Category Archives: Gene Medicine

Scientists at the University of Virginia (UVA) School of Medicine have developed a promising gene therapy to target the mutation behind a severe form of epilepsy.

The new Dravet syndrome treatment could help improve and extend the lives of people with the rare but debilitating disease.

The challenge: People born with Dravet syndrome start experiencing seizures when theyre still infants. Seizures continue throughout their lives and often lead to a host of health problems severe developmental delays, speech impairments, intellectual disability, and movement difficulties.

There is no cure for Dravet syndrome, and 10-20% of children born with it die before reaching adulthood.

Certain diets, medications, and therapies can help reduce the frequency and severity of seizures, but patients still require constant, lifelong care.

Between 10% and 20% of children born with Dravet syndome die before reaching adulthood.

The idea: In more than 80% of cases, people with Dravet syndrome have a mutation in a particular gene (called SCN1A) that results in reduced production of a critical protein in the brain.

This leads to a shortage of that protein in specialized brain cells, called interneurons, that protect against seizures.

No existing Dravet syndrome treatment directly addresses the underlying cause of the disease so the UVA team decided to make one that does.

The Dravet syndrome treatment: Dravet is usually caused by a single random mutation, but people generally carry two copies of every gene. The researchers aimed to use the second intact gene to treat the disease.

The treatment completely prevented seizures and premature death in infant mouse models of Dravet.

Using an approach they call Targeted Augmentation of Nuclear Gene Output (TANGO), the scientists developed a Dravet syndrome treatment that prompts the intact gene to increase protein production.

When tested in mouse models of Dravet syndrome, the treatment completely prevented seizures and premature death in infant mice.

The animals interneurons were more responsive, more active, and better able to do their jobs, according to a press release.

The big picture: Therapies that work in mice often fail in humans, but early results in human trials suggest this Dravet syndrome treatment has a shot.

More than 70% of children with Dravet in an ongoing phase 1/2A study experienced a reduction in seizure frequency following treatment, according to Stokes Therapeutics, the company developing the drug.

That study was small, with just 21 participants so far, and these are interim results, so its still too early to say whether the therapy (called STK-001) will ultimately make it to patients.

Still, if the results hold up in larger trials, the new treatment could help people with Dravet syndrome live longer, healthier lives.

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Gene therapy shows promise at treating severe form of epilepsy - Freethink

Shares of Mustang Biohave fallen more than 13% in premarket trading after the company announced the U.S. Food and Drug Administration had placed a hold on the companys Investigational New Drug application for its bubble boy gene therapy.

The Worcester, Mass.-based company said the regulatory agency placed a hold on the planned Phase II study pending Chemistry, Manufacturing and Controls (CMC) clearance for MB-207, Mustangs lentiviral gene therapy. Mustang intended to initiate a pivotal Phase II study to assess the gene therapys safety, tolerability, and efficacy as a potential treatment forX-linked severe combined immunodeficiency (XSCID), also known as bubble boy disease. The study would include patients who have been previously treated with a hematopoietic stem cell transplantation.

MB-207 has previously been granted Orphan Drug and Rare Pediatric Disease designations by the FDA, makingthe asset eligible for a rare pediatric disease voucher.

In addition to the planned MB-207 Phase II study, Mustang is conducting a Phase I/II XSCID study in newly diagnosed infants under the age of two with MB-107. Like MB-207, MB-107 has also been granted Rare Pediatric Disease, Orphan Drug and Regenerative Medicine Advanced Therapy designations.

Manuel Litchman, M.D., president and chief executive officer of Mustang Bio, said the company hopes to efficiently expedite the development of both MB-2017 and MB-107. He said they believe they are well positioned to address the FDAs CMC concerns.

While Mustangs gene therapy trial is temporarily prohibited from the beginning, the FDA did clear several other companies requests to begin clinical studies.

Mind Medicines LSD Formulation Moves into Phase IIb

New York-based Mind Medicines IND for a Phase IIb study of MM-120 for treatinggeneralized anxiety disorder (GAD) was given the go-ahead by the FDA. That trial had been on hold,but the hold was recently lifted after Mind Medicines address of participant monitoring protocols for the upcoming study. The Phase IIb trial is expected to begin later this year.

The company expects to enroll a total of 200 participants who will receive a single administration of up to 200 g of MM-120 or placebo. The study's primary endpoint is the reduction in anxiety symptoms for up to 12 weeks following a single administration of MM-120, a pharmacologically optimized form of LSD.

Imara Inc. Will Begin Cardiac Study in Second Quarter

Bostons Imara Inc. will begin assessing tovinontrine (IMR-687) in a Phase II studyto treatheart failure with preserved ejection fraction (HFpEF). The clinical trial is expected to begin in the second quarter of 2022. The trial will evaluate tovinontrine in approximately 170 patients 45 years of age or older with persistent HFpEF symptoms. The primary endpoint of the study will be change in NT-proBNP, with secondary endpoints that include safety and tolerability and the quality of life measures.

Tovinontrineis a highly selective and potent small-molecule inhibitor of phosphodiesterase-9 (PDE9).

Nanoscope Therapeutics Heads into Phase II with Stargardt Therapy

Texas-based Nanoscope received IND clearance from the FDA for a Phase II study of its Multi-Characteristic Opsin (MCO-010) ambient-light activatable optogenetic monotherapy. MC)-010 is being assessed as a gene therapy to restore vision in Stargardt patients. Stargardt, an inherited retinal disease, is a form of macular degeneration affecting children and adults.

Nanoscopes MCO-010 gene therapy reprograms healthy retinal cells to make them photosensitive. It uses proprietary AAV2 vectors. The Phase II trial is expected to begin in the first half of 2022.

Nanoscope is currently conducting a PhaseIIbstudy of MCO-010 for retinal pigmentosa (RP) patients. MCO-010 has received orphan drug designations from the FDA for RP and Stargardt.

SwanBio Takes Rare Disease Gene Therapy into the Clinic

Philadelphia-based SwanBiosgene therapy for the treatment of adrenomyeloneuropathy (AMN) has been cleared for a Phase I/II study. SwanBios lead candidate SBT101 is the first AAV-based gene therapy in development designed to compensate for the disease-causing ABCD1 mutation in AMN patients.

Adrenomyeloneuropathy is the adult-onset degenerative spinal cord disease that affects people with adrenoleukodystrophy, a rare, genetic and metabolic condition. The Phase I/II study will assess the safety and efficacy of the gene therapy. It is expected to begin in the second half of 2022.

Preclinical data shows that treatment with SBT101 demonstrated dose-dependent improvement of AMN disease markers in animal models. The gene therapy was also well-tolerated in non-human primates at six months post-treatment. The company said the SBT101 program builds on its ongoing natural history study of AMN.

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FDA Pulls on the Reins for Mustang's Gene Therapy as Others Advance - BioSpace

image:The Blood Proteoform Atlas (BPA) compiles ~56,000 proteoforms identified from 21 human cells types and plasma view more

Credit: Please credit Kelleher and Levitsky labs at Northwestern University

Northwestern University scientist have discovered families of proteins in the body that could potentially predict which patients may reject a new organ transplant, helping inform decisions about care.

The advancement marks the beginning of a new era for more precise study of proteins in specific cells.

Scientists tend to look at shifting patterns of proteins as if through goggles underwater, taking in just a fraction of available information about their unique structures. But in a new study to be published January 27 in the journal Science, scientists took a magnifying glass to these same structures and created a clarified map of protein families. They then held the map up in front of liver transplant recipients and found new indicators in immune cell proteins that changed with rejection.

The result, the Blood Proteoform Atlas (BPA), outlines more than 56,000 exact protein molecules (called proteoforms) as they appear in 21 different cell types almost 10 times more of these structures than appeared in similar previous studies.

Scratching the surface of potential

Were working to create the protein equivalent of the Human Genome Project, said Neil Kelleher, a leading expert in proteomics and co-corresponding author of the paper. The BPA is a microcosm of that, including a specific-use case.

Kelleher is the Walter and Mary Glass Professor of Molecular Biosciences and professor of chemistry in NorthwesternsWeinberg College of Arts and Sciencesand a professor of medicine inNorthwestern University Feinberg School of Medicine.He is also the director of theChemistry of Life Processes Institute(CLP) and faculty director ofNorthwestern Proteomics, a center of excellence within CLP that develops novel platforms for drug discovery and diagnostics.

Each human gene has at least 15 to 20 unique forms of processed proteins (proteoforms). And with 20,300 individual genes in the human body, there are millions of proteoforms created by genetic variation, modification or splicing. Kelleher said with a complete roadmap of each genes family of proteinsthe goal of a major science initiative known as the Human Proteoform Project discoveries about disease, aging and new therapeutics will accelerate.

The Kelleher lab uses state-of-the-art mass spectrometry and data analysis to identify proteofoms in cells and blood efficiently, keeping proteoforms intact in a form of top-down analysis rather than cutting them up into tiny pieces as with the industry standard.

Were starting to see the complexity, he said. In this paper, we demonstrate patient-, cell type- and proteoform-specific measurements, which allows us to get to better biomarkers.

A blood test for liver transplant rejection

Having team members across disciplines allows the project to conceptualize a move from lab bench to bedside. As Kelleher probes the scientific basis for phenomena in the cell, co-corresponding author and Northwestern Medicine transplant hepatologist Josh Levitsky works with him to understand how these could be applied to a specific system.

Levitsky, professor of medicine, surgery and medical education at Feinberg, originally connected with Kelleher through his leadership in the biomarkers space, in which measurable signs in the blood are used to predict health metrics in patients facing disorders and in this instance, liver transplant rejection.

It was really important for Neil that there was a biologically relevant example to contextualize how these proteoform panels can identify diseases non-invasively as markers, Levitsky said. And theres also a need in my field to have mechanistic biomarkers that are more relevant to their immune biological pathways. This could be the start of a new era in cell-specific markers.

Physicians must suppress the immune system with drug therapy and monitor liver transplant recipients for signs of rejection, often only responding after an episode has begun. Guesswork throughout this process could be eliminated with specific knowledge about whats happening at the most granular level.

With the BPA as a reference map, the team took blood samples from participants in one of Levitskys biomarker collection studies. They examined which proteoforms seemed to activate in response to the transplant and identified those that changed compared to patients without rejection.

Next, the Levitsky and Kelleher team developed a panel of 24 proteoforms from the initial study and looked at them in transplant recipient samples from across the country. They found the same proteoforms lit up as in the first trial.

Moving the field forward

The promise here is to be able to use this panel moving forward to be able to identify patients who have no signs of rejection versus those who have very early evidence of rejection, Levitsky said. If we can pick up on this several weeks before rejection actually happens, we might be able to modify immunosuppression.

Levitsky continues to examine how proteoforms change in transplant recipients over time to develop additional biomarkers that may inform how he treats patients down the line. Kelleher said as the number of cell types in the atlas grows, so too will potential ways to use it. In addition to broadening understandings of human biology, the BPA could have similar applications across immune disorders.

The study, The Blood Proteoform Atlas: A reference map of proteoforms in human hematopoietic cells, was conducted across six institutions with 26 scientists. Rafael D. Melani, a research assistant professor in the Kelleher Group, was the first author of the paper, along with Vincent R. Gerbasi, also from Northwestern, and Lissa C. Anderson from Florida State University.

The research was supported by the National Institute of General Medical Sciences of the National Institutes of Health (award numbers: P41 GM107569, R21LM013097, T32 GM105538 and R21 AI135827), the Human Biomolecular Atlas Program (award number: UH3 CA246635-02), Paul G. Allen Frontiers Program Award (award number 11715), the Knut and Alice Wallenberg Foundation grant (2016.0204) and the Swedish Research Council grant (2017-05327). Work performed at the National High Magnetic Field Laboratory is supported by the National Science Foundation Division of Materials Research and Division of Chemistry and the State of Florida.

The Blood Proteoform Atlas: A reference map of proteoforms in human hematopoietic cells

28-Jan-2022

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

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Researchers identify proteins that could predict liver transplant rejection - EurekAlert

A Phase 2 trial can begin investigations on MCO-010 gene therapy as treatment for patients with Stargardt disease. The multi-characteristic opsin ambient-light activatable optogenetic monotherapy may restore vision in patients with this rare macular degeneration.

The developer of MCO-010, Nanoscope Therapeutics Inc, announced that it received investigational new drug (IND) clearance from the US Food and Drug Administration (FDA).

The trial is expected to start in H1-2022. MCO-010 is designated as an orphan drug by the FDA for Stargardt disease and retinitis pigmentosa (RP).

The clincal-stage biotechnology company is currently conducting a Phase 2b multicenter, randomized, sham-controlled, double-masked study of MCO-010 for patients with retinitis pigmentosa.

Retinitis pigmentosa is a group of rare, genetic disorders associated with difficulty seeing at night and the inability to see peripherally due to the breakdown and loss of cells in the retina.

Stargardt is an inherited rare disease that affects children and adults. As a result of this retinal disease, photoreceptors in the eye degenerate. MCO-010 gene therapy makes them photosensitive by reprogramming the healthy retinal cells.

MCO-010 is a single intravitreal injection administered in a medical office setting. Proprietary AAV2 vectors deliver the MCO genes to the cells where they express polychromatic opsins and enable vision.

Patients with Stargardt and retinitis pigmentosa can utilize this therapy regardless of underlying gene mutations.

"Presently allexisting trialsattemptto slow down the progressionof vision loss in patients with Stargardt disease, Optogenetic approach is to restore vision. Thiscan bea groundbreaking attempt to evaluate optogenetic gene therapyto improve vision inStargardt patients. I'm excited by the potential MCO-010 has to restore vision for many patients with sight loss caused by outer retinal dystrophies including dry age-related macular degeneration," David Boyer, MD, Retina-Vitreous Associates Medical Group, adjunct clinical professor of ophthalmology, Keck School of Medicine, University of Southern California said in a statement.

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FDA Clears MCO-010 Gene Therapy as IND for Stargardt Macular Degeneration - MD Magazine

BEIJING & CAMBRIDGE, Mass.--(BUSINESS WIRE)--EdiGene, Inc., a global biotechnology company focused on translating gene-editing technologies into transformative therapies for patients with serious genetic diseases and cancer, announced a research and development collaboration with Haihe Laboratory of Cell Ecosystem to develop hematopoietic stem cell regenerative therapies and platform technology by combining resources and expertise from both sides.

The Haihe Laboratory of Cell Ecosystem, run by the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, is focused on conducting fundamental research, innovation, and translation in the cell ecosystem.

Under the agreement, both parties will jointly develop hematopoietic stem cell regenerative therapies, including the development of innovative genetically-modified hematopoietic stem cell therapies and the exploration of novel biomarkers to optimize quality control for stem cell production.

With top-notch resources and industry-university-research cooperation, well facilitate the development of cell-based medicine and therapies, said Professor Tao Cheng, Deputy Director of Haihe Laboratory of Cell Ecosystem and President of the Institute of Hematology and Blood Diseases Hospital at the Chinese Academy of Medical Sciences and Peking Union Medical College, a leading hematology researcher who has made a series of discoveries relating to the regulatory and regenerative mechanisms of hematopoietic stem cells. Hematopoietic stem cells (HSCs) have the potential for long-term self-renewal and can differentiate into various types of mature blood cells. These stem cells can be harnessed to provide treatment for a broad range of diseases such as hematological tumors, autoimmune diseases, and hereditary blood disorders. We believe that this collaboration with EdiGene will accelerate the innovation and translation in the field of HSCs, thus enabling healthier patients with new therapies."

Professor Cheng was awarded the second prize of the National Natural Science Award 2020 as the first author of work on basic and translational research that advanced the development of adult hematopoietic stem cells for therapeutic applications.

EdiGene is scaling up clinical translation and development of the first gene-editing hematopoietic stem cell therapy in China following the 2021 approval by the China National Medical Products Administration its IND for its investigational therapy ET-01. Our team has extensive experience in the development and translation of cutting-edge technologies including hematopoietic stem cell and gene editing, said Dong Wei, Ph.D., CEO of EdiGene. "This collaboration with Haihe Laboratory of Cell Ecosystem will further our exploration in the field of hematopoietic stem cells. The partnership with this leading academic institute and our translational know-how enable us to move forward in bringing more innovative treatment options to patients in China and around the world.

In 2021, EdiGene initiated a Phase I multicenter clinical trial of ET-01, its gene-editing hematopoietic stem cell therapy for transfusion-dependent -thalassemia. EdiGene has enrolled the first patient at the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. Currently, the clinical trial is being conducted in Tianjin and Guangdong-Hong Kong-Macao Greater Bay Area (Greater Bay Area). EdiGene also presented its latest research on new surface markers and migration of hematopoietic stem cells at the 63rd Annual Meeting of the American Society of Hematology (ASH) in 2021.

About Haihe Laboratory of Cell Ecosystem

The Haihe Laboratory of Cell Ecosystem ("the Laboratory"), run by the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, is one of the five registered Haihe Laboratories approved by Tianjin Municipal People's Government. With the goal of promoting population health with cell ecosystem, the Laboratory adheres to developing technological frontier, enhancing peoples health, and promoting research, innovation, and development of cell ecosystem in five key areas: cellular ecosystem, cellular ecology and immunity, cellular ecological imbalance and major diseases, cellular ecological reconstruction and frontier technology of cellular ecological research.

About Institute of Hematology and Blood Diseases Hospital (IH), Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS/PUMC)

Founded in 1957, IH is a tertiary specialty hospital under the National Health Commission of China and is the supporting unit of the National Clinical Research Center of Hematologic Diseases and the State Key Laboratory of Experimental Hematology. It is also the main founding unit of Tianjin Base, the core base of the Chinese medical science and technology innovation system with the goal of becoming "the innovation hub of hematology in China." IH mainly engages in basic research, applied research, clinical diagnosis and treatment of hematological diseases, standard-setting, new technology research, new drug evaluation, and translation in hematology and related fields. IH is leading in the diagnosis and treatment of hematological diseases in China and a global scale and has made original achievements. Since 2010, IH has been awarded first place in the Hospital Specialty Reputation Ranking (Hematology) for 12 consecutive years. It has won first place in the Hematology Specialty Ranking for ten consecutive years since 2010 and ranked the first in hematology by the Scientific and Technological Evaluation Metrics (STEM) for Chinese hospitals for eight consecutive years since 2014.

About EdiGene, Inc

EdiGene is a global, clinical-stage biotechnology company focused on translating gene editing technologies into transformative therapies for patients with serious genetic diseases and cancer. The company has established its proprietary ex vivo genome-editing platforms for hematopoietic stem cells and T cells, in vivo therapeutic platform based on RNA base editing, and high-throughput genome-editing screening to discover novel targeted therapies. Founded in 2015, EdiGene is headquartered in Beijing, with offices in Guangzhou and Shanghai, China and Cambridge, Massachusetts, USA. More information can be found at http://www.EdiGene.com.

More here:
EdiGene Enters Strategic R&D Collaboration with Haihe Laboratory of Cell Ecosystem to Develop Hematopoietic Stem Cell Regenerative Therapies and...

The 2021 Nobel Prize in physiology or medicine was awarded to David Julius and Ardem Patapoutian for their discoveries of receptors that sense temperature and pressure, work that exemplifies how difficult research can be. Through hundreds of mice, tens of thousands of cells and millions of bacterial colonies, the research groups that made the winning discoveries persisted in asking important questions about how the brain detects its surroundings.

Researchers in Julius and Patapoutians labs who made key discoveries at the bench worked through many technical problems and disappointments in pursuit of the molecules behind sensation. The Secret History of Touch tells five stories of their persistence. Here is the fourth.

COURTESY OF THE NOBEL FOUNDATION

A schematic shows how Bertrand Coste used patch-clamp electrophysiology to discover piezo1, applying a mechanical force to a cell while also measuring current (top line). Later experiments showed that the protein is a channel that opens in response to mechanical forces against a nearby membrane.

In the mid-2000s, Ardem Patapoutian, known for his studies of temperature sensitive ion channels called TRPs, wanted to transition into studying mechanotransduction.

Patapoutian did not have time for an interview for this story, but in an email, he wrote, After studying temperature sensation for 10 years, it was a natural transition to ask how mechanical force is sensed.

Like the search for the cold receptor, it was another risky question, fraught with the possibility of failure. Sanjeev Ranade, who joined Patapoutians lab as a graduate student to study thermosensation, said, Many labs had been looking for the identity of the gene or genes that allow us to sense touch. Many labs were not successful in finding these genes.

Courtesy of the Nobel Foundation

A schematic shows how Bertrand Coste used patch-clamp electrophysiology to discover piezo1, applying a mechanical force to a cell while also measuring current (top line). Later experiments showed that the protein is a channel that opens in response to mechanical forces against a nearby membrane.

So when physiologist Bertrand Coste joined the lab as a postdoc to search for the protein that lets human neurons sense pressure, Ranade said, It was one of those almost I cant believe youre doing this kind of projects.

Like Makoto Tominaga in David Julius lab, Coste was an experienced electrophysiologist who came to a new lab in California with a reputation for receptor hunting and immediately began to build a new electrophysiology rig. He had studied mechanosensory neurons as a graduate student and was skilled at recording from a neuron with an electrode while gently prodding it with a tiny glass probe a technique that few others in the world used.

Recording these mechanically activated currents naturally pushed me to the question of what are the ion channels that are involved in this activity, Coste said. Patapoutians lab, which lately had cloned TRPA1 and TRPM8, struck him as the ideal environment to try to answer the question.

Coste initially planned to sift through the DRG to find neurons that respond to mechanostimulation and then extract their RNA and screen for the genes governing pressure sensation. But pilot experiments made it clear that the strategy was impractical. So he took a different approach: He tested as many cell lines as he could lay hands on, looking for one that would respond to pressure by depolarizing. With immortalized cell lines you have endless materials, he said. Its easy to use, and every cell is a clone of the other cells.

Scripps Research Institute

From left, Bertrand Coste, Ardem Patapoutian, Bailong Xiao and Seung Eun Kim when Coste and Xiaos paper and Kims paper were published together in Nature in 2012.

Coste found a neuroblastoma line that fit the bill and winnowed down its list of highly expressed genes to the most interesting candidates: transmembrane proteins with unknown function that shared some characteristics with ion channels.

That left a list of dozens of genes. Coste began to use siRNA to knock them down one at a time and then prodded the altered cells, watching for one that would fail to respond to mechanical stimulation. Electrophysiology is highly reliable but also very slow. He averaged about two candidate genes a week, and, for a year or more, every single candidate he tested had no effect on the cells response. Not making progress can be tough. A few months in, after many trials and no success, Coste said, My mood was declining very fast.

We are scientists. We like to think, to problem solve, he said. While planning the screen and working around the technical issues, hed had a chance to solve problems. But the screen itself was very repetitive. Coste brought the problem to Patapoutian, explaining that even though he was excited about the possible results of the project, the mindless grind of doing the same experiment over and over again and getting no result was difficult. Patapoutian, according to Coste, was understanding; he assigned a technician to help and suggested a second, more tractable project he could work at on the side. I was relieved of doing every day the same thing, every day having negative results, Coste said.

Scripps Research Institute

A structure of the piezo channel

Finally, after ruling out 72 candidate genes, Coste found an siRNA that blunted the cells response to mechanical stimulation. Ranade said, They could have easily quit at 72, and said, OK, its been a year, we have nothing. And yet, they found it at 73.

The gene was mysterious, but it was large, with an estimated 24 to 36 transmembrane domains. Besides controlling the neuroblastoma cells mechanical response, when cloned into mechanically inert cells, it made them sensitive. The team dubbed it Piezo, after the Greek word for pressure, and soon found that mice have two closely related Piezo proteins.

Coste said characterizing the channel was exhilarating: After one year of screening every experiment you do is telling you something interesting on the activity of this channel.

Coste and many colleagues in the Patapoutian lab would go on to show that Piezo1 and Piezo2 play integral roles in mammals sense of touch and many other physiological functions. Even before that, Ranade said, it was clear that the finding was important. Every single one of us in the lab, when Bertrand found Piezos, we all kind of knew that he struck gold.

What keeps researchers going through failure after failure? ASBMB Today asked psychologist Ayelet Fishbach, who studies motivation, work and learning from failure.

Fishbach and colleagues recently published a study investigating work-related one-time failures. After taking a two-option multiple choice quiz, Fishbach and colleagues found, participants who had received negative feedback performed worse on a follow-up quiz than those who had received positive feedback.

Although the study investigated one-time failure to guess an insignificant piece of information rather than the longer and more fraught process of research, Fishbach said that its conclusions reflect her own experience as a researcher and mentor.

There are two categories of problems with learning from failure, she said. Cognitively, it can be harder to learn from the unexpected than the expected and more difficult to seek out the reasons that a hypothesis missed the mark than to accept that it was correct. Getting people to pay attention to what didnt work is notoriously hard, she said.

The second category is emotional. It is easier to ignore a failure than to engage with it. And sometimes people especially those with relatively little expertise in a field learn the wrong lesson from failure, concluding that they are unable to execute the task at hand. Whats more, Fishbach said, Doing something with no sense of progress is psychologically hard. You can tell yourself that one day it will pay off, but its not today or yesterday or tomorrow. And people give up.

Much like David Julius, Fischbach said that social support, encouraging words and help with troubleshooting from others can help keep people motivated. But, Julius pointed out, Its not just me. They have to have their own gyroscope. He added that there are times when he has doubted the future of a project and has gotten inspiration from persistent trainees.

Michael Caterina and the capsaicin receptor

How the Julius lab found that an ion channel senses heatMakoto Tominaga, Toby Rosen and TRPV1 heat sensation

Nobelists postdoc searches for a receptor for mint and cold

Patapoutians postdoc unearths the powerful Piezo geneBertrand Coste and the pressure receptor

Nobelists lab pins down pressure sensing in miceSeung Hyun Woo, Sanjeev Ranade and Piezo2 in the sense of touch

The rest is here:
Bertrand Coste and the pressure receptor - American Society for Biochemistry and Molecular Biology

Genes and Gene Expression

The gene is the fundamental unit of inheritance and the ultimate determinant of all phenotypes. The DNA of a normal human cell contains an estimated 30,000 to 120,000 genes,4,5 but only a fraction of these are used (or expressed) in any particular cell at any given time. For example, genes specific for erythroid cells, such as the hemoglobin genes, are not expressed in brain cells. The identity of each gene expressed in a particular cell at a given time and its level of expression is defined as the transcriptome.

According to the central dogma of molecular biology, a gene exerts its effects by having its DNA transcribed into an mRNA, which is, in turn, translated into a protein, the final effector of the gene's action. Thus, molecular biologists often investigate gene expression or activation, by which is meant the process of transcribing DNA into RNA, or translating RNA into protein. The process of transcription involves creating a perfect RNA copy of the gene using the DNA of the gene as a template. Translation of mRNA into protein is a somewhat more complex process, because the structure of the gene's protein is encoded in the mRNA, and that structural message must be decoded during translation.

Every gene consists of several functional components, each involved in a different facet of the process of gene expression (). Broadly speaking, however, there are two main functional units: the promoter region and the coding region.

Gene expression. A gene's DNA is transcribed into mRNA which is, in turn, translated into protein. The functional components of a gene are schematically diagramed here. Areas of the gene destined to be represented in mature mRNA are called exons, and (more...)

The promoter region controls when and in what tissue a gene is expressed. For example, the promoters of the globin gene are responsible for their expression in erythroid cells and not in brain cells. How is this tissue-specific expression achieved? In the DNA of the gene's promoter region, there are specific structural elements, nucleotide sequences (see Structural Considerations below), that permit the gene to be expressed only in an appropriate cell. These are the elements in the globin gene that instruct an erythroid cell to transcribe globin mRNA from that gene. These structures are referred to as cis-acting elements because they reside on the same molecule of DNA as the gene. In some cases, other tissue type-specific cis-acting elements, called enhancers, reside on the same DNA molecule, but at great distances from the coding region of the gene.6,7 In the appropriate cell, the cis-acting elements bind protein factors that are physically responsible for transcribing the gene. These proteins are called trans-acting factors because they reside in the cell's nucleus, separate from the DNA molecule bearing the gene. For example, brain cells would not have the right trans-acting factors that bind to the -globin promoter, and therefore brain cells would not express globin. They would, however, have trans-acting factors that bind to neuron-specific gene promoters.

The structure of a gene's protein is specified by the gene's coding region. The coding region contains the information that directs an erythroid cell to assemble amino acids in the proper order to make the -globin protein. How is this order of amino acids specified? As described in detail below, DNA is a linear polymer consisting of four distinguishable subunits called nucleotides. In the coding region of a gene, the linear sequence of nucleotides encodes the amino acid sequence of the protein. This genetic code is in triplet form so that every group of three nucleotides encodes a single amino acid. The 64 triplets that can be formed by 4 nucleotides exceed the 20 distinct amino acids used to make proteins. This makes the code degenerate and allows some amino acids to be encoded by several different triplets.8 The nucleotide sequence of any gene can now be determined (see below). By translating the code, one can derive a predicted amino acid sequence for the protein encoded by a gene.

The basic repeating units of the DNA polymer are nucleotides (). Nucleotides consist of an invariant portion, a five-carbon deoxyribose sugar with a phosphate group, and a variable portion, the base. Of the four bases that appear in the nucleotides of DNA, two are purines, adenine (A) and guanine (G), and two are pyrimidines, cytosine (C) and thymine (T). Nucleotides are connected to each other in the polymer through their phosphate groups, leaving the bases free to interact with each other through hydrogen bonding. This base pairing is specific, so that A interacts with T, and C interacts with G. DNA is ordinarily double-stranded, that is, two linear polymers of DNA are aligned so that the bases of the two strands face each other. Base pairing makes this alignment specific so that one DNA strand is a perfectly complementary copy of the other. This complementarity means that each DNA strand carries the information needed to make an exact replica of itself.

Structure of base-paired, double-stranded DNA. Each strand of DNA consists of a backbone of 5-carbon deoxyribose sugars connected to each other through phosphate bonds. Note that as one follows the sequence down the left-hand strand (A to C to G to T), (more...)

In every strand of a DNA polymer, the phosphate substitutions alternate between the 5 and 3 carbons of the deoxyribose molecules. Thus, there is a directionality to DNA: the genetic code reads in the 5 to 3 direction. In double-stranded DNA, the strand that carries the translatable code in the 5 to 3 direction is called the sense strand, while its complementary partner is the antisense strand.

In eukaryotes, the coding regions of most genes are not continuous. Rather, they consist of areas that are transcribed into mRNA, the exons, which are interrupted by stretches of DNA that do not appear in mature mRNA, the introns (see ). The functions of introns are not known with certainty. A purpose of some sort is implied by their conservation in evolution. However, their overall physical structure might be more important than their specific nucleotide sequences, because the nucleotide sequences of introns diverge more rapidly in evolution than do the sequences of exons. Overall, DNA that contains genes comprises a minority of total DNA. Between genes, there are vast stretches of untranscribed DNA that are assumed to play an important structural role.

In the nucleus, DNA is not present as naked nucleic acid. Rather, DNA is found in close association with a number of accessory proteins, such as the histones, and in this form is called chromatin.9 Although many of DNA's accessory proteins have no known specific function, they generally appear to be involved in the correct packaging of DNA. For example, DNA's double helix is ordinarily twisted on itself to form a supercoiled structure.10 This structure must unwind partially during DNA replication and transcription.11 Some of the accessory proteins, for example, topoisomerases and histone acetylases, are involved in regulating this process.

Genes specify the structure of proteins that are responsible for the phenotype associated with a particular gene. While the nucleus of every human cell contains 30,000 to 120,000 genes, only a fraction of them are expressed in any given cell at any given time. The promoter (with or without an enhancer) is the part of the gene that determines when and where it will be expressed. The coding region is the part of the gene that dictates the amino acid sequence of the protein encoded by the gene. DNA is a linear polymer of nucleotides. Ordinarily, the nucleotide bases of one strand of DNA interact with those of another strand (A with T, C with G) to make double-stranded DNA. In the cell's nucleus, DNA is associated with accessory proteins to make the structure called chromatin.

Read more:
Overview: Gene Structure - Holland-Frei Cancer Medicine ...

BRAZIL - 2021/02/18: In this photo illustration a Bluebird Bio logo seen displayed on a smartphone. ... [+] (Photo Illustration by Rafael Henrique/SOPA Images/LightRocket via Getty Images)

Our theme of Gene Editing stocks remains down by about 11% year-to-date, considerably underperforming the S&P 500 which is up by a solid 23% over the same period. The theme would have actually declined by about 46% year-to-date if we exclude a single stock, Intellia Therapeutics, which is up by about 130% year-to-date. So why have gene-editing stocks lagged this year, and is a recovery looking likely in 2022? Lets take a look.

The markets have soured on high-growth and futuristic stocks amid an increasingly hawkish stance by the Federal Reserve, which is now planning as many as three interest rate hikes next year. Gene editing stocks have been hit particularly badly as they dont really generate much revenue yet. Secondly, some of the companies have also witnessed clinical setbacks or seen mixed data from their clinical trials. For example, Bluebird bio saw a big setback as some safety issues emerged in an ongoing study of a drug to treat cerebral adrenoleukodystrophy back in August. Editas Medicine also published some disappointing clinical trial results for its lead candidate, EDIT-101, which is targeted at Leber Congenital Amaurosis 10, a rare eye disorder.

So whats the outlook like for the theme? The sector is largely out of favor with the market and could see some volatility through 2022 if investors continue to move out of riskier assets amid rising interest rates. Liquidity could also be an issue for smaller players Bluebird and Editas which have been burning through cash and have seen recent clinical setbacks raising questions about whether they will ever see commercial success. That being said, the long-term upside for gene editing as a larger theme appears promising, given the potentially revolutionary drugs under development, that could cure conditions from cancer to rare genetic disorders that currently lack treatments, to more chronic conditions such as diabetes. Considering this, the theme could see upside in the long term and the recent correction could be a buying opportunity.

Below youll find our previous coverage of the Gene Editing theme where you can track our view over time.

[8/13/2021] Will Modernas Interest Boost Gene Editing Stocks?

Our indicative theme of Gene Editing stocks has returned about 11% year-to-date, compared to the S&P 500 which is up by about 19% over the same period. However, the gains have overwhelmingly come from a single stock, Intellia Therapeutics, which is up by about 3x year-to-date, after the company announced positive results from early-stage clinical trials for its experimental treatment for transthyretin amyloidosis, marking the first time genome editing was carried out inside the human body to treat disease. The five other stocks in our theme remain down year-to-date. For instance, Editas Medicine remains down by about 6.8%, while bluebird bio remains down by about 56%.

That being said, we think the outlook for gene-editing stocks is looking better. Intellias progress bodes well for the broader gene-editing space, as it validates that gene-editing technology works in humans and also that it remains safe. As more of these companies move candidates into clinical stages and provide readouts, we could see movements in stock prices across the theme. Moreover, gene-editing companies could be ripe for buyouts. For instance, Covid-19 vaccine behemoth Modernas management indicated that it was interested in expanding into other areas, including gene editing. Considering that a majority of gene-editing stocks are small to mid-cap companies, they could easily be acquired by larger players such as Moderna.

[7/1/2021] Gene Editing Stocks Are Worth A Look After Intellias Big Breakthrough

Intellia Therapeutics - a gene-editing company co-founded by CRISPR pioneer and Nobel prize winner Jennifer Doudna - indicated that NTLA-2001, its experimental treatment for transthyretin amyloidosis provided very promising results in an early state trial. Although the study was small, including just six patients, the company noted that there were significant reductions in levels of a harmful liver protein that is associated with the disease after a single infusion. Intellia stock has rallied by almost 80% over the last three trading days following the news.

Now, we think that this could be a big deal for the broader gene editing sector, as well. This was the first report from a clinical trial of genome editing carried out inside the human body to treat disease, and the results should broadly validate that gene-editing technology works in humans and also that it remains safe. Our indicative theme of Gene Editing stocks has rallied considerably over the last week, and remains up by roughly 20% year-to-date, compared to the S&P 500 which is up by about 15% over the same period. That said, the gains are primarily driven by Intellia stock, which is up by almost 3x year-to-date, and the five other stocks in our theme have actually underperformed the market, or declined this year. For example, CRISPR Therapeutics is up by just about 6%, while Vertex Pharmaceuticals and Editas Medicine are down by 15% and 19%, respectively. Sangamo Therapeutics is down 23% (chart, 10-k), while bluebird bio is down by 26%. As more of these companies move candidates into clinical stages and provide readouts, we could see gains in stock prices across the theme.

[6/14/2021] Should You Add Gene Editing Stocks To Your Portfolio?

Our indicative theme of Gene Editing stocks is down by about 12% year-to-date, compared to the S&P 500 which is up by over 13% over the same period. The decline comes as investors move money from high-growth and futuristic sectors to more cyclical and value stocks to ride the post-Covid surge in economic activity over the next few quarters. Gene Editing players have been particularly badly hit by this shift, given that they are mostly clinical or pre-clinical stage biotechs with little or no revenues. Now, although most of the companies in our theme are currently losing money, and are presently out of favor with the market, the longer-term upside could be sizable, given that they are working on potentially revolutionary drugs that could cure conditions from cancer to rare genetic disorders that currently lack treatments, to chronic conditions such as diabetes.

Within our theme, Intellia Therapeutics was the strongest performer, rising by about 57% year-to-date, due to favorable views from brokerages and anticipation surrounding the companys NTLA-2001 drug, which is a single-course, potentially curative therapy for transthyretin amyloidosis. A data readout from the phase 1 study on the drug is due later this month. On the other side, Editas Medicine has been the worst performer in our theme, declining by about -47% year to date, partly due to its big rally late last year, multiple analyst downgrades, and some changes at the top management level.

[3/29/2021] Gene Editing Stocks Have Corrected. What Next?

Our indicative theme of Gene Editing stocks is down by about 19% year-to-date, compared to the S&P 500 which is up by about 6% over the same period. With the economic recovery expected to gather pace, on the back of declining Covid-19 cases and higher vaccination rates, bond yields have been trending higher, causing investors to move funds from highly valued growth names to more cyclical and value bets. Gene Editing players have been particularly badly hit by this shift, given that they are mostly clinical or pre-clinical stage biotechs with little or no revenues. That said, we think that this could be a good time to take a look at the sector, considering that these companies are working on potentially revolutionary developments that could cure conditions from cancer to rare genetic disorders.

Within our theme, Intellia Therapeutics was the strongest performer, rising by about 19% year-to-date. Last November, the company began dosing under its phase 1 study is to evaluate its drug NTLA-2001 which is a single-course, potentially curative therapy for transthyretin amyloidosis. A data readout is due sometime in the next several months. On the other side, Editas Medicine has been the worst performer, declining by about 42% year to date, partly due to its big rally late last year, multiple analyst downgrades, and some changes at the top management level. See our earlier updates below for a detailed look at the components of our Gene Editing stocks theme.

[2/10/2021] Gene Editing Stocks To Watch

Our indicative theme of Gene Editing Stocks is up by about 187% since the end of 2018 and by about 5% year-to-date. Gene editing has received more attention this year, as scientists used the technology to cure progeria syndrome in mice, raising hopes for therapy in humans as well. Progeria is a very rare genetic condition that causes premature aging in children, shortening their lifespan to approximately 14 years. Investors also remain interested in the sector, given that it could revolutionize medicine and also due to the fact that absolute valuations arent too high, with most of the companies remaining in the mid-cap space.

Within our theme, Intellia Therapeutics (NASDAQ: NTLA) has been the strongest performer year-to-date, rising by around 35% since early January. The company recently outlined strategic priorities for 2021, which include the continued advancement of a phase 1 study for a single-course therapy for protein misfolding disorder and the planned submission of regulatory applications for the treatment of acute myeloid leukemia and hereditary angioedema this year. On the other side, Vertex Pharmaceuticals, has declined by about 10% year to date, driven partly by weaker than expected Q4 2020 results. See our updates below for a detailed look at the components in our theme.

[1/27/2021] How Are Gene Editing Stocks Faring?

Gene-editing technology is used to insert, edit, or delete a gene from an organisms genome, and shows promise in treating medical conditions ranging from cancer to rare genetic conditions. Our indicative theme on Gene Editing Stocks has returned over 170% since the end of 2018, compared to the broader S&P 500 which is up by about 54% over the same period. The theme has returned about 2.4% year-to-date. Investor interest in gene-editing remains high, given the upside potential of the sector and considering that absolute valuations arent too high, with most of the stocks remaining in the mid-cap space. Intellia Therapeutics (NASDAQ: NTLA) has been the strongest performer in our theme this year so far, rising 18% since early January. The gains come as the company has outlined strategic priorities for 2021, which include the continued advancement of a phase 1 study for a single-course therapy for protein misfolding disorder and the planned submission of a regulatory application for the treatment of acute myeloid leukemia. [1] On the other side, Editas Medicine has declined by about 13% year to date, after the company indicated that it plans to raise additional capital, issuing about 3.5 million shares at $66 per share. See our update below for a detailed look at the components in our theme.

[1/8/2021] Gene Editing Stocks

Gene editing has emerged as a promising biotech theme. The technology is used to insert, edit, or delete a gene from an organisms genome, helping to replace the defective genes responsible for a medical condition with healthy versions. This technology is being used to develop treatments for a range of diseases from cancer to rare genetic conditions, that are otherwise hard to treat, and is also being considered for diagnostic purposes. While there are broadly three gene-editing technologies, clustered regularly interspaced short palindromic repeats or CRISPR, as it is popularly known, has emerged as the method of choice with most companies, considering that it is relatively inexpensive, simpler, and more flexible compared to other tools such as ZFN and TALEN.

While most gene-editing players remain in the clinical stage with a limited financial track record, funding has risen meaningfully and larger pharma companies are also partnering with these companies, considering that the treatments could be lucrative and the broader technologies may be highly scalable. While the upside remains large, investing in these companies is risky. Being a new technology that has never been used in humans before, there are risks of significant side effects or of the therapies not being effective. The economics of producing and selling these drugs also remains uncertain. These stocks are also volatile, seeing big swings as any new research or data on their potential or risk is outlined. Our indicative theme on Gene Editing Stocks - which includes names such as CRISPR Therapeutics, Editas Medicine, and others - has returned about 230% over the past 2 years, compared to the broader S&P 500 which is up by about 52% over the same period. Below is a bit more about these companies.

CRISPR Therapeutics AG is one of the best-known names in the gene-editing space. The company is working with Vertex Pharmaceuticals to co-develop CTX001, an experimental gene therapy that has provided promising results for people with sickle cell disease, and transfusion-dependent beta-thalassemia - disorders that affect the oxygen-carrying cells in human blood. The company is also developing cancer therapy candidates independently. The company was profitable last year, due to collaboration revenues from Vertex.

CRSP

Editas Medicine, another leading CRISPR-focused biotech company, with a flagship program, EDIT-101 is targeting the treatment of hereditary blindness. The company recently finished dosing for its first group of patients in earlier-stage human trials. The company also recently filed a request with the U.S. FDA to commence phase 1/2 study of EDIT-301 in treating sickle cell disease. The company also has multiple other pre-clinical drugs focused on genetic diseases.

Intellia Therapeutics is developing a drug for a rare and fatal disease known as transthyretin amyloidosis in collaboration with Regeneron. The drug is in phase 1 trials currently. The company is also working on ex-vivo Sickle Cell Anemia treatment with Novartis that involves editing cells outside the body before infusing them into the patient. The candidate is entering Phase 1/2 trails. While the company has 8 other candidates, they are still in the research or pre-clinical stages. [2]

Sangamo BioSciences focuses on multiple areas in the genomic medicine space, including gene therapy, cell therapy, in vivo genome editing, and in vivo genome regulation. The company pioneered the zinc finger nuclease gene-editing method. The companys most advanced development is a treatment for Hemophilia A, which is being developed with Pfizer and is in phase 3 trials. The company also has 4 candidates in the phase 1/2 stage and 13 in the Preclinical stage. [3]

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Returns Dec 2021

MTD [1] 2021

YTD [1] 2017-21

Total [2] EDIT Return -16% -57% 84% S&P 500 Return -1% 24% 107% Trefis MS Portfolio Return 0% 45% 289% [1] Month-to-date and year-to-date as of 12/22/2021

[2] Cumulative total returns since 2017

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Bluebird, Editas: Gene Editing Stocks Had A Tough Year. Will 2022 Be Better? - Forbes

RESEARCH TRIANGLE PARK The Triangle continues to emerge as a hotbed of life science and biopharmaceutical technologies, along with a global evolution in medicine,Paul Garofolo, the cofounder and chief executive officer for Locus Biosciences, tells WRAL TechWire.

There is a revolution occurring in medicine. We are evolving from the days where we discovered small molecules that produced a favorable result in a large number of patients, likely with some level of side effects, to precision medicines that directly address the problem for the intended patient, he says. It started with antibodies and other biologic therapies that revolutionized Oncology and Immunological diseases. It is moving towards cell and gene therapies where the technology is proving itself in ultrarare diseases, and much like their predecessor technologies, will move toward more broad-based applications over time.

And Locus expects to be a part of the future of medicine, having grown its workforce to 75 employees since the companys founding in 2015, after Garofolo had the CRISPR-Cas3 technology upon which the companys research is built introduced to him by a student at North Carolina State University.

Theres growth ahead, as well, said Garofolo, as the company expects to reach 100 employees in 2022, and recently landed a $25 million credit facility to expand the companys in-house manufacturing capabilities and drug discovery program.

Paul Garofolo. Locus Biosciences image.

Were unique in biopharma in that we are clinical stage and revenue generating, said Garofolo. We generate revenue from our partnerships with two of the top five global pharmaceutical companies and contracts with BARDA and CARB-X, which together provide a combination of milestone payments, R&D cost reimbursement, and manufacturing revenue.

Those partnerships, the first of which was signed in 2019 with Janssen Pharmaceuticals, also known as Johnson & Johnson, are worth as much as $1 billion.

That partnership with Johnson & Johnson yielded Locus $20 million up front and up to $798 million in potential development and commercial milestones, as well as royalties on product sales, said Garofolo, with the goal of the partnership being the development and manufacturing ofcrPhage products targeting two key bacterial pathogens.

The company signed a contract with the Biomedical Advanced Research and Development Authority (BARDA) in September 2020 that enabled the company to advance a $144 million precision medicine program to develop LBP-EC01, a crPhage product, to combat recurrent urinary tract infections caused by E. coli,, and later that year, the company inked a deal worth $15 million to develop a product to combat antibiotic-resistant K. pneumoniae infections through Phase 1 of clinical development with the Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator (CARB-X).

Garofolo told WRAL TechWire that he and his wife provided the initial funding for the company, then raised a seed round of $1.5 million in 2016, a $19 million Series A round in 2017, a convertible note of $20 million in 2020, and then the recent $25 million credit facility earlier this year. That positions the company for the future, Garofolo noted, adding that this access to valuable growth capital supporting the expansion of our discovery platform engine and in-house manufacturing capacity [will be] used to address critical unmet medical needs.

WRAL TechWire spoke with Garofolo about the company, and about the future of life science and biopharma. A lightly edited transcript of the conversation appears below.

Inside Locus Biosciences $25M capital plan: What startup plans to do

TW: Tell us more about Locus Biosciences, its six programs, and the companys position in the marketplace.

Garofolo: Locus is the worlds leading developer of products based on CRISPR-Cas3 systems. Were unique in biopharma in that we are clinical stage and revenue generating. As described above, we generate revenue from our partnerships with two of the top five global pharmaceutical companies and contracts with BARDA and CARB-X, which together provide a combination of milestone payments, R&D cost reimbursement, and manufacturing revenue.

Locus has one clinical program underway, and up to five more in urinary tract, respiratory and bloodstream infections anticipated to enter the clinic by 2023.

Locuscompletedthe worlds firstplacebo-controlled Phase 1bclinical trial of a CRISPR Cas3-enhanced bacteriophage product targetingE. coliin UTIs. The results demonstrated safety and tolerability for LBP-EC01, and the trial met all its primary and secondary endpoints. We are working towards initiating the LBP-EC01 Phase 2 study inearly 2022. In October 2020, Locus announced a contract with the Biomedical Advanced Research and Development Authority (BARDA) to support Phase 2 and Phase 3 clinical trials and other activities required to seek FDA approval of LBP-EC01.

In 2019, Locus announced an agreement with Janssen Pharmaceuticals, Inc. for an exclusive, worldwide research collaboration and license to develop, manufacture and commercialize two products generated using Locuss recombinant CRISPR-Cas3 engineered bacteriophage (crPhage) platform for the treatment of respiratory tract infections which cause significant morbidity and mortality. The collaboration focuses on developing unique bactericidal disease-modifying crPhage products. These products will treat serious respiratory tract infections and infections in other areas of the body.

RTPs Locus Biosciences secures up to $25M in credit, plans expansion

TW: Whats the difference betweenCRISPR-Cas9 and CRISPR-Cas3 in the context of CRISPR technology overall?

Garofolo: CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) is the adaptive immune system of bacterial cells, capable of capturing and incorporating an invaders DNA into the bacterias genome to fend off future attacks.

When reprogrammed, as Locus has done, CRISPR enzymes like Cas3 and 9 can be used to edit or destroy DNA, making it a very useful tool for gene therapy, antibacterials, and other applications.

CRISPR-Cas3 is the most common CRISPR-Cas system in nature. Cas3 is a powerful exonuclease that permanently degrades chromosomal DNA beyond repair with high specificity, leading to rapid death of the target bacterial cell. Cas3s DNA degrading effect is distinct from the more widely-known Cas9 which causes a clean break in the DNA that can be repaired by the cell.

While others use CRISPR-Cas9 to edit DNA in human cells and other organisms, Locus is concentrating its efforts on removing deadly pathogens from the human body. CRISPR-Cas3, loaded into a bacteriophage delivery vehicle (other gene therapy companies use AAV), is the ideal system to target DNA to destroy a bacterial cells genome beyond repair.

Simply put, Cas3 acts like a Pacman that gobbles up tens of thousands of DNA base pairs while Cas9 acts like a pair of scissors that make a precise cut in one place.

Genetically enhanced antibiotic from RTP firm advances in first-of-its-kind clinical trial

TW: The company describes on its website and in press statements two product lines, precision bacteriophage products and also engineered bacteriophage therapies. Tell us more about each, and the science behind the product lines.

Bacteria are directly associated with many human diseases. Bacteriophages, or phages, are naturally occurring viruses that infect and kill bacteria. Bacteriophage have been used as antibacterial therapy for more than 100 years. However, natural phages are not typically effective enough on their own to treat serious infections in humans. Locus believes its precision engineered bacteriophage platform has the potential to fundamentally change the way bacteria-related diseases are treated.

Our team of scientists collects natural bacteriophagethe natural predator of bacteriawith the best disease-fighting characteristics. Then, leveraging artificial intelligence and machine learning algorithms, Locus Biosciences identifies the best cocktail of bacteriophages to target a particular bacterial species that causes a specific disease. Next, we engineer these bacteriophages with CRISPR-Cas3, which drastically increases their ability to fight bacteria and treat diseases without killing the good bacteria the body needs without applying selective pressure to other bacteria that increases AMR (antimicrobial resistance)

Through its unique bacteriophage discovery, synthetic biology and manufacturing platform, Locus is developing two innovative categories of biotherapeutics to address significant unmet medical needs: precision products to fight deadly infections, including those caused by multi-drug resistant bacteria; and engineered bacteriophage therapies that utilize bacteria resident in the body to deliver therapeutic molecules, while leaving the rest of the microbiome intact. Both categories are engineered bacteriophage. The former, are CRISPR Cas3-enhanced bacteriophage (crPhage) that exquisitely eradicates bacteria. While developing crPhage we became experts in engineering bacteriophage, where we can now deliver any protein or peptide therapeutic we desire.

The incidence of antibiotic-resistant infections is growing rapidly with large-scale use of antibiotics. This is a particular concern with the overuse of antibiotics during a viral pandemic, such as those caused by H1N1 influenza or SARS-CoV-2.

Gene editing success could turn Triangle startup Locus Biosciences into a billion dollar unicorn

The need for new precision antibacterial therapies that selectively kill target bacteria while leaving good bacteria in the body unharmed is widely recognized. The development of non-traditional therapies that possess alternative properties to conventional small-molecule antibiotics represents a unique opportunity to advance the field of medicine and provide new treatment options to patients with antimicrobial-resistant infections which are a growing concern for our nations health security.

Furthermore, the one bug, one drug precision approach our platform employs, has significant implications for bacterial infections in patients receiving novel therapeutics for conditions such as cancer. Lifesaving checkpoint inhibitors, for example, which are used across several cancer types, are negatively impacted by antibiotic use in these fragile patients. By specifically targeting only the pathogen of interest, Locus precision medicines avoid negatively affecting patient responses to these important therapies.

Within immunology and oncology, the association between disease and bacteria is becoming clearer each day. Locus platform enables the company to directly remove bacteria driving/exacerbating disease while delivering biotherapeutics that can ameliorate disease pathogenesis.

Here we leverage the microbiome to manufacture the biotherapeutics inside the human body at the site of the disease, increasing the effective dose at the target site while decreasing systemic exposure. All designed to improve outcomes while decreasing side effects.

Gene editing firm Locus Biosciences adds another $7M to its 2020 cash haul

TW: Whats the current state of the industry and the sector, and what does the future hold, in 2022 and beyond?

Garofolo: There is a revolution occurring in medicine. We are evolving from the days where we discovered small molecules that produced a favorable result in a large number of patients, likely with some level of side effects, to precision medicines that directly address the problem for the intended patient. It started with antibodies and other biologic therapies that revolutionized Oncology and Immunological diseases. It is moving towards cell and gene therapies where the technology is proving itself in ultrarare diseases, and much like their predecessor technologies, will move toward more broad-based applications over time.

2022 will continue to see the explosive advancement of gene therapy and gene editing technologies that results in new companies and investments across the industry. As these technologies advance through the clinic in the years to come, we will see them applied more broadly to address genetic diseases that affect broader patient populations. We are already seeing the move from muscular dystrophy to sickle cell disease and beyond. From Locus, you will see our team take our CRISPR-Cas3 enhanced bacteriophage into a Phase 2 trial targeting urinary tract infections caused by E. coli a disease that affects millions of people each year in the US alone.

Triangle gene editing firm Locus lands $77M to support new antibacterial treatment

TW: What can you tell us about how the companys geographic location in the Triangle means for future opportunity?

The Locus manufacturing platform is the lynchpin of our success in progressing bacteriophage products by enabling internal control over the timing, quality and speed at which we can take drugs to the clinic. We leverage our teams deep manufacturing experience as well as our geography, as NC is an ideal manufacturing location due to the local economics and talent pool.

Our world-class 10,000 square foott modular cGMP biologics manufacturing facility meets the standards of the US (FDA), Europe (EMA), Japan (PMDA), and several other countries and regions, to enable the manufacture of our precision medicines while providing the capability to also manufacture gene therapy vectors and other advanced biologics. Our facility design allows for parallel production of multiple drug substances simultaneously, in isolated production suites, without risk of cross-contamination. It is optimized for viral vector manufacturing, including bacteriophage, adenovirus, AAV, and other vectors. Taken together, our facility and proprietary production processes allow for all viral products manufactured by Locus to meet or exceed US and international regulatory standards for parenterally administered drug products for clinical and commercial use.

The modular design also allows us to change-out or upgrade existing equipment that moves Locus from being able to produce clinical trial material to producing multiple early-stage commercial products in parallel; all while maintaining the same footprint.

Locus Biosciences lands $19M in funding for gene editing technology

Here is the original post:
Triangle gene editing firms CEO: There is a revolution occurring in medicine - WRAL TechWire

Gene editing the practice of adding, removing, or altering genetic data in specific locations in the genome is a relatively new area of genetic engineering that has demonstrated great therapeutic potential when it comes to treating or preventing genetic diseases.

One gene editing tool, CRISPR, has generated particular excitement in the scientific community due to its ability to easily alter DNA sequences and modify gene functions. Though we are yet to see an approved CRISPR-based therapy for humans, the technique holds great promise for the future of genetic medicine.

Spanish biotech Integra Therapeutics, founded in 2020, is building on this ground-breaking technology to improve the safety and effectiveness of advanced therapies that is, treatments involving gene therapy, cell therapy and tissue engineering.

The company is developing a therapeutic gene writing platform that it says will overcome the current limitations with gene therapies. The technology, which combines CRISPR techniques with the gene transfer efficiency of viral integrases and transposases, can be used to paste both small and large DNA sequences into genomes with high precision.

CEO Avencia Snchez-Mejas speaks to Pharmaceutical Technology about the young companys plans for the future and how Integras gene editing platform could improve advanced therapies for patients.

Darcy Jimenez: Integra Therapeutics spun out of Pompeu Fabra University. What led to the company being formed there and how is it being built from those beginnings?

Avencia Snchez-Mejas: My co-founder, Marc Gell, started a lab at the university four years ago and I joined him to develop this technology. Once we had a good prototype that was performing quite well at inserting small and large payloads into the genome, it was a good time to incorporate the company and bring the traction we needed for this to become a therapeutic product.

DJ: Integra is creating new gene editing tools to make advanced therapies safer and more effective. What are the limitations of the advanced therapies currently being delivered to patients?

ASM: In many the diseases, the affected gene is relatively large. At the moment, if you need to insert a full-length gene or large coding sequence that does not fit into the current viral vectors, youre left with no solutions.

Also, with the the viral vectors, such as retroviruses, that are currently used in the pharma industry, the gene is inserted in a non-controllable way. We wanted to have a machinery that we can program to insert only in the target area of the genome that we want. In that way, we can select a safe place to put the gene and then control its insertion at that location.

DJ: Can you talk me through how Integras platform works? What sets you apart from other established companies in the space?

ASM: With our platform, we combined the specificity of CRISPR-Cas9 systems with the efficiency and capacity of integrases and transposases that have evolved to write a large message into the genome. Our objective is to bring to the market the ability to do programmable transposition of large and small sequences.

We plan to do an analysis of which will be the best first indication we want to move into the regulatory phase. While its not settled yet, we will make a decision in the next year together with the funding partners.

DJ: The company recently raised 4.5 million in funding. What will this mean for Integra and its gene editing platform?

ASM: We are very proud that the investors trusted us and wanted to come on board to build this company. These funds will be used to finalise the prototype and do its final development which we will move into the regulatory phase. They will also be used to generate strong proof-of-concept data in relevant animal models. And thirdly, it will allow us to manage our intellectual property (IP) portfolio.

DJ: What does Integra have planned for next year? How do you envision the companys platform impacting the advanced therapy space in 2022?

ASM: We want to show what the platform is capable of doing in a relevant therapeutic setup. For now, that will be in animal models, but we envision ourselves being used as a reference in the ecosystem for advanced therapies.

For next year, we will focus on having a really strong proof of concept and a final prototype, and then probably in a few years, work to get approvals to do our first in-human clinical trials.

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Integra Therapeutics Q&A: building next-generation gene editing tools - pharmaceutical-technology.com