Category Archives: Gene Medicine

Mar 27th 2021

THE FIRST virus to have its genome read was an obscure little creature called MS2; the 3,569 RNA letters it contained were published in 1976, the hard-won product of some ten years work in a well-staffed Belgian laboratory. The SARS-CoV-2 genome, almost nine times longer, was published just weeks after doctors in Wuhan first became concerned about a new pneumonia. That feat has since been repeated with getting on for 1m different samples of SARS-CoV-2 in the hunt for fearsome variants like the one ravaging Brazil. Within weeks of its publication, the original genome sequence became the basis for the vaccines that today are stymieing the virus wherever supplies, politics and public confidence allow.

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It is hardly remarkable that medical science has moved on since 1976. But the covid-19 pandemic has brought the sharp joy of seeing decades of cumulative scientific progress in sudden, concerted action. The spate of data, experiments and insights has had profound effects on the pandemicand, indeed, on the future of medicine. It is also an inspiration. Around the world, scientists have put aside their own work in order to do their bit against a common foe. Jealously guarded lab space has been devoted to the grunt work of processing tests. Covid-19 has led to some 350,000 bits of research, many of them on preprint servers that make findings available almost instantaneously.

The basis of all this is the application of genetics to medicine in a systematic and transformative waynot just in understanding the pathology of diseases but in tracking their spread and curing and preventing them. This approach could underpin what is becoming known as natural securitythe task of making societies resilient in the face of risks stemming from their connection to the living world, whether because of disease, food insecurity, biological warfare or environmental degradation.

The application of genetics to medicine partly reflects huge, rapid gains in efficiency. Reading the DNA in a human genome cost $10m in 2007, today it takes less than $1,000 and a fraction of the time. Coupled with ever-better ways of synthesising and editing genes, this has enabled cleverness little short of the miraculous. Before the pandemic, these trailblazing techniques were not much talked about beyond the laboratory. Having shown their mettle against a brand new disease, they have burst out into the open.

Take the vaccination technology rapidly developed by Moderna of America and BioNTech of Germany, building on years of patient and often unsung work on RNA, a store of genetic information. It is remarkable that you can simply instruct the bodys cells to make the viral protein you have designed to prime the immune system. The RNA vaccines are testament to the insight of Eddie Cantor, a comedian, that it takes 20 years to become an overnight success.

With this proof of concept, the investments of companies that have worked hard on RNA may now pay off. To some extent, RNA medicine divorces form from function. An RNA vaccine against any disease is a message written in genetic code: a vaccine against malaria, or some form of cancer, can be made in the same way and with the same equipment as a SARS-CoV-2 vaccine. If this provides a platform for getting cells to do all sorts of specific things and to desist from others, as it promises to, medicine will become both more powerful and more personal. Therapies tailored to rare, even one-off, genetic abnormalities should become routine.

The pandemic has also demonstrated the value of gene-sequencing technologies. Observing SARS-CoV-2 as it mutates is essential if the world is to understand and defend itself against dangerous variants. Should covid-19 become endemic, as is likely, sequencing will become the basis for developing regular booster shots. More broadly, routine sequencing is one of the best ways of knowing what is out there. Companies have done brilliantly in producing powerful sequencing systems for trained technicians. Now the world needs cheap, ubiquitous and reliable systems that can be used in the prison sick bay or the rural health centre, on the farm or at the town sewage works, to act as early-warning systems for the spread of pathogens.

Another area of work is where the pandemic has revealed a gap. Even todays progress has yet to produce small-molecule antivirals to combat SARS-CoV-2. A focus for natural security should be drugs aimed at the viral families most likely to cause trouble in the future. This is not something that the market will support on its own. New mechanisms that involve governments will be needed, such as funds for R&D and trials and to buy stockpiles of medicine. Similar approaches should also be used for the looming threat of antibiotic-resistant bacteria.

These innovations will have big consequences. General-purpose RNA medicine asks new things of firms and regulatorsas do other platforms, including some forms of gene therapy. Regulators will need to take advantage of the fact that, say, a malaria vaccine and a SARS-CoV-2 vaccine are both made on the same platform by streamlining approval for them, while continuing to ensure safety.

Drugs firms will have to adapt, as some chronic conditions may, in effect, be cured. Many are used to concentrating on the long-lasting afflictions that most trouble the rich world: heart disease, cancer, metabolic disorders, neurodegenerative conditions and the like. If drug development is more targeted on instructing cells what to do, rather than finding novel molecules against specific proteins, some of the know-how on which old-style pharma is based will be less relevant. Firms will need new pricing models and a new focus to their research.

Technology will not, in itself, thwart pandemics. That goal also requires systems and institutions which use technology broadly and wisely. Without good systems, great technology will often provide only mediocre results, as it has in many covid-19 test-and-trace programmes. But the pandemic has shown that biomedical science has the tools and the enthusiasm to improve the world. The world must now build on both.

Dig deeper

All our stories relating to the pandemic and the vaccines can be found on our coronavirus hub. You can also listen to The Jab, our new podcast on the race between injections and infections, and find trackers showing the global roll-out of vaccines, excess deaths by country and the viruss spread across Europe and America.

This article appeared in the Leaders section of the print edition under the headline "Science after the pandemic"

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Science after the pandemic - Bright side of the moonshots | Leaders - The Economist

Samah A Loutfy,1 Zeinab F Abdallah,1 Mohamed Shaalan,2 Mohamed Moneer,3 Adel Karam,3 Manar M Moneer,4 Ibrahim M Sayed,5,6 Amer Ali Abd El-Hafeez,7,8 Pradipta Ghosh,8 10 Abdel-Rahman N Zekri1

1Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt; 2Surgical Oncology Department, National Cancer Institute, Cairo University, Cairo, Egypt; 3Surgical Oncology Department, Materia Teaching Hospital, Cairo, Egypt; 4Biostatistics and Epidemiology Department, National Cancer Institute, Cairo University, Cairo, Egypt; 5Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt; 6Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, CA, USA; 7Pharmacology and Experimental Oncology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt; 8Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, 92093, USA; 9Department of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA; 10Moores Cancer Center, University of California, San Diego, La Jolla, CA, 92093, USA

Correspondence: Samah A LoutfyVirology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Fom El-Khalig, Cairo, 11796, EgyptTel +201222840964Email samaly183@yahoo.com

Background: Mouse mammary tumor virus (MMTV) is thought to have a role in human breast cancer (BC) pathogenesis. BRCA1 and 2 genes mutations are well-established risk factors for BC. The purpose of this study was to evaluate the presence of MMTV in familial and non-familial Egyptian breast cancer patients. We also aimed to establish a correlation between BRCAs genes mutations and MMTV infection in those patients.Patients and Methods: The study was included 80 BC patients and 10 healthy women were included as a control group. We used PCR to amplify a 250-bp MMTV-like env sequence. We also used PCR followed by direct sequencing to identify the genetic variation of exons 2, 13, 19 of BRCA1 gene and exon 9 and region f of exon 11 of BRCA2 gene. High resolution melting (HRM) analysis was used to screen the selected exons of BRCA1/2 genes in order to detect different variants.Results: MMTV DNA-like env sequences were detected in 70%, 76% of familial and non-familial BC patients, respectively, and it was not detected in any of the control subjects. The presence of viral sequences was associated with larger tumor size in the sporadic patients. Seventy BC patients showed variations in BRCA1/2 genes according to HRM analysis and sequencing analysis showed two different sequences of polymorphism among 22 familial and non-familial BC patients.Conclusion: MMTV DNA was present among BC patients and it was associated with increased tumor growth. This indicates a potential role for MMTV in BC patients with and without deleterious mutation in BRCA1/2 genes.

Keywords: breast cancer, MMTV, BRCA1/2, HRM, Egypt

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

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MMTV-like env sequences and the association with BRCA1/2 | CMAR - Dove Medical Press

The two companies will launch in Korea Ocean Genomics advanced AI-based transcriptome analysis and biomarker platform (txome.ai) as both a cloud-based and on-premises solution. Geninus will leverage the txome.ai platform to expand its CancerSCAN clinical diagnostics platform for its hospital customers, and for biomarker discovery services with academic and biotechnology clients. Ocean Genomics and Geninus will also partner on the co-development of a series of RNA-informed multidimensional biomarkers for research and clinical use.

We are excited to embark on this partnership with Geninus said Carl Kingsford, co-founder and CEO, Ocean Genomics. Ocean Genomics expertise in AI and computational method development, together with Geninus translational experts and access to data is a powerful combination. Working together, we can advance the field and enhance the uses of RNA biomarkers in clinical and research applications and provide essential insights for clinicians who care for cancer patients.

Dr. Woong Yang Park, CEO, Geninus, said, Genome analysis for precision cancer medicine is becoming an essential process in hospitals. Gene expression analysis on tumor tissue RNA can deliver critical information for targeted therapy and immunotherapy. We expect to advance precision medicine by incorporating Ocean Genomics txome.ai into Geninus clinical diagnostics platform, CancerSCAN. We look forward to working with Ocean Genomics in co-developing biomarkers and expanding services to our academic and biotechnology customers.

About Ocean Genomics, Inc.

Ocean Genomics mission is to enable drug development and personalized medicine by combining AI with advanced gene-expression analysis to determine rich gene expression signatures and develop RNA-informed multidimensional biomarkers. DNA is a predictor of what might happen in the future, while RNA reveals whats happening now, making it an essential component in drug development, screening and monitoring, diagnosis and treatment selection. Analyzing RNA requires far more advanced software and computational methods than analyzing DNA.

Ocean Genomics provides the required specialized expertise in AI and transcriptomic analysis and advanced computational software solutions required to power discovery and development programs with life sciences companies and academic researchers. Ocean Genomics provides a self-service, fully configured, cloud-based platform, txome.ai, which provides advanced transcriptome analysis and biomarker generation.

For more information, please visit oceangenomics.com and connect with us on Twitter, and LinkedIn.

About Geninus Inc.

Geninus provides clinical genome analysis solutions for precision medicine clinics. CancerSCAN, a cancer genome diagnostics platform, is used to inform personalized cancer treatment with targeted therapeutics and immunotherapy in major hospitals in Korea and Japan. CancerSCAN includes an information management system, a bioinformatics pipeline, variant annotation, clinical reports, and datacenter. OncoSTATION, a user interface for CancerSCAN, can be installed within hospital information systems. In addition, Geninus operates a single cell genome analysis platform called Celinus for biomarker discovery. Through collaborations with clinicians and pharmaceutical companies, Celinus can unearth new druggable targets or diagnostic markers in tumor microenvironment cells.

For more information, please visit kr-geninus.com.

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Ocean Genomics Partners With Geninus to Co-Develop RNA-Based Biomarkers and Advance Research - BioSpace

The stock price of Benitec Biopharma Inc (NASDAQ: BNTC) a development-stage biotechnology company that focuses on the development of novel genetic medicines increased by 190.28% today as it went from a previous close of $3.19 to $9.26. The company shares were trading at over 80% pre-market today as well. Investors were responding to a Schedule 13G filing that showed Morgan Stanley now has 249,174 shares in the company, representing a 5.2% stake.

Last month, Benitec Biopharma had announced the successful results of the interim analysis of the BB-301 Pilot Dosing Study. And the proprietary DNA-directed RNA interference (ddRNAi) platform combines RNA interference (RNAi) with classical AAV-based gene therapy.

And through the use of the ddRNAi platform Benitecs goal is to create genetic medicines that (following a single administration) will enable target tissues to perpetually produce siRNA molecules which facilitate the sustained silencing of disease-causing genes. The ddRNAi platform also allows for concomitant delivery of wild-type replacement genes and these distinct genetic elements work in concert to silence the expression of disease-causing mutant genes and to simultaneously replace the mutant genes with normal (wild type) genes to restore the natural underlying physiology of the diseased tissues.

BB-301, the most advanced genetic medicine currently under development by Benitec, employs the proprietary platform which allows for a Silence and Replace approach to the treatment of Oculopharyngeal Muscular Dystrophy (OPMD). And BB-301 is a genetic medicine employing the Silence and Replace approach for the treatment of OPMD.

OPMD is known as a chronic life-threatening genetic disorder affecting approximately 15,000 patients in the United States, Canada, Western Europe, and Israel. OPMD is caused by a mutation in the gene encoding poly(A) binding protein nuclear 1 (PABPN1). And patients with OPMD lose the ability to swallow liquids and solids, and the natural history of the disorder is characterized by chronic malnutrition, aspiration, and fatal episodes of aspiration pneumonia.

There are no therapeutic agents approved for the treatment of OPMD. Unfortunately, there is not any surgical interventions capable of altering the long-term natural history of OPMD are available. And BB-301 received Orphan Drug Designation in the United States and the European Union which provides commercial exclusivity (independent of intellectual property protection) and opportunities for efficient pathways for regulatory review and approval. While OPMD is a rare (Orphan) disorder, the commercial opportunity for a safe and efficacious therapeutic agent in this indication exceeds $1 billion over the course of the commercial life of the product.

Benitec had scheduled a Scientific Advice Meeting in France in May 2021 to review the interim data and the Phase 1 clinical trial design. And the company continues to plan for the initiation of the first-in-human clinical study of BB-301 in OPMD patients in 2022. The interim data validated the promise of the Silence and Replace approach to disease management and Benitec plans to provide additional pipeline updates in the second half of 2021.

Disclaimer: This content is intended for informational purposes. Before making any investment, you should do your own analysis.

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BNTC Stock Price Increased 190.28%: Why It Happened - Pulse 2.0

The stock price of Benitec Biopharma Inc (NASDAQ: BNTC) a development-stage biotechnology company that focuses on the development of novel genetic medicines increased by over 80% pre-market. Investors are responding to a Schedule 13G filing showing that Morgan Stanley now has 249,174 shares in the company.

Last month, Benitec Biopharma had announced the successful results of the interim analysis of the BB-301 Pilot Dosing Study. The proprietary DNA-directed RNA interference (ddRNAi) platform combines RNA interference (RNAi) with classical AAV-based gene therapy.

And through the use of the ddRNAi platform Benitecs goal is to create genetic medicines that, following a single administration, will enable target tissues to perpetually produce siRNA molecules which facilitate the sustained silencing of disease-causing genes. The ddRNAi platform also allows for concomitant delivery of wild-type replacement genes, and these distinct genetic elements work in concert to silence the expression of disease-causing mutant genes and to simultaneously replace the mutant genes with normal (wild type) genes to restore the natural underlying physiology of the diseased tissues.

And BB-301, the most advanced genetic medicine currently under development by Benitec, employs the proprietary platform which allows for a Silence and Replace approach to the treatment of Oculopharyngeal Muscular Dystrophy (OPMD). BB-301 is a genetic medicine employing the Silence and Replace approach for the treatment of OPMD.

OPMD is known as a chronic life-threatening genetic disorder affecting approximately 15,000 patients in the United States, Canada, Western Europe, and Israel. And OPMD is caused by a mutation in the gene encoding poly(A) binding protein nuclear 1 (PABPN1). Patients with OPMD lose the ability to swallow liquids and solids, and the natural history of the disorder is characterized by chronic malnutrition, aspiration, and fatal episodes of aspiration pneumonia.

There are no therapeutic agents approved for the treatment of OPMD. And there is not any surgical interventions capable of altering the long-term natural history of OPMD are available. BB-301 received Orphan Drug Designation in the United States and the European Union which provides commercial exclusivity (independent of intellectual property protection) and opportunities for efficient pathways for regulatory review and approval. While OPMD is a rare (Orphan) disorder, the commercial opportunity for a safe and efficacious therapeutic agent in this indication exceeds $1 billion over the course of the commercial life of the product.

Benitec had scheduled a Scientific Advice Meeting in France in May 2021 to review the interim data and the Phase 1 clinical trial design. And the company continues to plan for the initiation of the first-in-human clinical study of BB-301 in OPMD patients in 2022. The interim data validated the promise of the Silence and Replace approach to disease management and Benitec plans to provide additional pipeline updates in the second half of 2021.

Disclaimer: This content is intended for informational purposes. Before making any investment, you should do your own analysis.

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BNTC Stock Price Increased Over 80% Pre-Market: Why It Happened - Pulse 2.0

Aging refers to the physiological changes we experience during our lifespan. Its also an inevitable part of life.

After all, our cells arent made to last forever. The structures and functions in our cells decline over time.

But why does this happen? For decades, scientists have been studying the subject. There are currently more than 300 theories on why we age, and experts are learning more every day.

Lets explore why humans age, and how you can slow down the effects.

Aging can be categorized into two types:

Cellular aging is due to intrinsic factors. Its related to the biological aging of cells.

Cells are the basic building blocks of the body. Your cells are programmed to divide, multiply, and perform basic biological functions.

But the more cells divide, the older they get. In turn, cells eventually lose their ability to function properly.

Cellular damage also increases as cells get older. This makes the cell less healthy, causing biological processes to fail. Cellular damage accumulates over time, too.

Damage-related and environmental aging is related to extrinsic factors. It refers to how our surroundings and lifestyle affect how we age.

This includes factors like:

Over time, these factors can damage our cells and contribute to aging.

Everyone experiences both types of aging. However, each form of aging varies from person to person, which explains why we age in different ways.

Its generally accepted that aging is caused by multiple processes, rather than one reason. Its also likely that these processes interact and overlap with each other.

Here are some of the most prominent theories:

Programmed aging theories posit that were programmed, or designed, to age. It maintains that cells have a predetermined lifespan thats naturally encoded into the body.

Programmed theories are also called active or adaptive aging theories. These theories include:

Programmed theories have many supporters. However, they suggest that habits linked to longevity, like quitting smoking and exercise, are useless. This is likely inaccurate, as research has continuously proven that these habits affect life expectancy.

Error theories, or damage theories, are the opposite of programmed theories. They hypothesize that aging is caused by cellular changes that are random and unplanned.

Error theories of aging include:

The genetic theory proposes that aging primarily depends on genetics. In other words, our life expectancy is regulated by the genes we got from our parents.

Since genes have predetermined traits, its thought this theory overlaps with programmed theories of aging.

Genetic theories include:

The limitation of genetic theories is that they disregard the importance of external factors. In fact, its estimated that just 25 percent of lifespan is influenced by genetics. This suggests that environmental and lifestyle factors play a major role.

Natural selection refers to the adaptive traits of an organism. These traits can help the organism adjust to their environment, so theyre more likely to survive.

According to evolutionary theories, aging is based on natural selection. It posits that an organism begins aging after they have reached their peak of reproduction and have passed down adaptive traits.

Evolutionary theories include:

These theories are still being researched and require more evidence.

Another theory is that biochemical reactions cause aging. These reactions occur naturally and continuously throughout life.

This theory is rooted in various concepts, including:

In recent decades, life expectancy around the world has increased. This is due many factors, including:

These factors can protect our cells and reduce cellular damage, thus increasing life expectancy.

In most parts of the world, women live longer than men. This is due to several biological, social, and environmental factors.

Women, on average, have more estrogen than men. Estrogen is the female sex hormone. Its been found to have anti-inflammatory and immune-boosting effects, which may protect women from certain diseases.

In contrast, the male sex hormone testosterone may suppress the immune system. Men typically have more of this hormone.

There are also behavioral differences between men and women. Generally, compared to men, women:

Though aging is inevitable, its possible to slow down some of the effects. You can do this by following healthy lifestyle habits.

Heres how to slow aging:

Aging is likely caused by a combination of reasons. Some theories suggest cells have a predetermined lifespan, while others claim its caused by error and damage. Other theories posit that aging is due to genetic, evolution, or biochemical reactions.

Aging is normal, but following a healthy lifestyle can help you live longer. Habits like eating well, exercising regularly, and wearing sunscreen can reduce your risk of disease and improve your quality of life.

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Why Do We Age, and Can Anything Be Done to Stop or Slow it? - Healthline

The single-center, prospective, observational study evaluated molecular response in patients with mNSCLC (n=51) receiving pembrolizumab-based therapy, as monotherapy or with chemotherapy, as first- or second-line treatment. Changes in ctDNA were evaluated from baseline to nine weeks post-therapy initiation, and correlated with clinical and radiographic response.

In the study, the Guardant360 test showed that molecular responders achieved improved durable clinic benefit (log mean 49.4% vs. 3.5%) and significantly longer progression-free survival (median 14.1 vs. 4.4 months) and overall survival (median 22.1 vs. 12.0 months) compared to non-molecular responders. Molecular response was also associated with radiologic response as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) .

Unfortunately, only a subset of patients with metastatic non-small cell lung cancer will respond to pembrolizumab-based therapy, and their failure to achieve clinical benefit becomes evident after their disease has progressed, said Helmy Eltoukhy, Guardant Health CEO. This study adds to the growing body of evidence showing that our Guardant360 test can effectively measure molecular response, giving clinicians an earlier indication whether to continue or stop treatment, explore other therapeutic regimens, or enroll the patient in a clinical trial.

The Guardant360 test is used to guide treatment in metastatic non-small cell lung cancer as the number of treatment-relevant genomic alterations continues to grow. Using next-generation sequencing, Guardant360 analyzes 83 genes using cell-free tumor DNA from blood samples. The Guardant360 test is broadly covered by Medicare for use across the vast majority of advanced solid tumors, including patients with metastatic non-small cell lung cancer. Last year, the FDA approved the Guardant360 CDx for tumor mutation profiling, also known as comprehensive genomic profiling (CGP), in patients with any solid malignant neoplasm (cancerous tumor).

"These are exciting results that further support the value of liquid biopsies as a noninvasive tool to measure early treatment responses by evaluating molecular response or changes in circulating tumor DNA," said Charu Aggarwal, MD, MPH, Leslye M. Heisler Associate Professor for Lung Cancer Excellence at Penns Perelman School of Medicine and Abramson Cancer Center "We look forward to additional studies to help make this approach a reality in the clinical setting to personalize immunotherapy based treatment decisions for patients with metastatic non-small cell lung cancer."

The publication, titled Serial Monitoring of Circulating Tumor DNA by Next-Generation Gene Sequencing as a Biomarker of Response and Survival in Patients With Advanced NSCLC Receiving Pembrolizumab-Based Therapy, can be found here: doi.org/10.1200/PO.20.00321.

About Guardant Health

Guardant Health is a leading precision oncology company focused on helping conquer cancer globally through use of its proprietary blood tests, vast data sets, and advanced analytics. The Guardant Health oncology platform leverages capabilities to drive commercial adoption, improve patient clinical outcomes, and lower healthcare costs across all stages of the cancer care continuum. Guardant Health has commercially launched liquid biopsy-based Guardant360, Guardant360 CDx, and GuardantOMNI tests for advanced stage cancer patients, and Guardant Reveal test for early-stage cancer patients. These tests fuel development of its LUNAR screening program, which aims to address the needs of asymptomatic individuals eligible for cancer screening and individuals at a higher risk for developing cancer with early detection.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of federal securities laws, including statements regarding the potential scope, impact or benefit of Guardant Health liquid biopsies which involve risks and uncertainties that could cause the actual results to differ materially from the anticipated results and expectations expressed in these forward-looking statements. These statements are based on current expectations, forecasts and assumptions, and actual outcomes and results could differ materially from these statements due to a number of factors. These and additional risks and uncertainties that could affect Guardant Healths financial and operating results and cause actual results to differ materially from those indicated by the forward-looking statements made in this press release include those discussed under the captions Risk Factors and Managements Discussion and Analysis of Financial Condition and Results of Operation and elsewhere in its Annual Report on Form 10-K for the year ended December 31, 2020 as well as in its other reports filed with the Securities and Exchange Commission, including, when filed, its Quarterly Report on Form 10-Q for the period ended March 31, 2021. The forward-looking statements in this press release are based on information available to Guardant Health as of the date hereof, and Guardant Health disclaims any obligation to update any forward-looking statements provided to reflect any change in its expectations or any change in events, conditions, or circumstances on which any such statement is based, except as required by law. These forward-looking statements should not be relied upon as representing Guardant Healths views as of any date subsequent to the date of this press release.

REFERENCES

1. Raja R, Kuziora M, Philip Z. Brohawn PZ, et al. Early Reduction in ctDNA Predicts Survival in Patients with Lung and Bladder Cancer Treated with Durvalumab. Clin Cancer Res; 2018: 24(24): 6212-6222. DOI: 10.1158/1078-0432.CCR-18-0386.

2. Aggarwal C,Thompson JC, Chien A, et al. Dynamic monitoring of circulating tumor DNA next-generation gene sequencing as a predictive biomarker of response and progression-free survival after pembrolizumab monotherapy in patients with advanced NSCLC. J Clin Oncol; 2019: 37:15 suppl, 3040-3040. DOI:10.1200/JCO.2019.37.15.

3. Kim ST, Cristescu R, Bass AJ, et al. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat Med; 2018: 24(9):1449-1458. DOI: 10.1038/s41591-018-0101-z.

4. Shaw AT, Martini JF, Besse B, et al. Early circulating tumor (ct)DNA dynamics and efficacy of lorlatinib in patients (pts) with advanced ALK-positive non-small cell lung cancer (NSCLC). J Clin Oncol; 2019: 37:15_suppl, 9019-9019. DOI: 10.1200/JCO.2019.37.15.

5. Pascual J, Cutts RJ, Kingston B, et al. Assessment of early ctDNA dynamics to predict efficacy of targeted therapies in metastatic breast cancer: Results from plasmaMATCH trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-02.DOI: 10.1158/1538-7445.SABCS20-PS5-02.

6. Mack PC, Redman MW, Moon J, et al. Residual circulating tumor DNA (ctDNA) after two months of therapy to predict progression-free and overall survival in patients treated on S1403 with afatinib +/- cetuximab. J Clin Oncol; 2020: 38:15_suppl, 9532-9532. DOI: 10.1200/JCO.2020.38.15.

7. Maron SB, Chatila WK, Millang BM, et al, Pembrolizumab with trastuzumab and chemotherapy (PTC) in HER2-positive metastatic esophagogastric cancer (mEG): Plasma and tumor-based biomarker analysis. J Clin Oncol; 2020: 38:15_suppl, 4559-4559. DOI: 10.1200/JCO.2020.38.15.

8. Modi S, Park H, Murthy RK, et al. Antitumor Activity and Safety of Trastuzumab Deruxtecan in Patients With HER2-Low-Expressing Advanced Breast Cancer: Results From a Phase Ib Study. J Clin Oncol; 2020: 38(17):1887-1896. DOI: 10.1200/JCO.19.02318.

9. Zhang Q, Luo J, Wu S, et al. Prognostic and Predictive Impact of Circulating Tumor DNA in Patients with Advanced Cancers Treated with Immune Checkpoint Blockade. Cancer Discov; 2020: 10:12, 1842-1853. DOI: 10.1158/2159-8290.CD-20-0047.

10. Thompson JC, Carpenter EL, Silva BA, et al. Serial Monitoring of Circulating Tumor DNA by Next-Generation Gene Sequencing as a Biomarker of Response and Survival in Patients With Advanced NSCLC Receiving Pembrolizumab-Based Therapy. JCO Precis; 2021: 5, 510-524. DOI: 10.1200/PO.20.00321.

Source: Guardant Health, Inc.

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Study Shows Guardant360 Liquid Biopsy Predicts Response to Pembrolizumab-Based Immunotherapy in Patients with Metastatic Non-Small Cell Lung Cancer -...

Background

After DNA helical structure discovery, the world continuous staircase outburst of several advanced technologies, which are currently heading toward translation into clinical practice. Over the last decades, several molecular techniques developed that help to edit the DNA codes and modify mRNA by post-transcriptional modifications. Gene therapy is the delivery of specific genetic material to modify the encoding of a gene product or to change the biological properties of tissues for the management of various disorders.1 Gene therapy overcomes the limitations associated with the recombinant therapeutic use of peptides, such as low bioavailability, instability, severe toxicity, clearance rates, and high production cost.2 Gene therapies act by different mechanisms including, replacing malfunction genes with the therapeutic genes, gene knockdown, or deactivating problem genes, and insert a new gene to treat a disease.3 Gene therapy can be done in either somatic or germline cells. In somatic cells, gene therapy only the modified tissues will be affected, but in germline cell gene therapy, genetic changes transmit to the offspring. So, there is no clinical trial on human germline gene therapy.4 Currently, somatic gene therapy is safe for the management of several disorders in human beings. Gene therapy effectively treats several diseases due to increased understanding of disease pathogenesis and improved gene delivery technologies.5 Gene therapy uses genetic material (ie, RNA or DNA) via a vector that facilitates the delivery of foreign genetic material into the host organ. The genetic material is administered into the target organ (in vivo gene therapy) or used to modify cells taken from the host that are then re-administered (ex vivo gene therapy). Gene therapy aims to provide a functional gene copy of the damaged gene(s), increase the availability of disease-modifying genes or suppress the activity of a damaged gene.6,7 Gene therapy has a broad spectrum of applications, from gene replacement and knockdown for genetic disorders including cancer, hemophilia, hypercholesterolemia, and neurodegenerative diseases to vaccination, each with different requirements for gene administration.8 Gene delivery systems consist of three components: a gene that expresses essential therapeutic peptides, a plasmid-based gene encoding system that regulates the activity of a gene in the target organ, and a gene delivery system that regulates the administration of the encoding gene to host tissue.9

Conventional gene therapy mostly depends on viral-based delivery of genes that either randomly integrates into the host genome (eg retroviruses) or remains as extrachromosomal DNA copy (eg AAV]) and expresses a protein that is missing or mutated in human disorder. In contrast to traditional gene therapy, gene editing provides more versatile tools for gene therapy, for example, precisely correct point variants, place an extra, healthy gene at a safe genomic location or disrupt a gene. The Current gene-editing process depends on the introduction of endogenous double-strand DNA breaks (DSBs) and repair mechanisms. When DSBs occur by nucleases, cellular DNA repair mechanisms are activated. There are two main mechanisms for repairing double-strand breaks, non-homologous end joining (NHEJ) and homology-directed repair (HDR). Genome-editing nucleases can be modified to recognize and break the genome at specific DNA sequences, resulting in DSBs, which are efficiently repaired by either NHEJ or HDR.10,11

NHEJ repair damaged DNA without a homologous template. Due to this reason, NHEJ may lead to deletions or insertions of nucleotides in the damaged loci; thus, it is error-prone. HDR differs from NHEJ since it repairs DNA damages using a homologous template. Generally, having used a homologous sequence, this form of DNA repair has less chance to cause errors. From a clinical viewpoint, HDR is favorable for restoring mutations in genes or for integrating genes for therapeutic purposes.1013

Currently, there are four different gene-editing nuclease enzymes available based on their structures: meganucleases, zinc-finger nucleases, transcription activator-like effector nucleases, and CRISPR-associated nucleases.

Are sequence-specific endonucleases that recognize unique large (1440 bp) target sites. It has low cytotoxicity that makes it an attractive tool for genome editing. Existing engineering techniques include the creation of fusion protein from existing MN domains and engineering MN specificity via the direct alteration of protein residues in the DNA-binding domain. The complexity in re-engineering and low editing efficiency limits the uses of MNs.14

Artificially produced by fusing site-specific zinc finger protein with the non-specific cleavage domain of the FokI restriction endonuclease. The DNA-binding component has 36 zinc finger repeats, and each can identify between 9 and 18 base pairs. ZFN has three zinc fingers that each identifies three base pair DNA sequence to form a three-finger array that attaches to nine base pair target sites and the non-specific cleavage domain.14,15 ZFPs deliver a site-specific DSB to the genome and facilitate local homologous recombination that enhances targeted genome editing. The ZFN-encoding plasmid-based targeted administration of the required genes decreases the limitations of viral administration. If ZFNs are not specific at the target site, off-target break may occur. Such off-target breakage may cause DBS that causes cell death. An Off-target break may facilitate the random integration of donor DNA.15,16

Are artificial DNA nucleases formed by fusing a DNA-binding domain with a nonspecific nuclease domain derived from Fok I endonuclease that specifically cut the required DNA sequence.15 TALE effectors DNA-binding domain has a repeating unit of 3335 conserved amino acids. Each repeat is similar, except positions 12 and 13, which are variable and have a strong correlation with specific nucleotide recognition. DNA cleavage domain is nonspecific from FokI endonuclease. The FokI domain acts as a dimer that needs two constructs with unique DNA binding for sites in the target genome. Both the number of amino acids between the TALE DNA binding domain and the FokI cleavage domain are essential for better activity. TALEN uses to edit genomes by inducing DSB that cells respond to with repair mechanisms.17,18

CRISPR is a heritable, adaptive immune system of bacteria that provides them with the memory of previous virus infections and defends against re-infection. Contrary to the human adaptive immune system, CRISPR is passed on to the next generation of bacteria, rendering the colony immune to future virus infections. CRISPR immunity depends on the integration of the invaders DNA (virus or plasmid) into the bacterial genome.19 CRISPR helps the bacterium to identify the viral sequences and break. CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats, which are interrupted by spacer sequences. These spacer sequences are viral sequences integrated during past viral infections when transcribed into short RNA sequences, are capable of guiding the Cas endonuclease to complementary sequences of viral DNA. Upon target identification, Cas binds to the viral DNA and cleaves it, protecting the prokaryotic cell from infection.20,21 CRISPR immune system modified to create a gene-editing tool that can target changes to the DNA. The most common is CRISPR/Cas9, which posses the Cas9 endonuclease and a short noncoding guide RNA (gRNA) that contains two components: a target-specific CRISPR RNA (crRNA) and a helper trans-activating RNA (tracrRNA). The gRNA unit guides Cas9 to a specific genomic locus via base pairing between the crRNA sequence and the target sequence.22 CRISPR-Cas-mediated gene repair, disruption, insertion, or deletion are thus finding applications in several areas of biomedical research, medicine, agriculture, and biotechnology.22,23

Since the emergence of recombinant DNA technology that helps gene-therapy, how to effectively and safely administer gene products is the major challenge. Vector is a vehicle that uses to deliver the gene of interest. An ideal vector can administer a gene to a specific tissue, accommodate enough foreign gene size, achieve the level and duration of transgenic expression enough to correct the defect gene, non-immunogenic, and safe. Delivery of the gene products done by Viral Vectors, Bactofection, and none viral Vectors (chemical and physical) method as summarized in Figure 1.24 The most important step in achieving gene therapy is choosing the vectors.

Figure 1 Overview of the delivery systems used in gene therapy.

Viruses were the first and the most widely used vectors to administer genes into the target tissue. Viral vectors ensure that almost all cells can infect, without affecting cell viability. Viruses have distinctive features that make them suitable for gene delivery in clinical practice. Surface proteins on viruses interact with their host receptors, which activate endocytosis. Once entered, viruses release their genome into the nucleus for viral gene expression.25,26 Herpes simplex virus (HSV), adenovirus (Ad), adeno-associated virus (AAV), and lentivirus (LV) are the most important viral vectors.27,28

Some bacteria specifically target tumor cells leading to RNA interference (RNAi) and gene silencing by inhibiting RNA activity, such as protein synthesis. Several in vivo and in vitro studies revealed that intracellular bacteria such as Salmonella spp., Listeria monocytogenes, Shigella flexneri, Bifidobacterium longum, E. coli, and Yersinia enterocolitica use to deliver plasmids pro-drug converting enzymes and cytotoxic agents into the target cell.29 Phase I trial is undergoing by using Listeria, Bifidobacterium, Salmonella, Shigella, and Clostridium gene therapy against cancer. Another clinical trial is ongoing on the effects of Lactococcus synthesizing interleukin 10 against colitis in Phase II.30,31

Viral-vectors-based gene transfer displays better and long-term gene encoding but has some limitations like immunogenicity, less specific to the target cell, carcinogenicity, high cost and cannot deliver large genome size. Non-viral methods display better advantages due to relatively safe, can deliver a large genome, and ease for production.3235 Chemical vectors, also known as non-viral vectors grouped as organic and inorganic vectors. The organic vectors consist of cationic lipid-based vectors: synthetic cationic polymers-based vector and peptide-based vectors. These cationic organic vectors form complexes with negatively charged DNA via an electrostatic bond. The complexes protect the genomic material and enhance cell uptake and intracellular delivery. Generally, non-viral vectors help to deliver small DNA, large DNA (plasmid DNA), and RNA (Si RNA, m RNA) into the target tissue.3638 Physical methods use different mechanical forces to facilitate the administration of gene material into the host tissues. It is an alternative to viral and chemical methods to decrease barriers that limit DNA delivery into the host tissues.39 It is feasible to deliver genes into target tissues by mechanical force. Indeed, there are several methods, and most have a similar mode of gene delivery, ie, physically formed transient pores in the cell membrane through which the genetic material enters into the host cell.40,41 Needle and jet injection, hydrodynamic gene transfer, electroporation, sonoporation, magnetofection, and gene gun bombardment are examples of physical DNA delivering methods.4244

Cancer occurs due to disrupting the normal cell proliferation and apoptosis process. Advances in cancer therapy need a novel therapeutic agent with novel mode of action, several mechanisms of cell death, and synergy with conventional management. Gene therapies possess all these profiles. Several gene therapy approaches were developed for the management of cancer, including anti-angiogenic gene therapy, suicide gene therapy, immunotherapy, siRNA therapy, pro-apoptotic gene therapy, oncolytic virotherapy, and gene directed-enzyme prodrug therapy.45 By November 2017, greater than 2597 clinical trials were conducted on gene therapy in the world. Among these trials, greater than 65% are associated with cancer, followed by monogenetic and cardiovascular diseases.8 The use of CAR T cell therapy showed promising results for the management of both myeloid and lymphoid leukemia. Until August 2019, only 22 gene products were approved for the treatment of different disorders. Most gene products used for the treatment variety types of cancers as shown in Table 1. Immuno-gene therapy is a potential treatment approach for the treatment of p53-deficient tumors (Imlygic, Gendicine, Yescarta, and Kymriah.47

Table 1 Gene Therapies Products Approved for Therapeutic Use

Oncolytic virotherapy (OV) is the most promising approach for tumor immunotherapy. OV uses replication-competent viruses that can proliferate selectively at tumor cells. Oncolytic viruses grouped as naturally occurring or genetically modified viruses. Natural occurring viruses like parvoviruses, and Newcastle disease viruses that selectively replicate in tumor cell without genetic modification. The second virus category, such as vesicular stomatitis viruses, adenoviruses, measles viruses, HSV and vaccinia viruses, genetically modified to improve the safety, tumor-specificity, and decrease virus pathogenicity. The therapeutic use of oncolytic viruses for cancer treatment is an immune-related treatment alternative. Oncolytic viruses act by directly lyses tumor cells and by introducing wild-type tumor suppressor genes into cells that lack the tumor suppressor gene.48,49 Change in p53 gene function is present in half of all malignancies, and the induction of wild-type p53 gene re-establishes the normal p53 expression. Several recombinant OVs expressing p53 were developed with the aim of producing more potent OVs that act in combination with host immunity or with other treatments modality to destroy tumor cells.49,50

Was the first approved gene product for the management of neck and head squamous cell carcinoma in 2003.50 Gendicine is a non-replicative an adenoviral vector, where the E1 gene is replaced with the tumor suppressor p53 cDNA gene. The expression of p53 in tumor cells triggers the antitumor effect by activating the apoptotic pathway, inhibit damaged DNA repair, and anti-apoptotic activity. P53 gene mutation is prevalent in several cancers. Therefore, Gendicine induces the expression of p53 restores its activity and destroys the tumor cells. Generally, Gendicine management showed 3040% complete response and 5060% partial response with a total response rate of 90%96% in different therapeutic use. Up-to-date greater than 30,000 patients managed by Gendicine.50,51

It is the first replicative, oncolytic recombinant ad5 (rAd5-H101) approved to treat refractory nasopharyngeal cancer. Loss of p53 gene linked with drug resistance and survival rate reduction in non-small cell cancer patients.50 Oncorine is an ad5 virus with a deletion in the E1B 55K gene. Host cell p53 gene inactivation is essential for wild-type to block the activation of apoptotic pathway. The removal of the E1B 55K gene inhibits viral proliferation in normal cells, allowing only proliferate in p53-deficient host cells. In tumor cells, viral proliferation causes oncolysis that is the mechanism to treat solid tumors. Following cancer cell lysis, adenoviruses release and infect another cell activating a serious of Oncorine-mediated cell death.52,53

It is a genetically modified oncolytic HSV-1 approved in Europe in 2015 for the management of non-resectable metastatic melanoma. Imlygic is the first oncolytic virus used for the management of advanced melanoma.48 The replacement of 34.5 and 47 genes with the human granulocyte-macrophage colony-stimulating factor (GM-CSF) gene modifies the HSV-1 gene. The 34.5 gene deletion causes tumor cell-selective replication and suppression of pathogenicity. The 34.5 gene blocks protein synthesis of the host cell during viral infection. Thus, suppressing 34.5 seizes the virus proliferation in normal cells. In tumor cells, the 34.5 gene deleted HSV-1 can replicate. The 47gene inhibits the host cell transporter associated with antigen presentation. The depletion of 47gene reduces MHC class I expression that increases antitumor immune activity.53 Besides, two human GM-CSF genes inserted into the virus providing high levels of GM-CSF production, and stimulate immune responses. Administration of Imlygic causes apoptosis of tumor cell enhanced antigen presentation and increased antitumor response.49,54

Is the first targeted injectable vector approved for the management of metastatic cancers. It is a replication-incompetent retroviral vector showing a SIG-binding peptide to bind to abnormal Signature (SIG) proteins in the tumor cell that increase vector concentration in tumor cells and express a dominant-negative human cyclin G1 inhibitor. After the entrance into the tumor cells, Rexin-G synthesizes cytocidal dnG1 proteins that inhibit the cell cycle in the G1 phase resulting in apoptosis of cancer cells.55,56

T cells destroy infected and tumor cells by detecting nonself antigens with the T cell receptor (TCR). CAR T is a T cell transduced with a chimeric antigen receptor specific to a tumor-associated antigen. CAR is chimeric because it contains the antigen-binding site of the B cell receptor and an intracellular TCR activation domain. CAR has three domains, an extracellular domain that has cancer-specific epitopes (scfv region) made from light (VL) and heavy (VH) chains of immunoglobin that target antigen (such as CD19), a transmembrane domain, and intracellular TCR derived stimulatory domains as showed in Figure 2. The scfv component binds to the target antigen in the MHC independent way leading to CAR clustering and stimulating T-cell via intracellular region that posses the TCR-derived CD3 chain, with or without co-stimulatory domains. Stimulated CAR T-cells give target-specific memory cells that inhibit tumor relapse.57 CD19targeted CAR T cells were the first CARs to be studied. CD19 is a promising target due to its expression limited to the B cell. Firstgeneration, CD19targeted CAR T cells were safe but ineffective. Second-generation CARs have a costimulatory domain with the CD3 activation domain show enhanced T cell activity. Two secondgeneration, CD19targeted CARs are in clinical use contain a 41BB costimulatory domain (19BBz) and a CD28 costimulatory domain and those with more than one additional co-stimulatory molecule are known as third-generation CAR.5759

Figure 2 Schematic diagram of CAR-T-cell products.

It is the first FDA approved CAR T-cell-based gene product to treat relapsed B-cell acute lymphoblastic leukemia. Kymriah has autologous T cells, modified with the lent virus to encode a CAR consist of a murine single-chain antibody fragment (scFv) selective for CD19, an intracellular domain 41BB (CD137), and CD3 zeta with CD8 transmembrane hinge. After binding to CD19 antigen-expressing cells, Kymriah initiates the antitumor effect via the CD3 domain. The intracellular 41BB co-stimulatory domains enhance the antitumor activity. The CD19 antigen is a 95-kD glycoprotein encoded as a surface antigen in diffuse large B-cell lymphoma (DLBCL) and other B-cell lymphomas.60,61 High response rates were recorded in patients with refractory DLBCL in Phase 2 clinical trials. The response rate was 50% at 3 months, 43% with a complete response at 6 months, and there were no patients with a complete response at 6 months who had a relapse by the median of 28.6 months.62

It is another CAR T-cell therapy used for the management of aggressive non-Hodgkin lymphoma. It is CD19 antigen-specific ex-vivo modified autologous T cells infected with a gamma-retroviral. It encodes a CAR comprising an extracellular murine anti-CD19 single-chain variable fragment fused to a cytoplasmic domain that possesses CD28 and CD3-zeta co-stimulatory domains.63,64

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) uses for the management of several hematopoietic malignancies. But, acute graft-versus-host-disease (aGvHD) and Graft rejection are barriers to its success. The treatment strategy for haplo-HSCT depends on T-cell depletion or administration of lymphotoxin agents like cyclophosphamide after stem cell infusion to selectively deplete activated alloreactive lymphocytes but causes prolonged immunodeficiency post-transplantation. Thus, treatment to enhance immune reconstitution after transplantation is necessary.65 Zalmoxis is a genetically modified allogeneic T cell using a retroviral vector encoding a human low-affinity nerve growth factor receptor (LNGFR) and HSV-TK Mut2 to transduce the allogeneic T immune cells. The LNGFR expression uses as a marker of the transduced T cells, and the HSV-TK Mut2 expression provides the suicide gene induction during the administration of the prodrug ganciclovir (GCV). Administration of the genetically modified donor T cells to T cell-depleted transplant patients (HSCT) reconstitutes the immunity to defend from infections. But, donor cells may specifically act as the host cells leading to Graft Versus Host Disease (GVHD). In this case, induction of suicide gene by GCV administration may kill the donor T cells encoding HSV-TK and control GVHD. Zalmoxis is a potential curative agent for HSCT patients when the matched donor does not exist. Zalmoxis provides post-transplant GvHD control, Graft versus Leukemia (GvL) improvement, relapse decrease, and immune reconstitution causes reduced infection.52,66

Gene silencing therapy is RNA interference (RNAi)-mediated knockdown of specific genes in tumor cells. RNAi is single or double-stranded noncoding RNAs (21 ribonucleotides) that induce sequence-specific degradation of complementary mRNAs via the cells internal machinery.67 siRNA is vital because most genes do not have inhibitors due to a lack of ligand binding sites and amino acid sequence homology with other proteins that limit target selectivity. RNAi consists of microRNA (miRNA), Small Interfering RNA (siRNA) and short hairpin RNA (shRNA). Two decades later after the discovery of RNAi, ONPATTRO (patisiran) approved for the first time for the management of the polyneuropathy of hereditary transthyretinmediated (hATTR) amyloidosis.68 Tumor suppressor genes, oncogenes, genes involved in cancer progression, and drug-resistance are promising targets for gene silencing by RNAi-based cancer treatment due to selective gene silencing effect and relatively fewer adverse effects than conventional chemotherapy.69 The merits of RNAi in cancer treatment are targeting several genes of different cellular pathways involved in cancer progression and develop a drug for a specific patient.70 Several studies conducted on animals revealed that targeting vital proteins in the cell cycle, such as Protein kinase N3 (PKN3), kinesin spindle protein (KSP), and polo-like kinase 1 (PLK1) by siRNA displayed a potent antitumor effect. Several liposomal siRNA dose preparations are in Phase 1 trials, such as treatments for pancreatic cancer (PKN3 siRNA), liver cancer (CEBPA siRNA), and neuroendocrine tumors (PLK1 siRNA).71

Suicide gene therapy uses viral or bacterial genes into malignant cells that metabolize non-toxic prodrug into a toxic compound. Several suicide gene systems were identified including the HSV-thymidine kinase gene (HSV-TK) with ganciclovir (GCV) and the cytosine deaminase gene (CD) with 5-fluorocytosine (5-FC).72 Gene-mediated cytotoxic immunotherapy is one strategy where an adenoviral vector possessing the herpes virus thymidine kinase gene (AdV-TK) is administered locally into the tumor site that causes local expression of the HSV-TK gene to the synthesis of viral thymidine kinase that converts GCV to GCV monophosphate. The next step is the administration of GCV that is a substrate of HSV-TK and phosphorylated to produce GCV monophosphate. Then, cellular kinases metabolize GVC-monophosphate into GVC-triphosphate. GCV triphosphate is a deoxyguanosine triphosphate analog, incorporated into the DNA chain causing chain termination and tumor cell death.73

The anti-tumor effect of the TK/GCV system showed promising results in animal models. A study on hormone-refractory prostate cancer patients treated with HSV-TK delivered by adenovirus followed by GCV. The result showed response was at the surrogate marker level and safe. Several studies are in Phase III trials.74 The cytosine deaminase (CD) enzyme exists in fungi and bacteria but not in mammalian cells, metabolizes cytosine into uracil. CD metabolizes the non-toxic prodrug 5-FC into 5-FU, which is subsequently metabolized by cellular enzymes into 5-FdUMP, 5-FdUTP, and 5-FUTP. Inhibition of thymidylate synthase and production of (5-FU) DNA and RNA are the mode of cell death induced by the CD/5-FC suicide system. 5-FU uses for cancer treatment but requires a high dose. This suicide system results in tumor-targeted chemotherapy with few side effects. The CD/5-FC system improved by the inclusion uracil phosphoribosyltransferase (UPRT) gene that phosphorylates 5-FU to 5-fluorouridine mono-phosphate, the first step of its pathway to activation.75 The anti-tumor effect of the CD/5-FC combination showed a better efficacy in animal models. A study on refractory cancer patients that involved intratumoral administration of TAPET-CD attenuated Salmonella bacterium encoding the E. coli CD gene in three patients. The study showed a significant effect and lack of side effects. An oncolytic adenovirus possessing a CD/HSV-1 TK gene was used in a phase I study in patients with prostate cancer. The result showed that the transgene encoding persistence in the prostate for 3 weeks after administration.76

Tumor-driven angiogenesis several growth factors are involved, such as vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), angiopoietins or IL-8, to secure oxygen and nutrients supply. Two major approaches are being pursued to block tumor angiogenesis. The first approach is down-regulation of pro-angiogenic factors expression, such as VEGF, and the second approach is up-regulation of expression of anti-angiogenic factors such as angiostatin, endostatin, and human soluble FMS-like tyrosine kinase receptor. Despite the successful therapeutic use of mAb like Bevacizumab for targeted therapy of cancer, the production and administration of therapeutic mAb are limited due to costly production. Therefore, gene-based studies were done to develop an angiogenesis-targeted cancer treatment.77,78

Gene therapy represents a novel alternative for the management of diseases that have no satisfactory cure. Gene therapy for cancer treatment has good progress in the last three decades, few drugs approved, while others are still in trials. Relatively gene therapy has better safety with tolerable adverse effects than chemotherapy for the treatment of cancer. In the future, tumor genomic analysis, assessment of host humoral and cellular immunity will facilitate a better selection of the most appropriate patient for gene therapy. Recent progress in developing safe and effective vectors for gene delivery, and understanding the activity of nucleases facilitate future genome editing as new treatment approaches for untreatable diseases like cancer.

The success of using autologous and allogenic chimeric antigen receptor integrated T-lymphocytes in mediating adoptive immunotherapy enhances the safety and effectiveness of gene therapy. Besides, the enhanced biological research, cheaper gene vectors will be available in the market, which increases gene therapy accessibility for most cancer patients. This will change the future of cancer treatment, from generalized cancer treatment strategies to individualized cancer treatment, based on the patients specific genome, immune status, and genetic profile of the tumor. Gene therapy is expected to be fast, effective, less toxic, and inexpensive, with higher cure rates. In November 2017, more than 2597 clinical trials are ongoing in several countries and a few of them are listed in Table 2. Until August 2019, 22 gene medicines had been approved by the drug regulatory agencies from various countries.79 Gene therapy gradually accepted by the government and the public since the 1980s and has become an important alternative to the existing treatments in the past few years. Therefore, gene therapy drugs, with safe vectors and advanced biotechnologies, would play a greater role in the prophylaxis and management of cancer in the future.

Table 2 Gene Therapies Products Candidates Under Clinical Trial

ADA, adenosine deaminase; Ad, adenovirus; AAV, adeno-associated virus; aGvHD, acute graft-versus-host-disease; allo-HSCT, allogeneic hematopoietic stem cell transplantation; CRISPR, Clustered Regularly Interspaced Short Palindromic Repeats; CAR, chimeric antigen receptor; DSBs, double-strand breaks; ERT, enzyme replacement therapy; HDR, homology-directed repair; HSV, herpes simplex virus; IRDs, inherited retinal degenerations; LV, lentivirus; NHEJ, non-homologous end joining; NMDs, neuromuscular disorders; OV, oncolytic virotherapy; tracrRNA, trans-activating RNA; TCR, T cell receptor; MNs, meganucleases.

All data are provided in the manuscript or found from published papers as cited.

I would like to acknowledge Mrs Fasika Abu for editing the manuscript for English Style.

The authors declare no competing interests in this work.

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[Full text] Current status of gene therapy for the treatment of cancer | BTT - Dove Medical Press

-- Protein expression in muscle was sustained for two years following treatment in the low dose cohort, with mean beta-sarcoglycan expression of 54% at 24 months, compared to 36% at Day 60, as measured by western blot ---- Mean NSAD score improvement of 5.7 points from baseline was sustained through 24 months in low-dose cohort, and mean NSAD score improvement of 4.0 points from baseline at one year in high-dose cohort ---- Results in both cohorts continue to reinforce the safety and tolerability profile of SRP-9003 --

CAMBRIDGE, Mass., March 18, 2021 (GLOBE NEWSWIRE) -- Sarepta Therapeutics, Inc.(NASDAQ:SRPT), the leader in precision genetic medicine for rare diseases, today shared new results from the ongoing study of SRP-9003 (rAAVrh74.MHCK7.hSGCB), the Companys investigational gene therapy for limb-girdle muscular dystrophy Type 2E (LGMD2E). In the first look at expression data from biopsies taken two years after a single administration of SRP-9003, results found sustained protein expression in muscle tissue. In functional outcomes assessments taken two years following treatment in Cohort 1 (low-dose cohort) and one year after treatment in Cohort 2 (high-dose cohort), patients continued to demonstrate stability in their NSAD (North Star Assessment for Dysferlinopathies) total score and improvements on timed function tests. Results are being presented today at the 2021 Muscular Dystrophy Association (MDA) Annual Clinical and Scientific Conference.

SRP-9003 is in development for the treatment of LGMD2E (also known as beta-sarcoglycanopathy and LGMDR4), a devastating monogenic neuromuscular disease caused by a lack of beta-sarcoglycan (beta-SG) proteins. SRP-9003 is a gene therapy construct that transduces skeletal and cardiac muscle, delivering a gene that codes for the full-length beta-SG protein, the absence of which is the sole cause of the progressive degeneration and a shortened lifespan characterized by the disease.

This data is the first look at longer-term expression data with any gene therapy for muscular dystrophy. The meaningful and sustained levels of beta-sarcoglycan protein expression at two years and continued strength of the functional outcomes measured are tremendously positive and support continued advancement of this investigational treatment for patients, said Louise Rodino-Klapac, Ph.D., executive vice president and chief scientific officer, Sarepta Therapeutics. In Cohort 2, we also saw strong expression of delta-sarcoglycan and gamma-sarcoglycan proteins in addition to beta-sarcoglycan, which suggests that SRP-9003 is working to restore the dystrophin associated protein complex, or DAPC, which provides biological support for the sustained functional benefits observed in both cohorts. LGMD2E is one of the most severe forms of LGMD and causes significant disability in children while frequently leading to early mortality and the data continue to suggest this treatment could bring much needed hope to these patients.

Efficient transduction in skeletal muscle and robust beta-sarcoglycan protein expression were seen in both dose cohorts following infusion with SRP-9003, and significant creatine kinase (CK) reductions were observed.

Cohort 1 (Dosed at 1.851013 vg/kg), 24 months following treatment:

Cohort 2 (Dosed at 7.411013 vg/kg), 12 months following treatment:

In an exploratory evaluation of all SRP-9003 treated patients compared to a natural history cohort; patients treated with SRP-9003 demonstrated significant improvements in functional outcomes after 24 months. The mean decline in total NSAD score for patients in the natural history cohort was 4.6 points while SRP-9003 treated patients demonstrated a mean improvement of 4.6 points for a clinically meaningful difference of 9.2 points.

Since the last update from this study in October 2020, there have been no new drug-related safety signals observed, and no decreases in platelet counts outside of the normal range and no evidence of clinical complement activation observed in either dose cohort.

About SRP-9003 and the StudySRP-9003 uses the AAVrh74 vector, which is designed to be systemically and robustly delivered to skeletal, diaphragm and cardiac muscle, making it an ideal candidate to treat peripheral neuromuscular diseases. AAVrh74 has lower immunogenicity rates than reported with other human AAV vectors. The MHCK7 promoter has been chosen for its ability to robustly express in the heart, which is critically important for patients with limb-girdle muscular dystrophy Type 2E (LGMD2E), also known as beta-sarcoglycanopathy and LGMDR4, many of whom die from pulmonary or cardiac complications.

This open label, first-in-human study is evaluating a single intravenous infusion of SRP-9003 among children with LGMD2E between the ages of 4 and 15 years with significant symptoms of disease. The SRP-9003 study has two cohorts, each studying a different dose-per-kilogram based on the weight of the patient. Three participants in the low-dose cohort (Cohort 1) were treated with a one-time infusion of SRP-9003 dosed at 1.851013 vg/kg and an additional three participants in the high-dose cohort (Cohort 2) received a one-time infusion dosed at 7.411013 vg/kg based on linear standard qPCR titer method. The six participants were between the ages of 4 and 13. Post-treatment biopsies were taken at 60 days.

Sarepta has exclusive rights to the LGMD2E gene therapy program initially developed at the Abigail Wexner Research Institute at Nationwide Childrens Hospital.

About Limb-girdle Muscular DystrophyLimb-girdle muscular dystrophies are genetic diseases that cause progressive, debilitating weakness and wasting that begin in muscles around the hips and shoulders before progressing to muscles in the arms and legs.

Patients with limb-girdle muscular dystrophy Type 2E (LGMD2E) begin showing neuromuscular symptoms such as difficulty running, jumping and climbing stairs before age 10. The disease, which is an autosomal recessive subtype of LGMD, progresses to loss of ambulation in the teen years and often leads to early mortality. There is currently no treatment or cure for LGMD2E.

Sarepta has five LGMD gene therapy programs in development, including subtypes for LGMD2E, LGMD2D, LGMD2C, LGMD2B and LGMD2L, and holds an option for a sixth program for LGMD2A.

AboutSarepta TherapeuticsAt Sarepta, we are leading a revolution in precision genetic medicine and every day is an opportunity to change the lives of people living with rare disease. The Company has built an impressive position in Duchenne muscular dystrophy (DMD) and in gene therapies for limb-girdle muscular dystrophies (LGMDs), mucopolysaccharidosis type IIIA, Charcot-Marie-Tooth (CMT), and other CNS-related disorders, with more than 40 programs in various stages of development. The Companys programs and research focus span several therapeutic modalities, including RNA, gene therapy and gene editing. For more information, please visitwww.sarepta.comor follow us onTwitter,LinkedIn,InstagramandFacebook.

Forward-Looking StatementsThis press release contains "forward-looking statements." Any statements contained in this press release that are not statements of historical fact may be deemed to be forward-looking statements. Words such as "believes," "anticipates," "plans," "expects," "will," "intends," "potential," "possible" and similar expressions are intended to identify forward-looking statements. These forward-looking statements include statements regarding, SRP-9003 being the ideal candidate to treat peripheral neuromuscular diseases; the potential benefits of SRP-9003, including its potential to restore the dystrophin associated protein complex (DAPC); the potential benefits of MHCK7 and the AAVrh74 vector, including its potential to be systemically and robustly delivered to skeletal, diaphragm and cardiac muscle; and potential market opportunities.

These forward-looking statements involve risks and uncertainties, many of which are beyond our control. Known risk factors include, among others: success in preclinical trials and clinical trials, especially if based on a small patient sample, does not ensure that later clinical trials will be successful; the data presented in this release may not be consistent with the final data set and analysis thereof or result in a safe or effective treatment benefit; different methodologies, assumptions and applications we utilize to assess particular safety or efficacy parameters may yield different statistical results, and even if we believe the data collected from clinical trials of our product candidates are positive, these data may not be sufficient to support approval by the FDA or foreign regulatory authorities; if the actual number of patients suffering from LGMD is smaller than estimated, our revenue and ability to achieve profitability may be adversely affected; we may not be able to execute on our business plans and goals, including meeting our expected or planned regulatory milestones and timelines, clinical development plans, and bringing our product candidates to market, due to a variety of reasons, some of which may be outside of our control, including possible limitations of company financial and other resources, manufacturing limitations that may not be anticipated or resolved for in a timely manner, regulatory, court or agency decisions, such as decisions by the United States Patent and Trademark Office with respect to patents that cover our product candidates and the COVID-19 pandemic; and even if Sareptas programs result in new commercialized products, Sarepta may not achieve the expected revenues from the sale of such products; and those risks identified under the heading Risk Factors in Sareptas most recent Annual Report on Form 10-K for the year ended December 31, 2020 filed with the Securities and Exchange Commission (SEC) as well as other SEC filings made by the Company which you are encouraged to review.

Any of the foregoing risks could materially and adversely affect the Companys business, results of operations and the trading price of Sareptas common stock. For a detailed description of risks and uncertainties Sarepta faces, you are encouraged to review the SEC filings made by Sarepta. We caution investors not to place considerable reliance on the forward-looking statements contained in this press release. Sarepta does not undertake any obligation to publicly update its forward-looking statements based on events or circumstances after the date hereof.

InternetPosting of InformationWe routinely post information that may be important to investors in the 'For Investors' section of our website atwww.sarepta.com.Weencourageinvestorsandpotentialinvestorsto consult our website regularly for important information about us.

Source:Sarepta Therapeutics, Inc.

Sarepta Therapeutics, Inc.

Investors:Ian Estepan, 617-274-4052iestepan@sarepta.com

Media:Tracy Sorrentino, 617-301-8566tsorrentino@sarepta.com

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Sarepta Therapeutics' Investigational Gene Therapy SRP-9003 for the Treatment of Limb-Girdle Muscular Dystrophy Type 2E Shows Sustained Expression and...

Dive Brief:

Biotech as a whole had a strong year in 2020. The Nasdaq Biotechnology index, which tracks the industry's stock market performance, rose by nearly 25%, recovering from a spring slump as COVID-19 became a pandemic to regain ground strongly.

Cell and gene therapy companies did even better, according to ARM, which calculated in its report stock performance that surpassed the broader NBI index.

The regenerative medicine sector, which includes tissue-based treatments as well as cell- and gene-based medicines, got larger, too. ARM counted roughly 1,100 developers worldwide, up about 100 from 2019.

"The future is now," said Janet Lambert, ARM's CEO, in an interview. "It's not like we're waiting for there to be a big and meaningful cell and gene therapy sector. There is a big and meaningful cell and gene therapy sector."

Recently, however, some of the most advanced companies have run into regulatory roadblocks or revealed disappointing study results. Cancer cases reported in trials of two closely followed gene therapies have renewed safety concerns, even if it appears the experimental treatments have not played a causative role.

Setbacks are to be expected amid the sector's fast growth, said Lambert, who noted the roughly 150 late-stage studies now ongoing. Many of those programs likely won't succeed, given the usual rates of clinical trial failure in biotech.

Unlike in the past, however, the pipeline of cell and gene therapies is so broad, and the number of companies involved so high, that setbacks for any one program are less likely to slow the entire sector than in past decades. And while the Food and Drug Administration has not cleared any new gene therapies since landmark approvals for Roche's inherited blindness treatment Luxturna and Novartis's spinal muscular atrophy therapy Zolgensma, the agency recently OK'd new CAR-T cell therapies for types of lymphoma.

Across Europe, the U.S. and China, regulators are expected to decide on approvals for eight regenerative medicine therapies this year, according to ARM. In the U.S., cancer cell therapies from Bristol Myers Squibb and Johnson & Johnson could reach market, as well as a tissue-based treatment from Mallinckrodt for severe burns.

Developers and regulators are also learning quickly, particularly in areas like manufacturing and quality control.

"One of the important things we need to work on is how best to regulate the [chemistry, manufacturing and control] aspects of cell and gene therapy," said Lambert.

"It's clearly a place we've struggled," she added, noting recent disagreements between the FDA and developers over CMC issues like testing assays.

ARM members are hoping to have more conversations with the agency earlier, Lambert said, although the FDA division in charge of cell and gene therapies has been stretched thin. In comments to the agency, ARM has advocated for the division to receive more resources and staff in renegotiations for the next FDA user fee agreement that will start in 2023.

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Record funding flowed into cell, gene therapy companies last year - BioPharma Dive