Category Archives: Human Genetic Engineering

Richard Feynman, one of the most respected physicists of the twentieth century, said "What I cannot create, I do not understand". Not surprisingly, many physicists and mathematicians have observed fundamental biological processes with the aim of precisely identifying the minimum ingredients that could generate them. One such example are the patterns of nature observed by Alan Turing. The brilliant English mathematician demonstrated in 1952 that it was possible to explain how a completely homogeneous tissue could be used to create a complex embryo, and he did so using one of the simplest, most elegant mathematical models ever written. One of the results of such models is that the symmetry shown by a cell or a tissue can "break" under a set of conditions. However, Turing was not able to test his ideas, and it took over 70 years before a breakthrough in biology technique was able to evaluate them decisively. Can Turing's dream be made a reality through Feynman's proposal? Genetic engineering has proved it can.

Now, a research team from the Institute of Evolutionary Biology (IBE), a joint centre of UPF and the Spanish National Research Council (CSIC), has developed a new type of model and its implementation using synthetic biology can reproduce the symmetry breakage observed in embryos with the minimum amount of ingredients possible.

The research team has managed to implement via synthetic biology (by introducing parts of genes of other species into the E. coli bacteria) a mechanism to generate spatial patterns observed in more complex animals, such as Drosophila melanogaster (fruit fly) or humans. In the study, the team observed that the strains of modified E. coli, which normally grow in (symmetrical) circular patterns, do as in the shape of a flower with petals at regular intervals, just as Turing had predicted.

"We wanted to build symmetry breaking that is never seen in colonies of E. coli, but is seen in patterns of animals, and then to discover which are the essential ingredients needed to generate these patterns", says Salva Duran-Nebreda, who conducted this research for his doctorate in the Complex Systems laboratory and is currently a postdoctoral researcher at the IBE Evolution of Technology laboratory.

Bacteria E. coli forming patterns induced by the new synthetic system. Credit: Jordi Pla /ACS.

Using the new synthetic platform, the research team was able to identify the parameters that modulate the emergence of spatial patterns in E. coli . "We have seen that by modulating three ingredients we can induce symmetry breaking. In essence, we have altered cell division, adhesion between cells and long-distance communication capacity (quorum sensing), that is to say, perceive when there is a collective decision", Duran-Nebreda comments.

The observations made in the E. coli model could be applied to more complex animal models or to insect colony design principles. "In the same way that organoids or miniature organs can help us develop therapies without having to resort to animal models, this synthetic system paves the way to understanding as universal a phenomenon as embryonic development in a far simpler in vitro system", says Ricard Sol, ICREA researcher with the Complex Systems group at the IBE, and head of the research.

The model developed in this study, the first of its kind, could be key to understanding some embryonic development events. "We must think of this synthetic system as a platform for learning to design different fundamental biological mechanisms that generate structures, such as the step from a zygote to the formation of a complete organism. Moreover, such knowledge on the frontier between mechanical and biological processes, could be very useful for understanding developmental disorders", Duran-Nebreda concludes.

Reference: Duran-Nebreda S, Pla J, Vidiella B, Piero J, Conde-Pueyo N, Sol R. Synthetic Lateral Inhibition in Periodic Pattern Forming Microbial Colonies. ACS Synth Biol. 2021. doi:10.1021/acssynbio.0c00318.

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Synthetic Biology Used To Develop a New Type of Genetic Design - Technology Networks

Through the social and economic disruption that COVID-19 caused in 2020, the biomedical research community rose to the challenge and accomplished unprecedented feats of scientific acumen. With a new year ahead of us, even as the pandemic grinds on, we at The Scientist thought it was an opportune time to ask what might be on the life science innovation radar for 2021 and beyond. We tapped three members of the independent judging panel that helped name our Top 10 Innovations of 2020 to share their thoughts (via email) on the year ahead.

Paul Blainey: Value is shifting from the impact of individual technologies (mass spectrometry, cloning, sequencing, PCR, induced pluripotent stem cells, next generation sequencing, genome editing, etc.) to impact across technologies. In 2021, I think researchers will increasingly leverage multiple technologies together in order to generate new insights, as well as become more technology-agnostic as multiple technologies present plausible paths toward research goals.

Kim Kamdar: Partially in reaction to the COVID-19 pandemic, one 2021 headline will be the continued innovation focused on consumerization of healthcare, which is redefining how consumers engage with providers across each stage of care. Consumers are even selective about their healthcare choices now, and the retail powerhouses like CVS and Walmart have and will continue to develop solutions to meet the needs of their customers. While this was already underway prior to the pandemic, the crisis has spurred on this activity with the goal of making healthcare more accessible and affordable and ultimately delivering on better health outcomes for all Americans.

Robert Meagher: I think this is easymRNA delivery. This is something that has been in development for years for numerous applications, but the successful development and FDA emergency use authorization of two COVID-19 vaccines based on this technology shines a very bright spotlight on this technology. The vaccine trials and now widespread use of the vaccines will give developers a lot of data about the technology, and sets a baseline for understanding safety and side effects when considering future therapeutic applications outside of infectious disease.

PB:Single-cell technology is here to stay, although its use will continue to change. One analogy to be drawn is the shift we saw from the popularity ofde novo genome sequencing (during the human genome project and the early part of the NGS [next-generation sequencing] era to the rich array of re-sequencing applications practiced today. I expect new ways to use single-cell technology will continue to be discovered for some time to come.

KK: Innovation in single-cell technology has the potential to transform biological research driving to a level of resolution that provides a more nuanced picture of complex biology. Cost has been a key barrier for broader adoption of single-cell analysis. As better technology is developed, cost will be reduced and there will be an explosion in single-cell research. This dynamic will also allow for broader adoption of single-cell technology from translational research to clinical applications particularly in oncology and immunology.

RM: Yesthere is continuing innovation in this space, and room for continued innovation. One area that we have seen development recently, and I see it continuing, is to study single cells not just in isolation, but coupled with spatial information: understanding single cells and their interactions with their neighbors. I also wonder if the COVID-19 pandemic will spur increased interest in applying single-cell techniques to problems in infectious disease, immunology, and microbiology. A lot of the existing methods for single-cell RNA analysis (for example) work well for human or mammalian cells, but dont work for bacteria or viruses.

PB: The promises of CRISPR and gene editing are extraordinary. I cant wait to see how that field continues to develop.

KK: Much of the CRISPR technology focus since it was unveiled in 2012 has been on its utility to modify genes in human cells with the goal of treating genetic disease. More recently, scientists have shown the potential of using the CRISPR gene-editing technology for treatment of viral disease (essentially a programmable anti-viral that could be used to treat diseases like HIV, HBV, SARS, etc. . . .). These findings, published in Nature Communications, showed that CRISPR can be used to eliminate simian immunodeficiency virus (SIV) in rhesus macaque monkeys. If replicated in humans, in studies that will be initiated this year, CRISPR could be utilized to address HIV/AIDS and potentially make a major impact by moving a chronic disease to one with a functional cure.

PB: New therapeutic modalities that expand the addressable set of diseases are particularly exciting. Cell-based therapies offer versatile platforms for biological engineering that leverage the power of human biology. It is also encouraging to see somatic cell genome editing technology advance toward the clinic for the treatment of serious diseases.

The level of innovation that occurred in 2020 to combat COVID-19 will provide a more rapid, focused, and actionable reaction to future pandemics.

Kim Kamdar, Domain Associates

RM: Besides the great success with mRNA-based vaccines that sets the stage for other clinical technologies based on mRNA delivery, the other area that is really in the spotlight this year is diagnostics. There are a lot of labs and companies, both small and large, that have some really innovative products and ideas for portable and point-of-care diagnostics. For a long time, this was often thought of in terms of a problem for the developing world, or resource-limited locations: think, for example, of diagnostics for neglected tropical diseases. But the COVID-19 pandemic and the associated need for diagnostic testing on a massive scale has caused us to rethink what resource-limited means, and to understand the challenge posed by bottlenecks in supply chains, skilled personnel, and high-complexity laboratory facility. There has been a lot of foundational research over the past couple of decades in rapid, portable, easy-to-use diagnostics, but translating these to clinically useful products often seemed to stall, I suspect for lack of a lucrative market for such tests. But we are now starting to see FDA [emergency use authorization for] home-based tests and other novel diagnostic technologies to address needs with the COVID-19 pandemic, and I suspect that this paves the way for these technologies to start being applied to other diagnostic testing needs.

PB: Seeing the suffering and destruction wrought by COVID-19, it is obvious that we need to be prepared with more extensive, equitable, and better-coordinated response plans going forward. While rapid vaccine development and testing were two bright spots last year, there are so many important areas that demand progress. As we learn about how important details become in a crisisno matter how small or mundanediagnostic technologies and the calibration of public health measures are two areas that merit major focus.

KK: The life science community response to the COVID-19 pandemic has already proven to be light-years ahead of previous responses particularly in areas such as vaccine development and diagnostics. It took more than a year to sequence the genome of the SARS virus in 2002. The COVID-19 genome was sequenced in under a month from the first case being identified. Scientists and clinicians were able to turn that initial information to multiple approved vaccines at a blazing speed. Utilizing messenger RNA (mRNA) as a new therapeutic modality for vaccine development has now been validated. Vaccine science has been forever changed. The pandemic has also focused a much-needed level of attention to diagnostics, forcing a rethink of how to increase access, affordability, and actionability of diagnostic testing. The level of innovation that occurred in 2020 to combat COVID-19 will provide a more rapid, focused, and actionable reaction to future pandemics. In addition, the elevation of a science advisor (Dr. Eric Lander) to a cabinet level position in the Biden administration bodes well for our future ability to ground in data and as President Biden himself framed, refresh and reinvigorate our national science and technology strategy to set us on a strong course for the next 75 years, so that our children and grandchildren may inhabit a healthier, safer, more just, peaceful, and prosperous world.

RM: One thing that really kick-started research to address COVID-19 was the early availability of the complete genome sequence of the SARS-CoV-2 virus, and the ongoing timely deposition of new sequences in nearreal-time as isolates were sequenced. This is in contrast to cases where deposition of large number of sequences may lag an outbreak by months or even years. I foresee the nearreal-time sharing of sequence information to become the new standard. Making the virus itself widely and inexpensively available, in inactivated form, as well as well-characterized synthetic viral RNA standards and proteins also helped spur research.

A trend Im less fond of is the rapid publication of nonpeer reviewed results as preprints online. Theres a great benefit to getting new information out to the community ASAP, but unfortunately I think the rush to get preprints up in some cases results in spreading misleading information. This problem is compounded with uncritical, breathless press releases accompanying the posting of preprints, as opposed to waiting for peer-review acceptance of a manuscript to issue a press release. I think the solution may lie in journals considering innovative approaches to speeding up peer review, or a way to at least perform a basic check for rigor prior to posting a preliminary version of the manuscript. Right now the extremes are: post an unreviewed preprint, or wait months or even years with multiple rounds of peer review including extensive additional experiments to satisfy the curiosity of multiple reviewers for high impact publications. Is there a way to prevent manuscripts from being published as preprints with obvious methodological errors or errors in statistical analysis, while also enabling interesting, well-done yet not fully polished manuscripts to be available to the community?

Paul Blaineyis an associate professor of biological engineering at MIT and a core member of the Broad Institute of MIT and Harvard University. The Blainey lab integrates new microfluidic, optical, molecular, and computational tools for application in biology and medicine. The group emphasizes quantitative single-cell and single-molecule approaches, aiming to enable studies that generate data with the power to reveal the workings of natural and engineered biological systems across a range of scales. Blainey has a financial interest in several companies that develop and/or apply life science technologies: 10X Genomics, GALT, Celsius Therapeutics, Next Generation Diagnostics, Cache DNA, and Concerto Biosciences.

Kim Kamdaris managing partner at Domain Associates, a healthcare-focused venture fund creating and investing in biopharma, device, and diagnostic companies. She began her career as a scientist and pursued drug-discovery research at Novartis/Syngenta for nine years.

Robert Meagheris a principal member of Technical Staff at Sandia National Laboratories. His main research interest is the development of novel techniques and devices for nucleic acid analysis, particularly applied to problems in infectious disease, biodefense, and microbial communities. Most recently this has led to approaches for simplified molecular diagnostics for emerging viral pathogens that are suitable for use at the point of need or in the developing world. Meaghers comments represent his professional opinion but do not necessarily represent the views of the US Department of Energy or the United States government.

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Experts Predict the Hottest Life Science Tech in 2021 and Beyond - The Scientist

The EU Green Deal and its Farm-to-Fork and Biodiversity Strategies stipulate ambitious policy objectives that will fundamentally impact agricultural businesses and value chains. Are these objectives realistic? And how do they fit with the EUs policies on food security, the internal market, international trade and multilateral economic agreements? As significant conflicts of goals become apparent, the discussion on expectations, preconditions and consequences is now underway.

The Farm to Fork Strategy concretely foresees a reduction of pesticide and fertilizer use of 50% and 20% by 2030, respectively. In addition, 25% of EUs agricultural land is supposed to be put under organic farming conditions, which generally means a reduction in productivity. Unfortunately, the strategy is less concrete about the important role of innovation in general and plant breeding innovation specifically to compensate for productivity losses and to contribute to a more sustainable agriculture.

On July 25, 2018 the European Court of Justice (ECJ) published its ruling on mutagenesis breeding, including targeted genome editing techniques. This ruling subjected new tools like CRISPR Cas-9 to the EUs strict rules and requirements for GMOs, and with that effectively prohibited European plant breeders and farmers from utilizing these powerful technologies. These regulatory obstacles are not based on evidence showing that genome editing poses a risk to human health or the environment, but rather on political interference in the regulatory approval process. The COVID pandemic made this abundantly clear. In July 2020, for example, the EU suspended some of its excessive genetic engineering rules to facilitate the development of COVID vaccines, and has since celebrated the approval of these important drugs while trying to prevent the use of biotechnology in agriculture.

Since the discovery of the laws of genetics by Gregory Mendel in 1866, plant breeders have continuously integrated the latest plant biology innovations into their toolbox to develop enhanced crops that help farmers sustainably grow the food we all depend on.

Europes seed sector, technology developers and public researchers have always been important actors in this evolving effort and remain global leaders in developing improved plant breeding methods. They work tirelessly to provide farmers with crop varieties that fit the needs of a highly productive and sustainable agriculture system and meet the exacting demands of consumers. It is no secret that these experts understand the value of new breeding techniques (NBTs) like CRISPR and want to employ them.

Contrary to the claim of some environmental groups that genome editing provides new avenues of control through modifying specific plant traits, most notably insect and herbicide resistance, industrial applications of this sort are only one aspect of NBT research, and a minor one at that. Our recent survey of 62 private plant breeding companies, 90% of which are small and medium size firms (SMEs), confirms that EU plant breeders are able and willing to use these technologies to develop a wide range of crop species and traits for farmers. From grape vine to wheat, NBTs can generate innovation to protect Europes traditional crops from pests and diseases and other threats posed by climate change.

Independent of their size, many companies are already using NBTs in their R&D pipelines for technology development, gene discovery and to produce improved plant varieties. These activities cover a wide range of agricultural and horticultural cropsfrom the so-called cash crops like maize and soybean to minor crops like pulses, forage crops and chicoryand span a wide diversity of characteristics, including yield, plant architecture, disease and pest resistance, food-quality traits and abiotic stresses like drought and heat.

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Uncertain future: Will Europe's Green Deal encourage or cripple crop gene-editing innovation? - Genetic Literacy Project

In recent months, even as our attention has been focused on the coronavirus outbreak, there have been a slew of scientific breakthroughs in treating diseases that cause blindness.

Researchers at U.S.-based Editas Medicine and Ireland-based Allergan have administeredCRISPR for the first time to a person with a genetic disease. This landmark treatment uses the CRISPR approach to a specific mutation in a gene linked to childhood blindness. The mutation affects the functioning of the light-sensing compartment of the eye, called the retina, and leads to loss of the light-sensing cells.

According to the World Health Organization,at least 2.2 billion peoplein the world have some form of visual impairment. In the United States, approximately200,000 people suffer from inherited forms of retinal diseasefor which there is no cure. But things have started to change for good. We can now see light at the end of the tunnel.

I am an ophthalmology and visual sciences researcher, and am particularly interested in these advances becausemy laboratory is focusingon designing new and improved gene therapy approaches to treat inherited forms of blindness.

Gene therapy involves inserting the correct copy of a gene into cells that have a mistake in the genetic sequence of that gene, recovering the normal function of the protein in the cell. The eye is an ideal organ for testing new therapeutic approaches, including CRISPR. That is because the eye is the most exposed part of our brain and thus is easily accessible.

The second reason is that retinal tissue in the eye is shielded from the bodys defense mechanism, which would otherwise consider the injected material used in gene therapy as foreign and mount a defensive attack response. Such a response would destroy the benefits associated with the treatment.

In recent years, breakthrough gene therapy studies paved the way to thefirst ever Food and Drug Administration-approved gene therapy drug, Luxturna TM, for a devastating childhood blindness disease,Leber congenital amaurosisType 2.

This form of Leber congenital amaurosis is caused by mutations in a gene that codes for a protein called RPE65. The protein participates in chemical reactions that are needed to detect light. The mutations lessen or eliminate the function of RPE65, which leads to our inability to detect light blindness.

The treatment method developed simultaneously by groups at University of Pennsylvania and at University College London and Moorefields Eye Hospital involvedinserting a healthy copy of the mutated genedirectly into the space between the retina and the retinal pigmented epithelium, the tissue located behind the retina where the chemical reactions takes place. This gene helped the retinal pigmented epithelium cell produce the missing protein that is dysfunctional in patients.

Although the treated eyes showed vision improvement, as measured by the patients ability to navigate an obstacle course at differing light levels,it is not a permanent fix. This is due to the lack of technologies that can fix the mutated genetic code in the DNA of the cells of the patient.

Lately, scientists have been developing a powerful new tool that is shifting biology and genetic engineering into the next phase. This breakthroughgeneeditingtechnology, which is called CRISPR, enables researchers to directly edit the genetic code of cells in the eye and correct the mutation causing the disease.

Children suffering from the disease Leber congenital amaurosis Type 10 endure progressive vision loss beginning as early as one year old. This specific form of Leber congenital amaurosis is caused by a change to the DNA that affects the ability of the gene called CEP290 to make the complete protein. The loss of the CEP290 protein affects the survival and function of our light-sensing cells, called photoreceptors.

One treatment strategy is to deliver the full form of the CEP290 gene using a virus as the delivery vehicle. But the CEP290 gene is too big to be cargo for viruses. So another approach was needed. One strategy was to fix the mutation by using CRISPR.

The scientists at Editas Medicine first showed safety and proof of the concept of the CRISPR strategy in cells extracted from patient skin biopsy and in nonhuman primate animals.

These studies led to the formulation of thefirst ever in human CRISPR gene therapeutic clinical trial. This Phase 1 and Phase 2 trial will eventually assess the safety and efficacy of the CRISPR therapy in 18 Leber congenital amaurosis Type 10 patients. The patients receive a dose of the therapy while under anesthesia when the retina surgeon uses a scope, needle and syringe to inject the CRISPR enzyme and nucleic acids into the back of the eye near the photoreceptors.

To make sure that the experiment is working and safe for the patients, the clinical trial has recruited people with late-stage disease and no hope of recovering their vision. The doctors are also injecting the CRISPR editing tools into only one eye.

An ongoing project in my laboratory focuses on designing a gene therapy approach for the same gene CEP290. Contrary to the CRISPR approach, which can target only a specific mutation at one time, my team is developing an approach that would work for all CEP290 mutations in Leber congenital amaurosis Type 10.

This approach involves usingshorter yet functional forms of the CEP290 proteinthat can be delivered to the photoreceptors using the viruses approved for clinical use.

Gene therapy that involves CRISPR promises a permanent fix and a significantly reduced recovery period. A downside of the CRISPR approach is the possibility of an off-target effect in which another region of the cells DNA is edited, which could cause undesirable side effects, such as cancer. However, new and improved strategies have made such likelihood very low.

Although the CRISPR study is for a specific mutation in CEP290, I believe the use of CRISPR technology in the body to be exciting and a giant leap. I know this treatment is in an early phase, but it shows clear promise. In my mind, as well as the minds of many other scientists, CRISPR-mediated therapeutic innovation absolutely holds immense promise.

In another study just reported in the journal Science, German and Swiss scientists have developeda revolutionary technology, which enables mice and human retinas to detect infrared radiation. This ability could be useful for patients suffering from loss of photoreceptors and sight.

The researchers demonstrated this approach, inspired by the ability of snakes and bats to see heat, by endowing mice and postmortem human retinas with a protein that becomes active in response to heat. Infrared light is light emitted by warm objects that is beyond the visible spectrum.

The heat warms a specially engineered gold particle that the researchers introduced into the retina. This particle binds to the protein and helps it convert the heat signal into electrical signals that are then sent to the brain.

In the future, more research is needed to tweak the ability of the infrared sensitive proteins to different wave lengths of light that will also enhance the remaining vision.

This approach is still being tested in animals and in retinal tissue in the lab. But all approaches suggest that it might be possible to either restore, enhance or provide patients with forms of vision used by other species.

Hemant Khanna is an Associate Professor of Ophthalmology at the University of Massachusetts Medical School. His lab investigates molecular and cell biological bases of severe photoreceptor degenerative disorders, such as Retinitis Pigmentosa (RP) and Leber Congenital Amaurosis (LCA). Find Hemant on Twitter @khannacilialab

A version of this article was originally published at the Conversation and has been republished here with permission. The Conversation can be found on Twitter @ConversationUS

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Inherited blindness has a new cure, thanks to CRISPR - Genetic Literacy Project

Genome editing is an exciting but still nascent field, and companies in the area face as many obstacles as they do opportunities. Sangamo CEO Sandy Macrae told us how his company is being cautious about the hype and finding ways to be financially viable in an emerging space.

Cutting edge is, for once, a truly apt description when it comes to gene editing both because the field is pushing medicine into areas we might never have dreamed possible, and because these technologies involve literally cutting DNA at a specific point in the genome.

This has, of course, garnered immense excitement Doctors Emmanuelle Charpentier and Jennifer Doudna were named winners of the Nobel Prize for chemistry in recognition of their discovery of CRISPR/Cas9 gene editing technology.

Since that discovery, a flurry of gene-editing focused biopharma companies have launched including Intellia Therapeutics, CRISPR Therapeutics, Caribou Biosciences and Mammoth Biosciences and the first drug therapies based on the technology are now in human testing for diseases like cancer.

California-based Sangamo Therapeutics is one such company that believes in the powerful potential of in vivo genome editing and regulation, together known as genome engineering, and has built up a sizable preclinical pipeline of genome regulation treatments for diseases such as Huntingtons disease and Amyotrophic lateral sclerosis (ALS).

But when I spoke to CEO Sandy Macrae during the JP Morgan Health Care Conference 2021, he stressed that companies cannot be successful in the area unless they are wise about the hype, and understand that focusing purely on in vivo editing is unlikely to be financially viable for some time.

Zinc fingers

Macrae had previously worked at GSK and Takeda before he was recruited by Sangamo.

Maybe in 50 years time well be using gene editing to lower cholesterol, but it wont replace statins in anyone but those with life threatening mutations for a long time

They wanted someone who had lots of experience in drug development, was a molecular biologist, and was stubborn enough to take on CRISPR! he jokes.

Since Macrae joined the company just four years ago, Sangamo has more than tripled its staff and raised $1.6 billion in funding. It has also built its own manufacturing site and launched partnerships with six big pharma companies.

This growth reflects the continued and increasing interest in gene therapy and with stock prices rising for editing companies across the board, Macrae says there has never been a more interesting time to be in genomic medicine.

When I started in 2016 it was still a very academic field without much industrial interest. Then over the next two or three years, gene therapy was accepted as something that companies got involved in, and several biotechs have been bought up by big pharma.

And Macrae notes that we still dont even know the full potential for the field.

At the moment its mostly being applied to ultra-rare diseases. That can be incredibly effective, but it doesnt allow for a sustainable business model. Thats why companies like ours have decided to move into larger unmet medical needs such as transplant, multiple sclerosis, or inflammatory bowel disease.

The companys primary technology is its zinc finger (ZF) platform. ZFPs can be engineered to make zinc finger nucleases, or ZFNs, which are proteins that can be used to edit genomes by knocking select genes in or out to specifically modify DNA sequences.

ZFPs can also be engineered to make ZFP transcription-factors, or ZFP-TFs, which are proteins that can be used to regulate genomes by selectively increasing or decreasing gene expression.

Zinc fingers are the most common control gene in the body, Macrae explains. We can place them near the promoter of a gene and repress or upregulate it.

The exact mechanism depends on the disease in question. For example, the company is working on repressing promoter genes in tauopathies in collaboration with Biogen, but its partnership with Novartis is focused on upregulating genes related to autism, both leveraging the ZFP-TF platform.

The genomic medicine journey

Genome editing and regulation are still in their early stages, though, and Macrae says the fields evolution is likely to come in waves.

First of all it will be used for ultra-rare monogenic disease. Then itll be used for common monogenic disease, then polygenic disease or diseases where theres a genetic component. And ultimately we will be able to add genetic influences to diseases that dont have a genetic cause. Hypertension is one example there are probably 20-30 genes that control your hypertension, and perhaps one day well be able to identify which ones we can turn up or down.

Thats some way off, but it could be a whole new way of treating people.

That said, Macrae notes that the industry needs to be cautious about this hype.

We have to be thoughtful and prudent, because the worst thing that could happen is that gene editing is used in the wrong kind of patient, where theres a risk without a benefit. That would just slow the whole field down.

This is still a new area of medicine, and every company is realising that we dont always know as much about some of these rare diseases as we thought we did. Weve never had treatments for these conditions before, and now that we do we often find that we need to know a lot more about the physiology and the pathology of the disease than we imagined.

Many companies in this area tell wonderful stories about preclinical potential, but once youre in a clinical trial it doesnt matter how clever your science is what matters is whether the patient gets better, and because of that you really need to understand the potential risk.

Gene editing, he says, still has to go through a long journey to truly reach this potential.

That involves collecting as much safety data and uncovering as much about the benefit-risk profile as we can, Macrae says. The benefit-risk for a child thats going to die without treatment is unquestioned. The benefit for lowering your cholesterol, when there are other tools you can use, is more uncertain. We shouldnt go there until we have enough data to be sure that its safe.

Maybe in 50 years time well be using gene editing for things like that but while many patients might benefit from gene editing for lowering cholesterol, its not going to replace statins for anyone but those with life threatening mutations for a long time.

On top of this, there are the well-documented manufacturing challenges that come with such a new field.

I think weve all learnt that we need to spend more time earlier on in developing the industrial processes, Macrae says.

The call I get most often from headhunters is, Do you know anyone that can do manufacturing in cell therapy? The field has grown so rapidly that there are very few people with experience in it. There is also a shortage of manufacturing sites.

This is part of the reason Sangamo has built its own manufacturing site in California and is building a European site in France.

Owning your own fate in manufacturing is really important, says Macrae. The process of gene editing needs lots of care and attention, and were at an early stage of the science where we dont know all the answers. Thats why its so important to have your own people in-house who know how to do it well.

Pragmatic genomics

As such, while Sangamo strongly believes in the potential of in vivo genome editing and regulation, Macrae says that early on the company made a pragmatic decision that it shouldnt depend on the field becoming financially viable anytime soon, and required a near-term strategy that would bring in revenue and benefit patients.

That is why the company is also working on gene therapy and ex vivo gene-edited cell therapy.

If youre working in gene editing, you can also work in gene therapy, because you already know a lot about delivery, vectors, molecular biology etc., Macrae explains. So it seemed like a sensible decision for us to work on that while gene editing is still an evolving field.

The companys gene therapy pipeline now includes treatments for PKU, Fabry disease and hemophilia A (in partnership with Pfizer).

The next easiest area for the company to take on with its existing capabilities was ex vivo gene-edited cell therapy.

In this area, Macrae says he is most excited about the companys CAR-Treg platform, from its acquisition of French company TxCell.

Tregs travel to the site of the inflammation and release mediators to calm it. We can put our localising CAR onto the Treg, which takes it specifically where we want it to go. For example, for multiple sclerosis you can use a CAR that takes the Treg to the myelin sheath.

You dont need to know the cause of the disease, you just need to know where the disease is.

Sangamo still anticipates, though, a time when in vivo genome editing and regulation is just as key to the business as these other two pillars and in fact Macrae anticipates that over time, Sangamo will shift its development focus to genome engineering as the field and science mature.

Gene therapy can ultimately only take you into the liver, he explains. There are 7,000 liver diseases, and only 10-20 of them that are big enough to run large clinical trials. Most of them are rare mutations.

Everyone is going to the liver and doing the same disease, and what was already a small population gets sliced and diced between several companies. We therefore dont see it as a long-term sustainable opportunity.

We have the advantage of also being able to edit cells in vivo, and eventually we will be able to do fundamental once-and-done editing in other tissues. Its just a matter of getting the field there.

About the interviewee

Sandy Macrae has served as Sangamos president and chief executive officer and as a member of the Board of Directors since June 2016. He has twenty years of experience in the pharmaceutical industry most recently serving as the global medical officer of Takeda Pharmaceuticals. From 2001 to 2012, Dr Macrae held roles of increasing responsibility at GlaxoSmithKline, including senior vice president, Emerging Markets Research and Development (R&D).

About the author

George Underwood is pharmaphorums Deep Dive magazine editor. He has been reporting on the pharma and healthcare industries for seven years and has worked at a number of leading publications in the UK.

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Gene editing: beyond the hype - - pharmaphorum - pharmaphorum

CAMBRIDGE, Mass., Jan. 29, 2021 /PRNewswire/ --Exacis Biotherapeutics, Inc., a development-stageimmuno-oncology company working to harness the immune system to cure cancer,today announcedthe addition of Dirk Huebner,MD,as its Chief Medical Officer. Exacis launched in 2020 to develop next generation mRNA-based cellular therapeutics to treat liquid and solid tumors.

Exacis CEO Gregory Fiore MD said, "Dirk is a wonderful addition and a great fit for our management team. His extensive experience in oncology drug development, including antibody related therapies will be instrumental as we build our pipeline to include high performance stealth edited NK and T cells, with and without CARs (ExaNK, ExaCAR-NK and ExaCAR-T). We look forward to Dirk's insights and medical leadership as we build the company and advance our portfolio."

Dr. Huebner joins Exacis from Mersana Therapeutics where he wasthe Chief Medical Officer,oversaw their clinical developmentand helped build thecompany'sclinical infrastructure. Dr Huebnerhas worked in oncology and immuno-oncology drug development and academiafor more than 25 yearsand brings a deep understanding of the needs in the oncology space as well as the ability to successfully deliverproducts to meet those needs.

Commenting on the new role, Dr. Huebner said, "I am thrilled to join the Exacis team and work with best-in-class technology to create innovative, next-generation engineered NK and T cell therapies that have the potential to improve outcomes and treatment experiences for patients with challenging hematologic and solid tumor malignancies."

About Exacis Biotherapeutics

Exacis is a development stageimmuno-oncologycompany focused on harnessing the human immune system to cure cancer. Exacis uses its proprietary mRNA-based technologies to engineer next generation off-the-shelf NK and T cell therapies aimed at liquid and solid tumors.Exacis was founded in 2020 with an exclusive license to a broad suite of patents covering the use ofmRNA-based cell reprogramming and gene editing technologiesfor oncology.

ExaNK, ExaCAR-NK and ExaCAR-T utilize mRNA cell reprogramming and mRNA gene editing technologies developed and owned by Factor Bioscience. Exacis has an exclusive license to the Factor Bioscience technology for engineered NK and T cell products derived from iPSCs for use in oncology and holds all global development and commercial rights for these investigational candidates.

About T and Natural Killer (NK) Cell Therapies

T and NK cells are types of human immune cells that are ableto recognize and destroy cancer cells and can be modified through genetic engineering to target specific tumors.

SOURCE Exacis Biotherapeutics, Inc.

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Exacis Biotherapeutics Announces Key Addition To Its Executive Leadership Team With Dirk Huebner MD Joining As Chief Medical Officer - PRNewswire