical insights, and computing infrastructure powered by Intel Xeon Scalable Processors and Intel Core i7 processors through the collaboration with the technology giant since its inception. SAJAG is the most recent example of this collaboration.

Much before COVID-19, Assams rural population was battling a deadly health condition hypertension. More than 50% of the hypertension cases in Assam lead to hemorrhagic strokes, as compared to a 20% margin in the rest of the country.

As a solution to this problem, Mumbai-based artificial intelligence (AI) startup, Qure.ai came forward during the pandemic with an innovation that sided in efficient management and care of stroke victims. They deployed an FDA-approved, CE-certified software qER, which can detect 12 critical abnormalities including strokes, clots and fractures. They also developed qXR, an AI-driven solution, which employs deep learning to provide comprehensive Chest X-ray screening to assist in the identification, treatment and management of asymptomatic COVID-19 symptoms in patients. With this technology in place doctors can now detect abnormalities like intracranial hemorrhage, atrophy, hydrocephalus, etc within just 1-2 minutes of a CT scan.

The most critical impact of this technology can be felt in the reduction of the time taken for diagnosis during emergencies like a stroke or trauma even in the absence of a specialist. The AI tech accurately highlights the need for intervention in critical areas and provides physicians with all the necessary information to make crucial decisions in time, adds Dr Pooja Rao, Qure.ais co-founder.

Working towards empowering the healthcare sector, the founders share that they were able to amass this impact with Intels help. With its cloud servers based on Intel processors and its x86 technology, they add that Qure.ai was able to successfully install its AI gateway on even lower-end basic computers because of Intels technology.

Boston-based social entrepreneur and cognitive scientist of Indian origin, Venkat Srinivasan along with Sanjay Gupta started English Helper, a tech-based learning solution for students in government schools. In 2013, they launched an initiative called RightToRead that introduced a multisensory reading and comprehension software that helps read out English textbooks using Artificial Intelligence.

Even before we start to speak, our brain begins to associate and relate everyday objects and situations with words, through sound and sight. It is through this visual and aural exposure that language learning develops into the spoken and written form making the multisensory approach the ideal one, says Vineet Mehra, Vice President and Chief Operating Officer (K12) of English Helper.

Available in three formsthe ReadToMe School Edition, ReadToMe Virtual Classroom and ReadToMe Student Edition softwaresthis innovation has helped bridge the gap in education, even during the pandemic. From a few hundred schools, today they have expanded to thousands of schools impacting millions of students. Utilising key capabilities of AWS instances powered by Intel Xeon Processors, they have managed to deploy the RightToRead program seamlessly across 28,000 schools in urban and rural India.

Started in 2017, Vacus Tech developed a unique technology that ensures a comprehensive and accurate monitoring in public places like offices, educational institutions and hospitals. Specialising in indoor positioning and tracking technology for safety purposes, Vacus Tech has leveraged its technology to ensure accurate monitoring of social distancing and following of COVID-19 protocols while indoors.Prior to the pandemic, our focus was to create smart buildings and workplaces that ensured safety and security of the employees working inside. But when the pandemic struck, a lot of automobile companies reached out to help track factory workers with respect to the following of COVID protocols, says co-founder Pratik Magar, who spent two years to build this technology along with co-founder Venugopal.Installed in employee ID cards, this innovation has not only encouraged employees to follow COVID guidelines at all times, but also simplified contact tracing in case of infection.

We participated in this startup accelerator programme before COVID. The platform helped us finalise our architecture and scale up the company. At the time we were able to produce only 3,000 to 4,000 tags and to scale beyond 10,000 tags we needed an efficient gateway that could handle such a big load. Thats when Intel helped us further with the AAEON UP Squared developer board. One of the fastest, this also comes with several security options that allow us to encrypt the data received, adds Pratik. With Intels help, they managed to source the gateway UP Squared board in record time, despite challenges posed by the lockdown.

India has the largest population of diabetic patients and a projection suggests it will hit almost 98 million people by 2030. An outcome of this is a condition called diabetic retinopathy, which is a leading cause of blindness and loss of vision in adults. Although the damage done due to diabetic retinopathy is serious and irreversible, early diagnosis and treatment can prevent loss of vision.Realising the potential need for a reliable solution, Sankara Eye Foundation, Leben Care and Intel technologies came together to develop a powerful innovative device called NETRA.AI that uses deep learning technology to efficiently diagnose retinal conditions, in less than a minute.NETRA.AI is built on Amazon EC2 C5 and M5 instances and powered by Intel Xeon Scalable processor. It also leverages Intels AI, DL Boost and Vector Neural Network to ensure accurate, accessible and affordable AI detection of retinal illnesses, to a large population, even with limited infrastructure, resources or an overburdened healthcare system. With the help of this technical backing, NETRA.AI has screened 3,293 patients and identified 812 at-risk patients so far.

In order to understand virus transmission and tackle the COVID-19 pandemic better, a healthcare startup called HaystackAnalytics devised a unique genome sequencing dashboard that was incubated by Indian Institute of Technology (IIT), Bombay and deployed for Brihanmumbai Municipal Corporation (BMC) in June 2021.Incubated under the Society for Innovation and Entrepreneurship (SINE) at IIT-B, Haystack created an analytical tool that aids public health officials and epidemiologists, better understand data that is retrieved from genome sequencing of ribonucleic acid (RNA) samples collected from Covid-19 patients.

Divided in four prominent stepssample processing, creation of a DNA library, sequencing the data from the genomes and analysing datathe process of genome sequencing is usually long and tedious.

Generally, it takes between 72 hours to 15 days to get the complete results of genome sequencing. Powered by Intel Xeon processors, Haystack is now able to complete the entire process and get results in less than 36 hours, with the help of assistance provided at the Intel Startup Program.

With Intels assistance we were able to reduce the turnaround time considerably. Initially when we started our analysis time would take around an hour but when we finished the programme, we were able to bring it down to 15 minutes. Essentially, through this technology, we are reducing a patients diagnostic journey and the cost. For instance, to identify a condition, instead of having to do multiple tests and therapies, the patient is now able to find the most likely cause and solution in a matter of just a few hours, says co-founder Anirvan Chatterjee.

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From Genome Sequencing to Helping the Visually-Impaired: 7 AI Innovations Changing Lives - The Better India

An extinct Japanese wolf appears to be the closest known wild relative of dogs, New Scientist reports.

It notes that the Japanese wolf, Canis lupus hodophilax, a subspecies of the gray wolf, went extinct in the early 1900s but that there are a number of museum specimens that researchers led by Yohey Terai at the Graduate University for Advanced Studies in Japan studied. As they report in a preprint posted to BioRxiv, the researchers analyzed the whole genomes of nine Japanese wolves and 11 Japanese dogs to find that Japanese wolves are the closest among gray wolves to dogs.

The Eurasian gray wolf lineage and the dog lineage split about 20,000 to 40,000 years ago, but the researchers uncovered some introgression from the ancestor of the Japanese wolves into the ancestor of East Eurasian dogs that occurred about 10,000 years ago.

Terai tells New Scientist that even if the dog ancestor lived in East Asia, that does not necessarily mean dogs were domesticated there. "It is not possible to determine when the dogs began to have a relationship with humans from the genome data," Terai tells it. New Scientist notes that archaeological evidence is needed to make that determination.

See the rest here:
Closest to the Dog | Genomeweb - GenomeWeb

Significance

Plants adaptations to and divergence in arid deserts have long fascinated scientists and the general public. Here, we present a genomic analysis of two congeneric desert plant species that clarifies their evolutionary history and shows that their common ancestor arose from a hybrid polyploidization, which provided genomic foundations for their survival in deserts. The whole-genome duplication was followed by translocation-based rearrangements of the ancestral chromosomes. Rapid evolution of genes in these reshuffled chromosomes contributed greatly to the divergences of the two species in desert microhabitats during which gene flow was continuous. Our results provide insights into plant adaptation in the arid deserts and highlight the significance of polyploidy-driven chromosomal structural variations in species divergence.

Deserts exert strong selection pressures on plants, but the underlying genomic drivers of ecological adaptation and subsequent speciation remain largely unknown. Here, we generated de novo genome assemblies and conducted population genomic analyses of the psammophytic genus Pugionium (Brassicaceae). Our results indicated that this bispecific genus had undergone an allopolyploid event, and the two parental genomes were derived from two ancestral lineages with different chromosome numbers and structures. The postpolyploid expansion of gene families related to abiotic stress responses and lignin biosynthesis facilitated environmental adaptations of the genus to desert habitats. Population genomic analyses of both species further revealed their recent divergence with continuous gene flow, and the most divergent regions were found to be centered on three highly structurally reshuffled chromosomes. Genes under selection in these regions, which were mainly located in one of the two subgenomes, contributed greatly to the interspecific divergence in microhabitat adaptation.

As individuals of each plant species cannot simply move to avoid stresses, biologists since Darwins era have been fascinated by their adaptations to environments with harsh climatic conditions such as deserts (1, 2). Several mechanisms generate novel genetic variation that enables plants to adapt to their environment, such as point mutation, gene duplication, and polyploidization (35). As one of these mechanisms, whole-genome duplication (WGD) or polyploidization, has frequently occurred throughout the evolutionary history of plants (68), and many polyploidization events have putative associations with environmental changes and subsequent adaptation to new niches (9, 10). Two types of polyploidy are recognized in plants and other organisms: autopolyploidy (involving duplication of a single species genome) and allopolyploidy (involving combination of different species genomes) (7, 11). The relative proportion of autopolyploids and allopolyploids are comparable, but allopolyploidy is generally expected to provide higher adaptive potential (12, 13). This is because it not only allows the pairing of chromosomes from each parent, with diploid-like meiotic behavior and disomic inheritance, but also leads to extensive chromosomal structural variations, morphological innovations, novel genic interactions, and hybrid vigor (7, 14). Such evolutionary consequences have been repeatedly confirmed in allopolyploid model species, for example, Arabidopsis, and widely cultivated allopolyploid crops, including cotton, wheat, and oilseed rape (1519).

In general, polyploid plants exhibit higher drought and salt tolerance than their diploid relatives (1215); however, little is known about how subsequent speciation and diversification occur in such polyploid genomes. To improve such understanding, we examined the contribution of polyploidization (if any) to adaptive evolution and speciation in the bispecific genus Pugionium, endemic to the Kubuqi Desert and Mu Us Desert in northwestern China (20). These inland deserts arose from rapid climate transformation since the early Miocene (21, 22), with consequent changes in vegetation, forest retreats, and the emergence of aridity-adapted species (23). The genus Pugionium belongs to the family Brassicaceae, which includes more than 3,700 species distributed around the world (24, 25). Many species of Brassicaceae are economically important crops that are cultivated as vegetables, condiments, fodder, and oilseeds (18, 24, 26). In addition, allopolyploidyusually associated with chromosomal structural variations (fusion, shuffling, or translocation) and changes in chromosome base numberis prevalent in the family (24, 2729). Brassicaceae are divided into five major lineages (24), and Pugionium belongs to Expanded Lineage II with isolated position (30). Although young leaves and shoots of Pugionium are consumed as vegetables by local communities (23), both species produce highly lignified roots, stems, and silicles, which have a clear adaptive value in dry and salty deserts. Pugionium cornutum has long roots and an erect stem that can be more than 1.5 m tall, while Pugionium dolabratum produces short roots and numerous basal bushy branches (Fig. 1A). Most populations of the two species have no overlapped distributions, but they do occur rarely in the same site with distinct microhabitat divergence (23) (SI Appendix, Results). Furthermore, P. cornutum and P. dolabratum are confined to the mobile and fixed dunes, respectively (23), and also display differences in leaf and silicle morphology, including the sizes of silicle valves and wings (31). In this study, we first sequenced and assembled genomes of the two Pugionium species and then assessed the genomic changes that had taken place during the ancestral adaptation of the genus to the desert environment. Next, we examined the genomic divergence of both species at the population level to investigate how speciation might occur in the desert.

The contrasted habit and morphology of the two Pugionium species and genomic structure of P. cornutum. (A) Morphological and habitat divergence of the two species (1, 2, and 3 for P. cornutum and 4, 5, and 6 for P. dolabratum) on the basal branching and stem height, leaf (lobe width), silique morphology (valve and wing length and angle ), and habitat (mobile and fixed dunes). (Scale bar: 1 cm.) (B) Collinearity within the P. cornutum genome. Color-coded lines in the middle (1) show gene synteny between chromosomes. Histograms from inside to outside show frequencies of tandem repeats (2), LTR/Gypsy retrotransposons (3), LTR/Copia retrotransposons (4), overall repetitive contents (5), and densities of genes (6), respectively.

Our examination of DAPI-stained mitotic chromosome spreads revealed 11 chromosome pairs (2n = 22) in both Pugionium species (SI Appendix, Fig. S1). The genome sizes were estimated to be 570 and 606 Mb for P. cornutum and P. dolabratum, respectively (SI Appendix, Figs. S2 and S3). A high-quality reference genome of P. cornutum was obtained with 81.3 Gb (143x) Nanopore long reads and 44.7 Gb (78x) short reads (SI Appendix, Table S1). With the aid of the chromosome conformation capture technique (SI Appendix, Fig. S4), the genome of P. cornutum was further assembled into 11 chromosomes (Fig. 1B and SI Appendix, Fig. S5). The resulting assembly of P. cornutum was 550 Mb, with a scaffold N50 of 37.1 Mb and a contig N50 of 311.7 kb (SI Appendix, Table S2). For P. dolabratum, 211 Gb (356x) short reads and 10.7 Gb (18x) Pacbio long reads were used to de novo assemble the genome into large scaffolds, with scaffold N50 being 357.8 kb and contig N50 being 68.4 kb (SI Appendix, Tables S3 and S4). We assessed the quality of genome assemblies using RNA sequencing (RNA-seq ) data obtained from roots, stems, leaves, and flowers (SI Appendix, Table S5). The results showed that most coding regions were well represented in the assemblies (SI Appendix, Table S6). Moreover, 97.9 and 97.4% of the 2,326 eudicot-specific BUSCO genes were identified in the genome assemblies of P. cornutum and P. dolabratum, respectively (SI Appendix, Table S7).

In total, 72.8 and 65.0% of the genome sequences were identified as repetitive elements for P. cornutum and P. dolabratum, respectively (Fig. 1B and SI Appendix, Tables S8 and S9), and the vast majority of repeats were classified as tandem repeats and long terminal repeat (LTR ) retrotransposons. An analysis of LTR retrotransposons indicated an increase in the activity during the last three million years (SI Appendix, Fig. S6). A total of 31,412 and 30,614 protein-coding genes were predicted for P. cornutum and P. dolabratum, respectively (SI Appendix, Table S10), and 27,982 (89.1%) of these genes were distributed on the assembled chromosomes of P. cornutum. In addition, most of these genes were successfully annotated by at least one public database (SI Appendix, Table S11), with complete BUSCO scores of 95.1 and 94.2% for P. cornutum and P. dolabratum, respectively (SI Appendix, Table S12), indicating near completion of both the assemblies and annotations.

Our comparative chromosome painting analyses based on cross-species hybridization, using BAC contigs specific to the chromosomes of Arabidopsis thaliana, suggested two copies of genomic blocks (GBs) in the Pugionium pachytene chromosome complements (SI Appendix, Fig. S7). This pointed to a potential WGD (tetraploidization) that had occurred during the origin of Pugionium. This WGD was further confirmed by genome collinearity and synonymous divergences of paralogous gene pairs within collinear blocks (Fig. 1B and SI Appendix, Figs. S8S11). Based on the divergence of paralogous gene pairs, this WGD was estimated to have occurred 18 Mya (SI Appendix, Fig. S9) when Lineages I and II diverged (30, 32) and was more recent than the family-specific At- WGD (43 Mya) (33). Phylogenetic analyses of different datasets were then performed to examine whether the tetraploidy arose from autopolyploidization or allopolyploidization. We first constructed gene trees using six species, that is, P. cornutum, Arabidopsis lyrata, Capsella rubella, Eutrema salsugineum, Schrenkiella parvula, and Aethionema arabicum, and assessed the pattern of gene tree topologies. For the 5,461 genes that were single copy in each of the six genomes, the placement of P. cornutum as sister to Lineage II was supported by 42.0% (bootstrap supports 70% ) of gene trees, while 17.8% (bootstrap supports 70%) placed P. cornutum sister to Lineage I plus II (SI Appendix, Fig. S12), suggesting a likely hybrid origin because of the high inconsistent tree topologies. Then, we carried out phylogenetic analyses of the two duplicate paralogs from the At- polyploidization and the possible homologs in Pugionium and Eutrema. Most duplicated homologs in Pugionium did not cluster into one monophyletic group as expected for autopolyploidization (SI Appendix, Fig. S12). Finally, 8,268 gene trees constructed based on homolog groups that contain one gene from A. arabicum and at least one homolog in all other genomes were used to perform multilabeled trees (MUL-trees) analysis, and the optimal MUL-tree also supported an allopolyploid origin of P. cornutum (SI Appendix, Fig. S13).

In order to further confirm allopolyploidization and uncover the origin of the two parental Pugionium (sub)genomes, the genome of P. cornutum was used to examine the association of GBs specific to previously defined ancestral Brassicaceae genomesancestral Proto-Calepineae Karyotype (ancPCK, n = 8) (29) and Proto-Calepineae Karyotype (PCK, n = 7) (27). The conserved association of blocks K-L and M-N on Pugionium chromosome 3 indicated that one parental (sub)genome was ancPCK-like (denoted as SG1, Fig. 2A and SI Appendix, Fig. S14). In contrast, the association K-L+Wa on Pugionium chromosome 9 pointed to a PCK-like (sub)genome (denoted as SG2). Despite the extensive postpolyploidization shuffling, these comparative analyses have collectively shown that the ancestral Pugionium genome originated through an allotetraploid WGD based on hybridization between ancPCK- and PCK-like genomes (Fig. 2A). This ancestral allopolyploid genome experienced an extensive postpolyploid diploidization, reducing the chromosome number from n = 15 to n = 11 (Fig. 2A). Among the 11 chromosomes in the Pugionium genome, five chromosomes remained conserved (chromosomes 1, 2, 6, 10 and 11), whereas the remaining six chromosomes were greatly reshuffled by translocations and inversions (Fig. 2A). Three chromosomes (3, 4, 7) showed high chromosomal structural variations as compared to the ancestral genomes.

The origin and postpolyploid evolution of the allotetraploid Pugionium genome. (A) The ancestral Pugionium genome presumably originated from hybridization between an ancPCK-like genome (n = 8, subgenome SG1) and a PCK-like genome (n = 7, subgenome SG2). Capital letters denote GBs and their associations important for inferring the ancestral (sub)genomes. (B) Phylogenetic tree for Pugionium and 11 other plants. A WGD was identified in Pugionium, paralleling independent mesohexaploidy events in Leavenworthia and Brassica. More changes in the numbers of gene family members apparently occurred in the ancestor of P. cornutum and P. dolabratum because of polyploidization than in the ancestor of E. salsugineum and Brassica rapa. (C) The seven phenylalanine ammonia-lyase (PAL) genes on three Pugionium chromosomes derived from allopolyploidization. (D) Collinear gene blocks between Pugionium and E. salsugineum indicate that genes of the PAL family from both ancestral parents were retained in Pugionium; other collinear genes are shown in yellow, and genes not in collinear blocks are displayed in creamy white.

According to their associated gene tree topologies, duplicated GBs in the genome of P. cornutum were partitioned into subgenomes SG1 and SG2 (SI Appendix, Figs. S15 and S16 and Table S13). Based on the modeled postpolyploidization interchromosomal rearrangements and loss of chromosomal segments (SI Appendix, Fig. S14), we identified a total of 10,985 and 14,936 protein-coding genes in the subgenome SG1 and SG2, respectively. Here, biased fractionation resulted in the preferential retention of genes from one parental genome (SI Appendix, Table S14). Based on these 14,936 genes, which were phylogenetically closer to Lineage II, the divergence time between subgenome SG2 and E. salsugineum was estimated to be 12 Mya. This suggests that the allotetraploid WGD recovered for Pugionium or with its related but unsampled genera should have occurred around this age or later. We then examined expression levels of the homeologous gene pairs in order to investigate the presence or absence of the subgenome dominance. Using RNA-seq data from different tissues, we found biased gene expressions between the two subgenomes with genes located in the subgenome SG2 having significantly higher expression than those from SG1 (SI Appendix, Figs. S17 and S18). In addition, around 42.0% of the homoeologous gene pairs were estimated to show at least twofold differentiated expressions between the two subgenomes (SI Appendix, Fig. S19).

We next determined gene families experienced expansion and contraction in the Pugionium genus based on annotated genomes of the two Pugionium species and other species from Brassicaceae (Fig. 2B and SI Appendix, Table S15). Out of the 2,466 gene families specifically expanded in Pugionium, 2,143 contained duplicated genes derived from WGD as determined by the presence of collinear blocks. Gene families expanded via WGD were enriched in multiple Gene Ontology categories related to organ developments and stress responses, including leaf development, root development, seed development, cellular response to salt stress, and response to light stimulus, while those expanded via tandem duplications were overrepresented in functional categories associated with root meristem growth, secondary metabolite biosynthetic process, and DNA (cytosine-5-)-methyltransferase activity (Datasets S1 and S2). We found that 40 out of 58 transcription factor gene families had expanded in Pugionium (SI Appendix, Table S16). Most of them are involved in responses to abiotic stress. For example, members of RAV and GRAS gene families were reported to respond to salty and cold stresses. In addition, we found that gene families related to ionic and osmotic equilibrium (CIPK and CDPK), drought tolerance (ABF and DREBs), and lignin biosynthetic pathway (PAL and MSBP) were also expanded within Pugionium (Fig. 2 C and D and SI Appendix, Figs. S20S22 and Tables S17S19). Expansions of these gene families should have supplied genetic foundations for this genus to adapt to the challenging habitats. In addition, we also found that genes located in the subgenome SG2 showed higher expression levels than those in SG1 in these gene families, which further confirmed that the biased gene expression played a likely role for plant adaptation during diploidization after allopolyploidization (SI Appendix, Table S18).

In addition to morphological differentiation (Fig. 1A), two Pugionium species appear to show local adaptation to different microhabitats (SI Appendix, Figs. S23S26 and Tables S20S23) as found for other closely related desert plants (34). To explore the genetic basis of the divergence, we conducted whole-genome resequencing of five populations (a total of 20 individuals) for each species (Fig. 3A and SI Appendix, Table S24). The linkage disequilibrium of both species decayed to half maximum within 5 kb (Fig. 3B). The principal component (PC) analysis distinguished the two species along PC1 (variance explained 19.1%, TracyWidom P = 3.0 1013; Fig. 3C), and our population structure analysis similarly revealed two distinct genetic clusters (Fig. 3D and SI Appendix, Fig. S27). We then evaluated four models of speciation, that is, strict isolation, isolation with migration, isolation after migration, and secondary contact (SI Appendix, Fig. S28 and Table S25), using a composite likelihood approach. The best-fit model suggested that two Pugionium species diverged with a continuous gene flow (SI Appendix, Table S26) around 1.65 Mya (Fig. 3E), suggesting sympatric or parapatric speciation through microhabitat selections.

Population structure and interspecies divergence of Pugionium. (A) Locations of 10 sampled populations. (B) Linkage disequilibrium decay based on the squared correlation coefficient between SNPs in P. cornutum and P. dolabratum populations. (C) Results of the PC analyses of SNPs within the two species. (D) Population structure of all sampled individuals of the two species (with K = 2 as the best inferred value). (E) The best-fit demographic divergence of the two species modeled by fastsimcoal2. Effective population sizes, divergence time and estimates of gene flow between species are displayed on the schematic plot. MYA, million years ago. (F) Manhattan plots of FST, dXY, , and between and within the two Pugionium species using a 50-kb nonoverlapping window. Genomic regions of high divergence in 11 chromosomes (Top) and genes under selection in those regions on chromosome 4 and 7 (Bottom) are highlighted in red. Pco, P. cornutum; Pdo, P. dolabratum.

We identified a total of 42 genomic regions (50 kb in size) in assembled chromosomes of P. cornutum that exhibited high divergence between P. cornutum and P. dolabratum (i.e., upper 1% of the empirical FST distribution) (SI Appendix, Table S27), which also had significantly elevated dXY compared to other genomic regions (P = 2.1 1013, MannWhitney U test; Fig. 3F). Out of these 42 regions, 27 and 15 were identified in subgenome SG1 and SG2, respectively, without biased distributions (P = 0.06) (Fig. 3F and SI Appendix, Table S27). However, 86% of these regions were found to be located on chromosomes 3, 4, and 7 (Fig. 3F), which were formed by recombination among multiple ancestral chromosomes (SI Appendix, Fig. S14). Genome-wide FST and dXY were positively correlated, especially for the three chromosomes (SI Appendix, Fig. S29). Furthermore, nucleotide diversity was found to be significantly lower in these regions for both P. cornutum (P = 5.3 1015) and P. dolabratum (P < 2.2 1016; Fig. 3F), suggesting that selection might have acted on these regions. A total of 236 genes were identified from these highly divergent regions, and the vast majority of these genes were found to be located on chromosome 4 (68.6%) and 7 (28.8%). The expression of some of these genes in four different tissues showed contrasting difference between the two species (SI Appendix, Figs. S30 and S31). Using a HudsonKreitmanAguad test, 197 of these genes were inferred to be under selection, and most of them were located in subgenome SG2 (SI Appendix, Table S28). Homologs of these genes were identified to be involved in root development (BDG1, KUA1, ABCB4, GH3.9), leaf morphogenesis (AS2, KUA1, FL6, GRF3), xylem differentiation (LHL3), seed germination and seedling development (NAC25, MED7B, STM), salt tolerance (BHLH112, GolS1, TSPO), drought resistance (BDG1, PUB23), oxidative stress response (NUDT2), and flavonoid biosynthesis (MYB12) (Fig. 3F). The two Pugionium species have distinct differences in morphology and habitat, with P. cornutum only occurring on mobile dunes, whereas P. dolabratum is distributed in fixed or semifixed deserts (Fig. 1A). They displayed contrasting patterns in seed germination speed and growth rate in response to salinity stress and desert burials (SI Appendix, Figs. S23S26 and Table S23). Therefore, the divergence selection of those genes might be responsible for morphological differentiation of root, shoot, and leaf and further contributed to local adaptation of the two Pugionium species to different microhabitats.

To further test whether copy number variations of specific gene families between the two species contributed to speciation, we used the two de novo genomes to identify the genes of three amino acid loop extension (TALE) and histidine kinases (HKs) gene families, members of which were revealed to have crucial functions in regulating various development processes and responses to abiotic stress in plants (SI Appendix). Compared to other Brassicaceae species, these families were expanded in both Pugionium species but with interspecific copy number variations between them (SI Appendix, Figs. S32 and S33 and Table S29). In the TALE gene family, we found that P. dolabratum contained more copies for BLH11, KNAT2, and KNAT6 compared with P. cornutum. The BLH11 ortholog from Medicago truncatula (PINNA1) was identified as a determinacy factor during leaf morphogenesis (35). In Arabidopsis, KNAT2 and KNAT6 were also confirmed to play essential roles in regulating proximaldistal development of leaves by the repression from AS2 (36), which was also found to have experienced positive selection in the two Pugionium species (SI Appendix, Table S28). For the HKs gene family, more homologic copies were detected in P. cornutum for AHK2 and AHK4, which encode two cytokinin receptors involved in shoot and root development, as well as tolerance to salt and drought stress (3739). In addition, expression divergence of these gene copies was also detected between the two species (SI Appendix, Figs. S32 and S33). Thus, the copy number variations in these gene families may also have contributed to the morphological divergences between the two species as well as the respective adaptations to mobile and stable desert dunes.

Based on comparative chromosome painting analyses (SI Appendix, Fig. S7) and divergence distributions of the paired paralogs, we inferred the occurrence of a WGD presumably specific to the genus Pugionium and clear postpolyploid chromosomal structural variation. Further analyses suggested that this WGD probably involved allopolyploidization rather than autopolyploidization and occurred around 12 Mya or later, postdating the divergence of two ancestral parental lineages (n = 8 and 7, respectively; Fig. 2A) 18 Mya. Similar allopolyploidizations, involving ancPCK- and PCK-like parental genomes, were previously reported in the genus Ricotia (n = 13 and 14) (40) and Lunaria (n = 14) (41). However, the ancestral allopolyploid Pugionium genome experienced more extensive descending dysploidy (from n = 15 to n = 11) during its postpolyploid diploidization, associated with the origin of three highly rearranged chromosomes (Fig. 2A). The allopolyploid origin of Pugionium seems to have facilitated its survival through adaptation to the changing environments of northwest China during their desertification since the early Miocene (21, 42). Inter alia, gene families involved in drought tolerance, ionic and osmotic equilibrium, and lignin biosynthesis expanded in the Pugionium genomes significantly (SI Appendix, Fig. S20 and Table S17).

Genomic evidence indicates that the two species started to diverge around 1.65 Mya, during the Quaternary, when a global increase in aridity (20, 43, 44) might have led to the development of contrasting desert microhabitats, mobile and fixed dunes, thereby promoting the initial divergence of the two species through microhabitat adaptation with parapatric or sympatric distribution. This hypothesis is corroborated by our speciation modeling of joint site frequency spectra across the total genome, which suggests the occurrence of continuous and strong gene flow through their evolutionary divergence history. We further found that the high-divergence regions in the Pugionium allopolyploid genome were mainly distributed on three chromosomes with most structural variations generated by translocation-based reshuffling during postpolyploidization diploidization. In addition to copy number variations of gene families, genes with positive selection signals in these regions are highly involved in root development, leaf morphogenesis, and microhabitat adaptation (seed germination and dry/salt tolerance), corresponding well with interspecific divergences in these respects (SI Appendix, Tables S21 and S23). Therefore, our results suggest that polyploidy-driven chromosomal structural variation may have played an important role in subsequent speciation and further extensive diversification (45) in addition to well-known rapid differentiations of the duplicated genes and novel genic interactions (46).

Mitotic chromosome spreads were used primarily for chromosome counting and pachytene spreads for comparative chromosome painting analysis. Long reads were generated using GridION and PacBio RS II. Paired-end and mate-pair short reads were generated using the MGISeq 2000 and Illumina HiSeq platforms. Genomes were assembled using MaSuRCA. Transposable elements were identified using Tandem Repeats Finder, RepeatMasker, RepeatModeler, and LTR_Finder. Genes were predicted using AUGUSTUS, GlimmerHMM, PASA, Exonerate, and EVidenceModeler. Collinear gene blocks were identified with MCscanX. Synonymous substitution rates were calculated using PAML. Following genome alignments and chaining by LASTZ, GRAMPA was used to determine the likeliest mode of polyploidy. Gene expression levels were estimated using Salmon and DESeq. Clean reads from population data were mapped to the P. cornutum genome using the bwa-men algorithm. Genome-wide single nucleotide polymorphisms (SNPs) were called by GATK. ADMIXTURE and Eigensoft were used for population structure analysis. Coalescence-based simulation of speciation patterns was performed in fastsimcoal2. The interspecific reproductive isolation within the genus, and differences between the two species in microhabitat adaptation, were experimentally confirmed at desert sites. Detailed information on all the experimental and analytical procedures is available in SI Appendix.

The whole-genome sequencing data, transcriptome sequencing data, and genome assemblies have been deposited in the National Center for Biotechnology Information Sequence Read Archive (https://www.ncbi.nlm.nih.gov/sra) under accession numbers PRJNA685118 and PRJNA760666.

This work was equally supported by the Second Tibetan Plateau Scientific Expedition and Research program (2019QZKK0502), the National Natural Science Foundation of China (91731301, 91331102, and 41771055), and also the Fundamental Research Funds for the Central Universities (SCU2021D006 and 2020SCUNL207). T.M. and M.A.L. were supported by the Central European Institute of Technology 2020 project (LQ1601).

Author contributions: Q.H., Z.X., E.N., and J.L. designed research; Q.H., Y.M., T.M., S.S., L.Z., Q.Y., D.W., and M.A.L. performed research; Q.H., Y.M., T.M., S.S., C.C., P.S., L.F., Y.Z., X.F., W.Y., J.J., T.L., P.Z., and M.A.L. analyzed data; and Q.H., T.M., M.A.L., Z.X., E.N., and J.L. wrote the paper.

Reviewers: M.A.B., The University of Arizona; and L.L., Fudan University.

The authors declare no competing interest.

This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2025711118/-/DCSupplemental.

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