Category Archives: Gene Medicine

Amid the surge in Omicron cases, one of the commonly asked questions is how long should an infected patient quarantine, especially if they are double-vaccinated.

As per World Health Organization (WHO), the overall threat posed by the variant of concern largely depends on three key aspects its transmissibility, how well the vaccines and prior SARS-CoV-2 infection protect against it, and how virulent the variant is as compared to other variants.

Dr Abhishek Subhash, Consultant Internal Medicine at Bhatia Hospital said that in India, currently, the isolation period for Omicron patients is 14 days. In the US, it is 10 days for vaccinated patients, and five days after taking the booster shots.

In the US, where the Holiday season is in progress, there is a recommendation to reduce the 10-day quarantine, as per White House medical adviser Anthony Fauci.

Thats certainly an important consideration which is being discussed right now, said Fauci, director of the National Institute of Allergy and Infectious Diseases, reported CNN. This will help asymptomatic people return to work or school, the proper precautions, as per Fauci.

While breakthrough infections are rising among the fully vaccinated population, the symptoms are milder, experts point out. As a result of extensive vaccination drives, the severity of the disease is milder and has shown good response to conventional medications that we use for Covid 19, said Dr Gopi Krishna Yedlapati, consultant interventional pulmonologist, Yashoda Hospitals, Hyderabad.

Countries can and must prevent the spread of Omicron with proven health and social measures. Our focus must continue to be to protect the least protected and those at high risk, said Dr Poonam Khetrapal Singh, Regional Director, WHO South-East Asia Region.

How is Omicron detected?

As per Indias Ministry of Home and Family Affairs (MoHFW), the most accepted and commonly used method of diagnostic for SARS-CoV2 variant is the RT-PCR method. This method detects specific genes in the virus, such as Spike (S), Enveloped (E) and Nucleocapsid (N) etc to confirm the presence of virus.

However, in case of Omicron, as the S gene is heavily mutated, some of the primers may lead to results indicating absence of the S gene (called as S gene drop out). This particular S gene drop out along with the detection of other viral genes could be used a diagnostic feature of Omicron. However, for final confirmation of the omicron variant genomic sequencing is required, reads the Ministrys statement.

Treatment

The treatment protocols are similar in both delta and omicron, that is isolation for 14 days and strict monitoring of the infection and proper check-up with the pulmonologist, stated Dr Yedlapati.

Even if it does cause less severe disease, the sheer number of cases could once again overwhelm health systems. Hence, as per WHO, health care capacity including ICU beds, oxygen availability, adequate health care staff and surge capacity need to be reviewed and strengthened at all levels.

How to prevent it?

The precautions and steps to be taken remain same as before. As per MoHFW, it is essential to mask yourself properly, take both doses of vaccines (if not yet vaccinated), maintain social distancing and maintain good ventilation.

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Double vaccinated and still infected with Omicron? Heres how long you should isolate - The Indian Express

Physicians at a Boston hospital adjusted medical management for nearly three-quarters of patients with infantile- or childhood-onset epilepsy who were diagnosed with genetic epilepsy, researchers reported at the annual meeting of the American Epilepsy Society. The findings provide new insight into the usefulness of genetic tests in children with epilepsy of unknown cause.

Genetic testing is significantly impacting medical care in a population of individuals with infantile- or childhood-onset epilepsy. Genetic testing should be included as part of the standard evaluation of individuals with unexplained pediatric epilepsy as a means of achieving diagnostic precision and informing clinical management, study lead author Isabel Haviland, MD, a neurologist with Boston Childrens Hospital/Harvard Medical School, said in an interview.

According to Haviland, the causes of epilepsy are unexplained in an estimated two-thirds of pediatric epilepsy cases. Increasingly, when genetic testing is available, previously unexplained cases of pediatric epilepsy are being found to have single-gene etiologies, she said. Though a genetic diagnosis in this population has implications for medical care, the direct impact on medical management in a clinical setting has not been measured. We aimed to describe the impact of genetic diagnosis on medical management in a cohort of individuals with pediatric epilepsy.

Researchers tracked 602 patients at Boston Childrens Hospital who received next-generation gene sequencing testing from 2012 to 2019. Of those, Haviland said, 152 (25%) had a positive result that indicated genetic epilepsy (46% female, median age of onset = 6 months [2-15 months]). These patients were included in the study.

We documented an impact on medical management in nearly three-fourths of participants (72%), Haviland said. A genetic diagnosis affected at least one of four categories of medical management, including care coordination (48%), treatment (45%), counseling about a change in prognosis (28%), and change in diagnosis for a few individuals who had a prior established diagnosis (1%).

As examples, she mentioned three cases:

Testing revealed that a subject has a disease-causing genetic variant in a gene called PRRT2. This gene is involved in the release of neurotransmitters in the brain, Haviland said. Thanks to his diagnosis, he was treated with the antiseizure medication oxcarbazepine, which is often effective for epilepsy caused by variants in this gene. He had excellent response to the medication and later became seizure free.

A subject had a variation in the SCN1A gene that causes types of epilepsy. At the time of his diagnosis, there was a trial for a medication called fenfluramine being offered for individuals with SCN1A variants, and his family elected to participate, she said. This medication was later approved by the [Food and Drug Administration] for SCN1A-related epilepsy.

Testing identified disease-causing variant in the GRIN2A gene in another subject. This gene is involved in brain cell communication, Haviland said. This individual was treated with memantine, which acts on the specific biological pathway affected by the gene. This treatment would not have been considered without the genetic diagnosis as it is currently only approved for Alzheimers disease.

In addition, Haviland said, researchers found that there was impact on medical management both in those with earlier age of epilepsy onset (under 2 years) and those with later age of onset, as well as both in those with developmental disorders (such as autism spectrum disorder, intellectual disability and developmental delay) and those with normal development.

As for the cost of genetic tests, Haviland pointed toa 2019 studythat she said estimated epilepsy panel testing runs from $1,500 to $7,500, and the whole exome sequencing from $4,500 to $7,000. Insurers sometimes cover testing, but not always, she said. In some cases, insurance will only cover testing if it is documented that results will directly alter medical management, which highlights the importance of our findings.

No study funding was reported. Haviland and several other authors report no disclosures. One author reports consulting fees from Takeda, Zogenix, Marinus, and FOXG1 Research Foundation. Another author reports research support from the International Foundation for CDKL5 Research.

This story originally appeared onMDedge.com, part of the Medscape Professional Network.

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Genetic Tests Prompt Therapy Adjustments in Epilepsy - Medscape

The Omicron variant of COVID-19 has quickly taken over as the dominant strain of the virus in the United States. Omicron, which was responsible for just 0.7% of COVID-19 cases in the country on December 4, was responsible for a whopping 73.2% of cases on December 18and that percentage is expected to grow.

With this, Omicron has unseated the Delta variant as the dominant strain of SARS-CoV-2, the virus that causes COVID-19, in the country. If youre diagnosed with COVID-19, its more than understandable to want to know what strain of COVID you have. While doctors say this isnt easy information to obtaineven for themthere may be a way to learn what strain of COVID-19 you have. Heres what you need to know about how to know what strain of COVID you have.

When the Centers for Disease Control and Prevention (CDC) releases information on percentages of variants in the U.S., theyre not analyzing every single positive test in the country to get those numbers, explains Thomas Russo, M.D., professor and chief of infectious disease at the University at Buffalo in New York.

Instead, the CDC conducts genetic sequencing on a percentage of positive tests across the country. For example, to get the latest results, the CDC analyzed 160 test results from Alabama, 4,157 from Arizona, 18,424 from California, and so on, to get a breakdown of what percentage of those positive tests matched up with a particular strain of COVID-19.

CDC officials and lab technicians dont even know whose test results theyre analyzingfor privacy purposes, theyre de-identified before testing. Meaning, your name is taken out of the equation. As a result, the CDC couldnt call you or your doctor and say what strain of COVID-19 you had, even if they had the manpower to do it, Dr. Russo points out.

Not usually, and there are a few reasons for this. The tests that are run by doctors in offices and hospitals dont sequence and specify the variant, says infectious disease expert Amesh A. Adalja, M.D., a senior scholar at the Johns Hopkins Center for Health Security. The rapid antigen tests that are often used to get quick results instead just tell if the test result is positive or negative for COVID-19.

Even a PCR test, which is considered the gold standard of COVID-19 testing, is not going to tell youits not going to sequence the test, Dr. Adalja says. PCR testing can also take days to give you results, which is why your doctor will typically just do a rapid test in their office to help you know quickly whether you have COVID-19 or not, Dr. Russo explains.

Heres where things get a little tricky. The Omicron variant has a particular genetic sequencing that can show up differently on PCR test results that you wouldnt see with other strains of COVID-19, like Delta. Its called S-gene target failure and can show up as a band drop-out on the test results, Dr. Russo says.

This can give you a hint that its Omicron, but its not definitive, Dr. Adalja says. Right now, if you got a PCR test, the lab technician could tell you that this looks consistent with Omicron.

That said, Dr. Adalja points out that most family medicine doctors arent going to be asking about thisthey typically just want to know if you're positive or negative. Its more something that infectious disease experts and microbiologists would ask about. Still, he says, If you wanted to know and your doctor gave you a PCR test, you could ask them if there was S-gene target failure. If there is, for all intents and purposes, thats an Omicron.

Theres a slight caveat with all of this, though: Dr. Russo points out that not every case of Omicron shows up with S-gene target failure on a PCR test result. Were still trying to understand why that is, he says. So, its possible to have Omicron and not have that show up on a PCR test resultor you could simply be infected with the Delta strain.

It wont be a slam-dunk diagnosis, but there may be some indication if you have one variant or the other, depending on your COVID-19 symptoms and vaccination status, Dr. Russo says.

If youre fully vaccinated, its been at least two weeks since youve had a booster shot, and you still contract COVID-19, the odds are high that you have the Omicron variant, Dr. Russo says. Statistically speaking, youre more likely to be infected with Omicron than Delta anyway, he says. But thats particularly true if youve been boostedOmicron seems to be more resistant to vaccination.

According to a recent CDC study, those symptoms may include:

But if you havent been vaccinated against COVID-19, Omicron and Delta are likely to cause similar symptoms of COVID-19. Per the CDC, those include:

For the average-risk patient, it doesnt really matter, Dr. Russo says. At the end of the day, if youre infected, you want to go ahead and monitor for more serious symptoms like shortness of breath and present to your healthcare provider, regardless of if youre infected with Delta or Omicron, he says. For healthcare providers, symptoms and severity of illness usually drive treatment.

There is one exception, though. Certain monoclonal antibody treatments dont work against Omicron, Dr. Adalja says. He specifically cites the Eli Lilly monoclonal antibodies as being expected to be less effective against the variant, while GSKs monoclonal antibody treatment is expected to do well against Omicron. Its important from a clinical perspective for someone who is high risk to know that information, Dr. Adalja says.

Still, getting that information within the needed timeframe may be challenging unless the diagnosis was via PCR and S-gene target failure occurred and that information was readily available to the provider, Dr. Russo says. Basically, there are a lot of ifs involved. Given that Omicron is now the dominant strain of COVID-19, Dr. Adalja says that resources are likely to shift to allow for more production of GSK's monoclonal antibody treatment, just to be safe.

Overall, doctors say its not vital for you or most other COVID-19 patients to know what strain of the virus you have. However, it doesnt hurt to ask.

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How to Know What Strain of COVID-19 You Have - Do Doctors Know What Variant You Have? - Prevention.com

DUBLIN, Dec. 21, 2021 /PRNewswire/ -- The "Global Advanced Therapy Medicinal Products CDMO Market Size, Share & Trends Analysis Report by Product (Gene Therapy, Cell Therapy, Tissue Engineered), Phase, Indication, Region, and Segment Forecasts, 2021-2028" report has been added to ResearchAndMarkets.com's offering.

The global advanced therapy medicinal products CDMO market size is expected to reach USD 12.9 billion by 2028, according to the report. It is expected to expand at a CAGR of 12.0% from 2021 to 2028.

The advanced therapy medicinal products are a group of biological products for human use that involve gene therapy products, cell therapy products, and tissue-engineered products. The growth of the market is credited to the increasing clinical trials of ATMP and the rising awareness and belief among researchers regarding the benefits of advanced therapy. The COVID-19 pandemic has significantly disrupted the cell and gene therapy industry due to the complexity in the manufacturing process.

The COVID-19 pandemic has adversely affected the overall medical industry, but the pandemic boosted the operations and development of advanced therapy due to the high requirement of the products such as mesenchymal stromal cells (MSCs) for the treatment of the virus. The regulations put forward by the FDA and government authorities have created a safe environment for the healthcare workers and allowed emergency approval for the supply of essential raw materials and faster development of the vaccines and other therapy products.

Technological advancement has been a major part of tissue engineering in the last few years. This method helps to replace or restore the injured tissues and organ function. Similarly, gene and cell therapy is attracting many patients for the treatment of rare diseases, the cases of which are augmenting globally.

Advanced Therapy Medicinal Product CDMO Market Report Highlights

Key Topics Covered:

Chapter 1 Methodology and Scope

Chapter 2 Executive Summary

Chapter 3 Advanced Therapy Medicinal Products CDMO Market: Variables, Trends, & Scope3.1 Market Segmentation and Scope3.2 Market Dynamics3.2.1 Market Driver Analysis3.2.1.1 Rising number of clinical trials for ATMP3.2.1.2 Increasing outsourcing activities3.2.1.3 Growing awareness of the treatment3.2.2 Market Restraint Analysis3.2.2.1 Stringent regulatory approvals3.2.2.2 High cost of outsourcing3.3 Penetration & Growth Prospect Mapping3.4 Advanced Therapy Medicinal Products CDMO: Market Analysis Tools3.4.1 Industry Analysis - Porter's3.4.1.1 Porter's Five Forces Analysis3.4.2 PESTEL Analysis

Chapter 4 Advanced Therapy Medicinal Products CDMO Market: Product Estimates4.1 Market Share Analysis, 2020 & 20284.2 Gene Therapy4.2.1 Gene therapy market, 2016 - 2028 (USD Billion)4.3 Cell Therapy4.3.1 Cell therapy market, 2016 - 2028 (USD Billion)4.4 Tissue Engineered4.4.1 Tissue engineered market, 2016 - 2028 (USD Billion)4.5 Others4.5.1 Market, 2016 - 2028 (USD Billion)

Chapter 5 Advanced Therapy Medicinal Products CDMO Market: Phase Estimates5.1 Market Share Analysis, 2020 & 20285.2 Phase I5.2.1 Phase I market, 2016 - 2028 (USD Billion)5.3 Phase II5.3.1 Phase II market, 2016 - 2028 (USD Billion)5.4 Phase III5.4.1 Phase III market, 2016 - 2028 (USD Billion)5.5 Phase IV5.5.1 Phase IV market, 2016 - 2028 (USD Billion)

Chapter 6 Advanced Therapy Medicinal Products CDMO Market: Indication Estimates6.1 Market Share Analysis, 2020 & 20286.2 Oncology6.2.1 Oncology market, 2016 - 2028 (USD Billion)6.3 Cardiology6.3.1 Cardiology market, 2016 - 2028 (USD Billion)6.4 Central Nervous System6.4.1 Central nervous system market, 2016 - 2028 (USD Billion)6.5 Musculoskeletal6.5.1 Musculoskeletal market, 2016 - 2028 (USD Billion)6.6 Infectious Disease6.6.1 Infectious disease market, 2016 - 2028 (USD Billion)6.7 Dermatology6.7.1 Dermatology market, 2016 - 2028 (USD Billion)6.8 Endocrine, Metabolic, Genetic6.8.1 Endocrine, metabolic, genetic market, 2016 - 2028 (USD Billion)6.9 Immunology & inflammation6.9.1 Immunology & inflammation market, 2016 - 2028 (USD Billion)6.10 Ophthalmology6.10.1 Ophthalmology market, 2016 - 2028 (USD Billion)6.11 Haematology6.11.1 Haematology market, 2016 - 2028 (USD Billion)6.12 Gastroenterology6.12.1 Gastroenterology market, 2016 - 2028 (USD Billion)6.13 Others6.13.1 Others market, 2016 - 2028 (USD Billion)

Chapter 7 Advanced Therapy Medicinal Products CDMO Market: Regional Analysis

Chapter 8 Company Profiles8.1 Strategic Framework8.2 Company Profiles8.2.1 Celonic8.2.1.1 Company Overview8.2.1.2 Financial performance8.2.1.3 Product Benchmarking8.2.1.5 Strategic Initiatives8.2.2 Bio Elpida8.2.2.1 Company Overview8.2.2.2 Financial performance8.2.2.3 Product Benchmarking8.2.2.6 Strategic Initiatives8.2.3 CGT Catapult8.2.3.1 Company Overview8.2.3.2 Financial performance8.2.3.3 Product Benchmarking8.2.3.6 Strategic Initiatives8.2.4 Rentschler Biopharma SE8.2.4.1 Company Overview8.2.4.2 Financial performance8.2.4.3 Product Benchmarking8.2.4.6 Strategic Initiatives8.2.5 AGC Biologics8.2.5.1 Company Overview8.2.5.2 Financial performance8.2.5.3 Product Benchmarking8.2.5.6 Strategic Initiatives8.2.6 Catalent8.2.6.1 Company Overview8.2.6.2 Financial performance8.2.6.3 Product Benchmarking8.2.6.6 Strategic Initiatives8.2.7 Lonza8.2.7.1 Company Overview8.2.7.2 Financial Performance8.2.7.3 Product Benchmarking8.2.7.5 Strategic Initiatives8.2.8 WuXi Advanced Therapies8.2.8.1 Company Overview8.2.8.2 Financial performance8.2.8.3 Product Benchmarking8.2.8.5 Strategic Initiatives8.2.9 BlueReg8.2.9.1 Company Overview8.2.9.2 Financial performance8.2.9.3 Product Benchmarking8.2.9.6 Strategic Initiatives8.2.10 Minaris Regenerative Medicine8.2.10.1 Company Overview8.2.10.2 Financial performance8.2.10.3 Product Benchmarking8.2.10.5 Strategic Initiatives8.2.11 Patheon8.2.11.1 Company Overview8.2.11.2 Financial performance8.2.11.3 Product Benchmarking8.2.11.5 Strategic Initiatives

For more information about this report visit https://www.researchandmarkets.com/r/rjc62f

Media Contact:

Research and Markets Laura Wood, Senior Manager [emailprotected]

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Outlook on the Advanced Therapy Medicinal Products CDMO Global Market to 2028 - Rising Number of Clinical Trials for ATMP is Driving Growth -...

Introduction

Breast cancer (BC) accounts for the highest incidence of tumors globally and is the leading cause of death of female cancer patients.1 In recent years, the application of precise surgery and adjuvant systemic treatments (chemotherapy, radiotherapy, endocrine therapy, and molecular targeting drugs) dramatically enhances the therapeutic effect. The prognosis of BC patients remains unsatisfactory, however. Screening and diagnosis are essential to reduce BC patients incidence rate and mortality rate in the early stage.2 Although clinical, pathological, and molecular features are commonly used to predict prognosis, the underlying pathogenesis of BC invasiveness is still poorly understood. Minimally invasive biomarkers to detect early BC and gauge treatment response are crucial in BC research.3

Tumor microenvironment (TME) plays a vital role in tumor progression and the overall efficacy of cancer treatments, such as immunotherapy, chemotherapy, and radiotherapy.4,5 The abundance of immune infiltrating cells in TME affects tumor initiation, progression, metastasis, and treatment resistance.6

Tissue type plasminogen activator (PLAT) and urokinase type plasminogen activator (PLAU), two essential proteins of the plasminplasminogen system, not only participated in the intravascular dissolution of blood clots but also played a significant role in tumor progression and metastasis.7 PLAU has been involved in different steps of cancer progression, such as tumorigenesis,8 angiogenesis,9 cell invasion, and metastasis.10 PLAT can affect the development of many tumors. BC patients with low PLAT levels often have a poor prognosis, while PLAT levels are higher in melanoma, neuroblastoma, acute myeloid leukemia, and pancreatic cancer.11,12

Our study evaluated the expression level of PLAT in BC and the relationships between PLAT expression and clinical pathological characteristics, together with prognosis, through publicly available data from The Cancer Genome Atlas (TCGA). PLAT protein expression was assessed with UALCAN databases. Moreover, the possible molecular functions of PLAT were screened by using GSEA software (version 4.1.0). Furthermore, the relationships between PLAT and immune infiltrating cells were explored using TIMER, TISIDB database, and ssGSEA algorithm. We investigated the correlation between PLAT expression level, clinicopathological characteristics, and DNA methylation with TCGA data. Our findings reveal the predictive value of PLAT in BC and show a potential correlation between PLAT and immune infiltrating cells, which will help clarify a possible mechanism for BC.

Transcriptional data of mRNA-sequencing, DNA methylation data, phenotype, and survival profiles of BC patients were accessed from UCSC Xena (https://xenabrowser.net/),13 which analyzes data from TCGA. The pre-processing steps were conducted by R (version 4.1.0) and Perl (version 5.30.2) software.

We selected 1071 primary BC samples, and 96 paired normal samples with clinicopathological profiles such as age, sex, menopausal status, histological type, TNM stage, and PAM50 subtype14 for further analysis. PAM50 algorithm using the 50-gene classifier divides BC into five intrinsic subtypes: luminal A, luminal B, HER2-enriched, basal-like, and normal-like. We explored the different expressions of PLAT in all clinicopathologic features. PLAT methylation data of 890 samples and its correlated gene expression levels were applied to calculate the methylation score of PLAT and the relationships between gene expression, DNA methylation, and clinicopathologic profiles.

Profiles of overall survival (OS) and progression-free survival (PFS) were downloaded from TCGA survival data. From this data, 1071 samples were assigned to high and low expression groups based on the median score of PLAT. R survival package was employed to generate KaplanMeier (KM) curves, while the optimal cut-off point for survival curves was generated through the res. cut function in the survminer package. Univariable and multivariable Cox regression models were established through the coxph function in the survival package, which was used to confirm whether PLAT is an independent prognostic factor of BC.

The clusterProfiler R package15 was employed to perform gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses on the basis of differentially expressed genes (DEGs_ (| log2FC | 1, FDR < 0.05) between two different expressed groups. P-values were adjusted by the BH method. We used Spearman correlation coefficient analysis to show the relationship between PLAT and co-expression genes. GSEA was conducted based on KEGG (v7.4) gene-set collections using GSEA software (v4.1.0 6)16,17 to uncover pathways in the DEGs groups. Gene sets with NOM p-value < 0.05 were considered significant.

The gsva package18 was utilized to conduct the ssGSEA,19 which can be applied to evaluate the scores of immune infiltrating cells and calculate the activity of immune-related pathways. TIMER (https://cistrome.shinyapps.io/timer/)20 contains an abundant resource for systematically exploring the immune infiltrates between various tumors. We employed TIMER 2.0 gene module to calculate the relationships between PLAT mRNA expression and the infiltration of immune cells. TISIDB database (http://cis.hku.hk/TISIDB)21 is a portal web containing a variety of tumor and immune system resources. In this study, TISIDB providers the correlations between PLAT and the immune system.

Gene expression profiles, methylation degree, and clinical characteristics were compared through Wilcoxon signed rank tests and displayed by box plot. Survival rates were assessed by applying KM curves and the log rank test. The Pearson chi-square test was employed to analyze the correlation between PLAT expression and DNA methylation level. R version 4.1.0 was used in all tests conducted. A statistically significant difference was considered when p < 0.05.

We achieved PLAT expression and BC-related clinical profiles from the TCGA database. The detailed data are summarized in Supplementary Table 1. PLAT had a lower expression in BC tissues than in normal tissues both in TCGA-BRCA all samples (Figure 1A) and paired samples (Figure 1B). The CPTAC dataset of the UALCAN database was used to analyze the PLAT protein expression. PLAT in BC tissues was significantly lower than in normal tissues, which was consistent with the gene expression level (Figure 1C). After that, PLAT expression in BC with different clinical characteristics such as gender, menopausal status, histological type, molecular subtype, N stage, and T stage displayed statistical differences. The expression level of PLAT in women was lower than that in men (Figure 1D), and it was lower in postmenopausal women than premenopausal women (Figure 1E). Invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) are the two main histological types of BC. The expression level of PLAT in IDC was lower than in other types, including ILC. But there was no significant difference between ILC and other types (Figure 1F). Among the five PAM50 molecular subtypes of BC, luminal A, luminal B, HER2-enriched, basal-like, and normal-like, the expression level of PLAT was statistically different, in which luminal A was the highest and basal-like was the lowest (Figure 1G). The expression level was lower in the advanced stage in the T stage (Figure 1H); however, it was higher in the advanced N stage (Figure 1I).

Figure 1 Associations between PLAT expression and clinicalpathological parameters in BC. Low expression of PLAT was observed in tumor tissues both in all samples (A) and paired samples (B). Protein expression of PLAT in normal and primary tumor tissues with CPTAC samples (C). PLAT expression was analyzed in female and male (D), postmenopausal and premenopausal (E) patients, with different histological types (F), including invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), and all other specific types, different PAM50 molecular subtypes (G), different tumor size (H) (T1 versus T2, T3, and T4), and different lymph node metastasis status (I) (N0 versus N1, N2, and N3). T1, tumor 20 mm in greatest dimension; T2, Tumor >20 mm but 50 mm in greatest dimension; T3, Tumor >50 mm in greatest dimension; T4, Tumor of any size with direct extension to the chest wall or the skin (ulceration or macroscopic nodules); invasion of the dermis alone does not qualify as T4; N0, no regional lymph node metastasis; N1, metastases in 1 to 3 axillary lymph nodes; N2, metastases in 4 to 9 axillary lymph nodes; and N3, metastases in 10 or more axillary lymph nodes. The asterisks represent the statistical p-value (ns: p > 0.05, *p 0.05, **p 0.01, ***p 0.001, ****p 0.0001).

We explored whether PLAT expression was correlated with the prognosis of BC patients. KM curves were utilized to evaluate the influence of PLAT expression on OS and DFS. The high PLAT expression group has a longer OS than low expression patients (Figure 2A) but there was no statistical significance in DFS (Figure 2B). We further investigated OS in the different molecular subtypes. Statistical significance of OS difference was found in all luminal samples, especially in luminal B subtypes (Figure 2C).

Figure 2 Prognostic value of PLAT expression in BC. (A) Low PLAT expression was associated with a poor OS in BC patients using KaplanMeier plotter. (B) DFS had no statistically significant difference in high and low PLAT expression groups. (C) Low PLAT expression was inferred as a poor OS in all luminal samples and all luminal B samples. (D) Forest plots show the association between PLAT expression and clinicopathological features using univariate and multivariate COX hazard analysis.

Univariate and multivariate regression analyses were applied to evaluate whether PLAT is an independent prognostic factor for BC. Univariate Cox hazard analysis identified that age (HR = 1.033, 95% CI:1.0201.046, p < 0.001), menopausal status (HR = 2.025, 95% CI:1.3473.045, p < 0.001), T stage (HR = 1.459, 95% CI:1.1971.779, p < 0.001), N stage (HR = 1.600, 95% CI:1.3471.901, p <0.001), M stage (HR = 4.860, 95% CI:2.9008.144, p < 0.001), Stage (HR = 2.187, 95% CI:1.7442.742, p < 0.001), and PLAT (HR = 0.886, 95% CI:0.7970.984, p = 0.024) were prognostic factors of BRCA. Multivariate analysis revealed that, after excluding other confounding factors, age (HR = 1.044, 95% CI:1.0231.067, p < 0.001), N stage (HR = 1.451, 95% CI:1.0522.000, p = 0.023), and PLAT (HR = 0.850, 95% CI:0.7420.974, p = 0.020) were still prognostic factors of BCRA (Figure 2D). The above results show that PLAT is an independent prognostic factor for BC and is a protective factor.

All TCGABRCA samples were assigned to two groups in the light of PLAT expression to gain insight into PLAT biological clues in BC. The volcano plot and heatmap show DEGs between the two groups (Figure 3A and B). PLAT and its co-expression genes are shown in Figure 3C. GO, and KEGG enrichment analyses were conducted based on 93 genes that had a positive correlation with PLAT to identify PLAT-related pathways and biological functions. The top 30 enriched GO terms are shown in Figure 3D. We can see that PLAT was mainly enriched in the pathway related to response to steroid hormone, humoral immune response, intracellular steroid hormone receptor signaling pathway, steroid hormone mediated signaling pathway, and response to progesterone. KEGG enrichment showed that PLAT was closely related to the pathways that correlate with BC and the immune response, such as the estrogen signaling pathway, apelin signaling pathway, IL-17 signaling pathway, and BC (Figure 3E).

Figure 3 DEGs and enrichment analyses of PLAT in BC. (A) Volcano plot and (B) heatmap show the DEGs in high and low PLAT expression patients. (C) Correlation of PLAT and the top 40 coexpressed genes. (D and E) GO enrichment and KEGG pathway analysis of PLAT in BC. The red box highlights the pathways correlated with BC and immune infiltrates. (F) The GSEA results showed that the terms antigen processing and presentation, natural killer cell mediated cytotoxicity, homologous recombination, and nucleotide excision repair were differentially enriched in BC samples with high PLAT.

We further used GSEA to predict PLAT-related pathways between patients with different PLAT expressions; 70 of 178 gene sets were up-regulated in the low PLAT group, and 15 pathways were enriched at NOM p < 0.05 and FDR < 0.25. The presenting figures include antigen processing and presentation, natural killer cell mediated cytotoxicity, homologous recombination, and nucleotide excision repair (Figure 3F). These results show that PLAT may affect immune cell infiltration.

Immune characteristics are closely related to tumor progression. Through the functional analyses, we evaluated the enrichment scores of 16 immune cells and the activity of 13 immune-related pathways between the two expressed groups by employing ssGSEA. The low expression subgroup of PLAT generally had higher levels of infiltration of immune cells, especially of aDCs, CD8 + T cells, DCs, iDCs, macrophages, pDCs, Tfh, Th1 cells, Th2 cells, TILs, and Treg cells. Except for the parainflammation pathway, the other 12 immune pathways performed higher activity in the low expression group than in the high expression group (Figure 4A). After that, we evaluated the relationship between the PLAT expression in BRCA and immune cell infiltration in TIMER. The finding revealed that the expression level of PLAT had a negative correlation with the infiltration of neutrophil (Rho = 0.175, p = 2.59e-08), T cell cd4+ (Rho = 0.158, p = 5.16e-07), B cell (Rho = 0.117, p = 2.12e-04) and dendritic cell (Rho = 0.098, p = 2.08e-03). Meanwhile it had a positive correlation with the infiltration level of T cell CD8+ (Rho = 0.2, p = 2.13e-10) and macrophage (Rho = 0.266, p = 1.45e-17). Not surprisingly, tumor purity was negatively correlated with PLAT expression level (Figure 4B). Then, to understand the association between PLAT and immune infiltration, TISIDB was employed to evaluate the association between PLAT expression and various immune characteristics. Figure 4C shows the relationship between PLAT and tumor-infiltrating lymphocytes (TILs) like CD4, CD8, DC, and B cell and Figure 4D the relationship between PLAT and immunostimulators like IL2RA, ICOS, TNFRSF13C, and PVR. Figure 4E shows the relationship between PLAT and immunoinhibitors like CD274, PDCD1, PDCD1LG2, and CTLA4 and Figure 4F the relationships between PLAT and MHC molecules like TAP2, HLA-DOB, TAP1, and HLA-F. Figure 4G shows the relationship between PLAT and chemokines like CXCL10, CCL8, CCL18, and CCL7. Figure 4H shows the relationship between PLAT and chemokine receptors like CCR8, CXCR6, CCR1, and CCR5. The results mentioned above indicate that PLAT widely participates in adjusting many immune molecules in BC and influences the immune infiltration in TME.

Figure 4 Associations of the PLAT expression level with tumor immune infiltration in BC. (A) Comparison of the enrichment scores of 16 immune cells and 13 immune-related pathways between low- and high-expression groups. (B) The correlation of PLAT expression with infiltration levels of neutrophil, CD4+T cell, B cell, and dendritic cell in BC is available on the TIMER 2.0 database. (C) Correlations between the abundance of tumor-infiltrating lymphocytes (TILs) and PLAT (plus the four TILs with the highest correlation) in the TISIDB database. (DF) Correlations between immunomodulators and PLAT (plus the four immunomodulators with the highest correlation, respectively) in the TISIDB database. (G and H) Correlations between chemokines (or receptors) and PLAT (plus the four chemokines (or receptors) with the highest correlation, respectively) in the TISIDB database. The asterisks represent the statistical p-value (*p 0.05, **p 0.01, ***p 0.001).

After the studies mentioned above, we continued to explore the possible reasons for the difference in PLAT expression. The box plot shows the methylation degree of each methylation site of PLAT DNA. Sites cg03960326 and cg18460120 had a higher degree of methylation and sites cg22038738 and cg04563438 had lower methylation degree (Figure 5A). Subsequently, the association between DNA methylation level and gene expression was calculated. Figure 5B shows that there is a negative association between DNA methylation and gene expression on the whole. When analyzing a single site, it was found that the methylation levels of cg13880167, cg12091331, cg04563438, cg03960326, cg00491021, and cg22038738 were negatively correlated with gene expression (Figure 5C). After that, survival analysis was further conducted according to the methylation degree of each site. It was found that, among the six DNA methylation sites of PLAT that had a negative correlation with gene expression, the methylation degree of the cg03960326 site was significantly related to OS (Figure 5D). We further assessed the methylation differences of the cg03960326 site of PLAT DNA in different clinical feature groups. We can see that there are no distinctions in methylation levels between different TNM and stages. However, there existed differences in methylation levels of cg03960326 site in people with different menopause status, tumor histological types, and PAM50 molecular types (Figure 5E). These differences are contrary to the previous differences of PLAT gene in cases with different clinical features, which also verifies the negative relationship between DNA methylation and gene expression.

Figure 5 Correlation of DNA methylation level with PLAT expression and clinical features. (A) Methylation level of 8 methylation site in PLAT. (B) Correlation of PLAT expression with gross methylation level. (C) Correlation of PLAT expression with different methylation sites (cg13880167, cg12091331, cg04563438, cg03960326, cg00491021, and cg22038738). (D) High methylation level of cg03960326 site was associated with a poor OS in BC patient. (E) Methylation level of cg03960326 site was analyzed with different menopausal status, histological types and PAM50 molecular subtypes. The asterisks represent the statistical p-value (ns: p > 0.05, **p 0.01, ***p 0.001, ****p 0.0001).

PLAT, a serine protease, mainly takes part in the intravascular dissolution of blood clots.22 Previous studies have shown that PLAT promoter hypermethylation can down-regulate the expression of nasal polyps gene, resulting in excessive fibrin deposition, which can be used as a therapeutic target of NP.23 PLAT can also promote angiogenesis by mobilizing CD11 + cells.24 It can be applied to the treatment of acute stroke25,26 and non-small cell lung cancer.27 It is also an estrogen-induced protein in the human BC cell line.11 BC is one of the highest incidence rate diseases in the world, which has a poor prognosis. Early detection and timely treatment are the most effective methods to improve the survival rate of BC patients. Traditional prognostic factors include tumor type, grade, size, and lymph node status. They can provide some course information, but they are not very accurate. Tumor immunotherapy provides a new remedy option for BC. Therefore, we assessed the role of PLAT in BRCA.

We analyzed BC cases in the context of RNA-seq data, methylation profiles, and clinical characteristics achieved from TCGA. The findings revealed that the expression level of PLAT was lower in BC patients. And patients in an advanced stage or with a more aggressive histological type may have lower expression levels in general. Consistent with that, lower expression of PLAT in TCGABRCA profiles was related to shorter overall survival, especially in the luminal B subtype. So, we deem that higher PLAT expression is related to a better prognosis of BC. After that, univariate and multivariate Cox regression analyses showed that PLAT was an independent prognostic factor affecting the prognosis of BC patients and could be used as a predictive marker.

The enrichment analysis showed that PLAT was related to the immune and tumor-associated pathway. Infiltrating immune cells are an essential component of TME.28 Recently, immunotherapy for the interaction between immune cells and BC cells has been developed as an alternative to classical anticancer therapy.29,30 PLAT has been affirmed to predict the prognosis of multiple tumor types such as colon cancer, ovarian cancer, lung cancer, and BC.31,32 There is evidence proving that tumor-infiltrating lymphocytes (TIL) that existed before the treatment of BC can predict treatment response and improve prognosis.33 TIL plays a vital role in chemotherapy response and clinical prognosis of all subtypes of BC.34 In our study, the low expression subgroup of PLAT generally had higher levels of infiltration of immune cells and higher activity of immune-related pathways. PLAT expressed level had a negative correlation with the infiltration level of neutrophil, T cell CD4+, dendritic cell, and B cell. Meanwhile, it had a positive correlation with the infiltration level of T cell CD8+ and macrophage. PLAT expression is closely related to TILs, immunomodulatory factors, and chemokines. Our results verified the association between PLAT and the prognosis and immune infiltration of BC, suggesting that PLAT can help predict treatment response and improve prognosis.

DNA methylation plays a vital role in gene-expressed regulation, mainly related to transcriptional inhibition.35 Therefore, we continue to search for the possible causes of different gene expressions. Our results showed a negative relationship between the degree of DNA methylation and gene expression level. By further analyzing the methylation level of PLAT DNA in the cg03960326 site, which is significantly related to OS, methylation differences were observed in patients with different tumor histological types, molecular subtypes, and menopause. These differences are opposite to the previous differences of the PLAT gene in other clinical feature groups. This also verified that DNA methylation was negatively related to PLAT expression, which might cause PLAT expression differences.

Immune infiltration in the TME has been shown to play a critical role in cancer progression and occurrence and to affect clinical outcomes of cancer patients.36 In triple-negative BC, tumor-associated macrophages derived from peripheral blood monocytes promote tumor growth and progression by several mechanisms that include the secretion of inhibitory cytokines, the reduction of effector functions of TIL, and the promotion of Treg cells. Besides, tumor-associated macrophages have been shown to directly and indirectly modulate PD-1/PD-L1 expression in tumor environment.37 Immunotherapy has raised significant concern in the treatment of cancer, which aims to eliminate cancer cells by enhancing natural defenses. The blockade of PD-1/ PD-L1 and CTLA4 has achieved remarkable therapeutic success in multiple kinds of cancer, including BC. An in-depth understanding of immune infiltration cells in the TME is essential to uncover the underlying molecular mechanisms and provide new strategies to improve immunotherapeutic efficacy.

Previous analysis showed that PLAT, a tumor suppressor gene, has differential expression levels and independent prognostic value and is significantly correlated with tumor-related pathways and immune infiltrating cells in TME. However, one study has shown that PLAT cannot foresee the response to systemic adjuvant therapy.11 The presented research only shows the results of online databases. To further confirm this conclusion, we will conduct PCR and IHC on our clinical samples and further analyze the different clinical characteristics and survival information. Finally, the internal molecular mechanism of PLAT and tumor immune cell infiltration will be further explored. Therefore, further research is needed to improve the proof of the biological impact of PLAT.

PLAT can be considered a prognostic factor and biomarker to provide personalized treatment, improve the survival rate, and contribute to developing immunological treatment strategies.

BC, breast cancer; TME, tumor microenvironment; PLAT, tissue-type plasminogen activator; PLAU, urokinase type plasminogen activator; TCGA, The Cancer Genome Atlas; OS, overall survival; PFS, progression-free survival; GO, Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; TIL, tumor-infiltrating lymphocytes.

This study was approved by the institutional ethical committee of the First Affiliated Hospital with Nanjing Medical University.

We would like to acknowledge the TCGA, TIMER, and TISIDB databases for free use.

This study is supported by the Natural Science Foundation of Jiangsu Province (BK20171506).

The authors report no conflicts of interest in this work.

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12. Daz VM, Planaguma J, Thomson TM, Revents J, Paciucci R. Tissue plasminogen activator is required for the growth, invasion, and angiogenesis of pancreatic tumor cells. Gastroenterology. 2002;122(3):806819. doi:10.1053/gast.2002.31885

13. Cline MS, Craft B, Swatloski T, et al. Exploring TCGA pan-cancer data at the UCSC cancer genomics browser. Sci Rep. 2013;3:2652. doi:10.1038/srep02652

14. Parker JS, Mullins M, Cheang MC, et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol. 2009;27(8):11601167. doi:10.1200/JCO.2008.18.1370

15. Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012;16(5):284287. doi:10.1089/omi.2011.0118

16. Mootha VK, Lindgren CM, Eriksson KF, et al. PGC-1-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet. 2003;34(3):267273. doi:10.1038/ng1180

17. Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102(43):1554515550. doi:10.1073/pnas.0506580102

18. Hnzelmann S, Castelo R, Guinney J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinform. 2013;14:7. doi:10.1186/1471-2105-14-7

19. Barbie DA, Tamayo P, Boehm JS, et al. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature. 2009;462(7269):108112. doi:10.1038/nature08460

20. Li T, Fu J, Zeng Z, et al. TIMER2.0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res. 2020;48(W1):W509w514. doi:10.1093/nar/gkaa407

21. Ru B, Wong CN, Tong Y, et al. TISIDB: an integrated repository portal for tumor-immune system interactions. Bioinformatics. 2019;35(20):42004202. doi:10.1093/bioinformatics/btz210

22. Kruithof EK, Dunoyer-Geindre S. Human tissue-type plasminogen activator. Thromb Haemost. 2014;112(2):243254. doi:10.1160/th13-06-0517

23. Kidoguchi M, Noguchi E, Nakamura T, et al. DNA methylation of proximal PLAT promoter in chronic rhinosinusitis with nasal polyps. Am J Rhinol Allergy. 2018;32(5):374379. doi:10.1177/1945892418782236

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25. Pea-Martnez C, Durn-Laforet V, Garca-Culebras A, et al. Pharmacological modulation of neutrophil extracellular traps reverses thrombotic stroke tPA (tissue-type plasminogen activator) resistance. Stroke. 2019;50(11):32283237. doi:10.1161/strokeaha.119.026848

26. Zhu J, Wan Y, Xu H, Wu Y, Hu B, Jin H. The role of endogenous tissue-type plasminogen activator in neuronal survival after ischemic stroke: friend or foe? Cell Mol Life Sci. 2019;76(8):14891506. doi:10.1007/s00018-019-03005-8

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30. Hall M, Liu H, Malafa M, et al. Expansion of tumor-infiltrating lymphocytes (TIL) from human pancreatic tumors. J Immunother Cancer. 2016;4:61. doi:10.1186/s40425-016-0164-7

31. Hwang WT, Adams SF, Tahirovic E, Hagemann IS, Coukos G. Prognostic significance of tumor-infiltrating T cells in ovarian cancer: a meta-analysis. Gynecol Oncol. 2012;124(2):192198. doi:10.1016/j.ygyno.2011.09.039

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Low expression of PLAT in Breast cancer | IJGM - Dove Medical Press

Dec. 21, 2021 07:00 UTC

LONDON--(BUSINESS WIRE)-- MiNA Therapeutics Limited (MiNA or the Company), the pioneer in small activating RNA (RNAa) therapeutics, announces the expansion of its Board, with the appointment of Susan Clement-Davies and Professor Sir Robert Lechler as Independent Directors, effective 1 January 2022.

Susan is an experienced life sciences financier with over 25 years of capital markets and investment banking experience, including as Managing Director of Equity Capital Markets at Citigroup Global Markets Limited and Managing Director at Torreya Partners LLC. Susan is currently a Non-Executive Director of Scancell Holdings, a UK listed biotechnology company developing innovative immunotherapies, EvgenPharma plc, a UK-listed clinical stage drug development company, and Exploristics, a world-leading provider of biosimulation software and biostatistics services for clinical trials. Susan is also Corporate Finance Advisor for Theolytics, a biotechnology company developing anticancer viral therapies, and an Advisor for Oxford Sciences Innovation, the worlds largest university-partnered venture firm. In addition, Susan is a member of the Innovation Advisory Group for the Chelsea and Westminster Hospital NHS Foundation Trust.

Robert is a recognised leader in biomedical research, management and governance with over 40 years of distinguished experience in academic medicine, having started his immunology career in 1979. Since then, Robert has held various leadership roles in a range of hospitals and laboratories, including serving as Head of Imperial College Londons Division of Medicine, Vice Principal (Health) of Kings College School, and Executive Director of Kings Health Partners Academic Health Sciences Centre. He has also been at the forefront of scientific innovation, nationally, through his Presidency of the Academy of Medical Sciences, Membership of the UK Council for Science and Technology, and Chairmanship of the UK MHRA Clinical Trials Expert Advisory Group. In 2012, Robert was Knighted in the Queens Birthday Honours for his services to academic medicine, which has centred around immunology, cancer and transplantation. He is currently a Non-executive Director of Quell Therapeutics, a biopharmaceutical company specialising in addressing a range of autoimmune and inflammatory diseases through cell therapy.

Nagy Habib, Chairman and Head of R&D of MiNA Therapeutics, commented: We are thrilled to welcome Susan and Robert to MiNAs Board of Directors to support our strengthened senior leadership team as we remain focused on driving the Companys next phase of growth. Susan's expertise in finance and as a biopharma company director, combined with Roberts leadership in biomedicine will be invaluable as we continue to advance our pipeline through clinical development and expand our partnerships to scale and amplify the impact of our pioneering RNAa technology for patients.

Susan Clement-Davies, Independent Director of MiNA Therapeutics, commented: I am extremely excited to be joining MiNA. What the team has achieved, particularly in recent years, is impressive and I hope to bring my experience in the life sciences sector to further unlock MiNAs significant potential.

Professor Sir Robert Lechler, Independent Director of MiNA Therapeutics, commented: This is a fantastic opportunity to be involved with a pioneering company in such an interesting space. The Companys RNAa approach and pipeline is a truly innovative way of treating diseases and I look forward to guiding MiNA on its journey, which I believe will be highly successful.

About MiNA Therapeutics MiNA Therapeutics is the leader in small activating RNA therapeutics. Harnessing innate mechanisms of gene activation, small activating RNA therapeutics are a revolutionary new class of medicines that can restore or boost normal function in patients' cells. We are advancing a proprietary pipeline of new medicines with an initial focus on cancer and genetic diseases, while collaborating with leading pharmaceutical companies to apply our technology platform across a broad range of therapeutic areas. Based on our unique know-how in RNA activation we are expanding the possibilities of RNA-based medicine for patients. http://www.minatx.com

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MiNA Therapeutics Appoints Two Independent Directors With Extensive Industry Experience to Support Next Phase of Growth - BioSpace

Although unproven, this novel sickle cell therapy serves as a potential cure. More measures need to be taken to determine long-term function and organ improvement.

Although unproven, this novel sickle cell therapy serves as a potential cure. More measures need to be taken to determine long-term function and organ improvement.New research fromUniversity of Alabama at Birmingham, published in theNew England Journal of Medicine, suggests a gene therapy called LentiGlobin could provide a permanent cure for sickle cell disease.

Julie Kanter, M.D., director of the UABAdult Sickle Cell Clinic, says patients treated with this therapy are beginning to show signs of producing stable amounts of normal red blood cells containing hemoglobin.

SCD occurs in about one out of every 365 Black or African American births, according to the Centers for Disease Control and Prevention, and about one in 13 Black or African American babies is born with sickle cell trait.

Kanter says there are several types of gene therapy (gene addition/transfer, gene editing, gene correction and gene silencing), but this particular therapy is gene addition or transfer.

In this therapy, we do not change or edit the gene that causes sickle cell disease, Kanter said. Instead, we use a viral vector to deliver a new gene that will make a healthy hemoglobin a beta hemoglobin into the stem cell. This is like coding new instructions into the cell.The old instructions for hemoglobin S are still there, but now the cell can make HbA and HbS. The vector can deliver more than one copy of the instructions to each cell usually between one and four copies so the cell can make moreHbA than HbS.

A vector is part of a virus. Kanter compares vectors to envelopes and letters.

I like to think of it as an envelope, she said. We take out the bad part of a virus (the letter) and leave the empty envelope. We put a new gene (the new letter) with the right instructions into the envelope and send it into the stem cells.The viral parts of the letter are removed so patients dont get the virus itself they only get the letter coding for the new hemoglobin, called HbAT87Q.

T87Q is a special type of hemoglobin A that is slightly different from regular hemoglobin A and has two advantages:

Kanter says that, although this therapy is providing a significant amount of hope, researchers continue to test to make sure the therapy remains safe.

In an earlier part of this study, we were not able to get enough of the new gene into each cell, Kanter said.Not enough envelopes were delivered.

This caused the stem cells to be extra stressed and the patients to still have some parts of sickle cell disease.They had only slight improvements compared to group C.

Unfortunately, the stressed-out cells are also more likely to make bad clones, which can cause cancer, she said.Two patients in group A developed leukemia because the cells were too stressed.

It is important to note that this was not caused by the viral vector or the new gene (not from the LentiGlobin) but from the stress of the procedure and the insufficient cell correction.

We need to see that we have fixed this problem in group C and no one else develops leukemia, Kanter said. We also need to make sure this procedure both reduces pain/stops all pain crisis and prevents organ damage from sickle cell.This will take time. We will have to watch people for the next two to 15 years and measure their organ function compared to those who did not get this therapy.

Much of Kanters career has been dedicated to helping those with SCD. A therapy like this is a game changer, according to Kanter.

It means a lot, she said.People with sickle cell disease have endured unnecessary hardship for more than 100 years. They have fewer medications and therapies than many other diseases and have received much less attention and funding. We need new and better options for people with sickle cell disease.

She also says this is just a beginning.

This therapy gives us hope and promise for a better future for those living with sickle cell disease.

We need to make these treatments available, and we need all people with sickle cell disease to have a sickle cell doctor to make that happen, she said. We need the therapy to be affordable so that people everywhere living with this disease have the option for gene therapy.Right now, most people with sickle cell disease live in sub-Saharan Africa and in India.They dont have even the basic treatments they need like vaccines, penicillin or hydroxyurea that can make a huge difference in peoples lives with SCD. Eventually we need people in these areas to have equal opportunity to better outcomes.

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New gene therapy could provide cure for sickle cell disease, according to UAB study - The Mix

DURHAM Drug giant Pfizer on Wednesday cut the ribbon on a new manufacturing facility in Durham that will focus on gene therapy treatments for various illnesses.

The $68.5 million, 85,500-square-foot plant near the intersection of Interstate 40 and Interstate 540 will be home to Pfizers BioTherapeutics Pharmaceutical Sciences group. More than 50 jobs will be created, said BethAnne Bort, the site lead and analytical research and development director, and another 40 will move from a Pfizer site in Chapel Hill.

This new facility delivers and provides our team with expanded capabilities and space to pioneer breakthroughs for our patients, Bort said.

Gene therapy is a form of medicine that involves delivering genes to targeted tissues in the body to produce missing or non-functioning proteins. Bort said that, by using genes as medicine, the underlying cause of a disease can be targeted at the cellular level, potentially with just one treatment.

Gene therapy represents the next wave of innovation for patients living with rare diseases, for whom there are limited treatment options currently available, Paul Mensah, vice president of BioTherapeutics Pharmaceutical Sciences, said in a statement. [The Durham plant] represents the next step in strengthening Pfizers in-house gene therapy capabilities and underscores the unique ability, expertise and resources we have to guide gene therapy through the entire development and manufacturing process and deliver this potentially life-changing technology to patients.

Pfizers current gene therapy portfolio includes three late-stage clinical programs for hemophilia A, hemophilia B and Duchenne muscular dystrophy, as well as 12 pre-clinical programs investigating potential treatments for rare cardiology, endocrine, hematology, metabolic and neurology diseases. One or two clinical studies on those treatments are expected to start each year.

Pfizer already has a major plant in Sanford that makes and tests various vaccines and gene therapy treatments.

From a diverse pool of talent to the presence of research universities, state leaders say the Triangle is the ideal place for biotech companies to set up shop.

Since 2017, gene therapy companies have invested more than $1 billion in North Carolina, state Commerce Secretary Machelle Sanders said.

Bill Bullock, senior vice president of the North Carolina Biotechnology Center, said the state has added more than 12,000 life science jobs in the last three years, and the momentum doesnt appear to be slowing down.

There are still dozens of companies actively looking at North Carolina all across the spectrum, from research and development to diagnostics to medical testing to manufacturing, Bullock said. Its a growth industry, and its here to stay.

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Durham gene therapy plant to help Pfizer develop treatments for rare diseases - WRAL Tech Wire

A team of scientists led by the University of Michigan Health Rogel Cancer Center has found that a class of United States Food and Drug Administration-approved drugs can effectively stop a highly aggressive type of uterine cancer in its tracks, paving a quick path toward new treatment strategies for a deadly cancer with limited therapeutic options.

Collaborating with researchers from Case Western Reserve University and Memorial Sloan Kettering Cancer Center, the team showed that ribonucleotide reductase, or RNR, inhibitors target two mutations in the gene that encodes the tumor suppressor PP2A, present in up to 40% of uterine serous carcinomas.

The team reported its findings in Cancer Research.

Uterine cancer is the most common gynecologic cancer with more than 60,000 cases diagnosed each year in the U.S. The endometrioid subtype is most common and in general responds well to targeted immunotherapies. By contrast, the uterine serous subtype has few genetic mutations that would make it a candidate for targeted therapies, and patients face rapid disease progression and a dire prognosis.

While uterine serous carcinoma represents only 10% of uterine cancers, it accounts for the majority of deaths. We showed that the PP2A mutation is common in uterine serous carcinoma, and we found a potential new treatment option for these patients, said first author Caitlin OConnor, Ph.D., a research fellow in the Division of Genetic Medicine at Michigan Medicine. We can rapidly translate this bench work to patients.

PP2A is a tumor suppressor, stopping cancer growth much like the brakes on a car. In previous studies, the team showed that about a third of uterine serous carcinomas harbor two mutations that disable the brake, said senior author Goutham Narla, M.D., Ph.D., chief of genetic medicine at Michigan Medicine. We asked ourselves, how can we take advantage of these mutations?

To start, the researchers ran a high-throughput screen of 3,200 drug compounds against uterine serous cell samples from patients with recurrent cancer. The results showed that a family of anti-cancer drugs called ribonucleic reductase inhibitors killed cancer cells that harbored the mutations.

Researchers then narrowed their focus to one of the drug screen hits, the RNR inhibitor clofarabine, and tested it in a mouse model of uterine serous carcinoma. RNR inhibitors interfere with the growth of tumor cells by blocking the formation of DNA. Consistent with the cell-based data from the drug screen, clofarabine shrank the tumors in mice.

To further explore RNR inhibition as a potential therapeutic strategy for uterine serous carcinoma, the team did a retrospective analysis of patients treated with the RNR inhibitor gemcitabine as a later-line therapy for this subtype, compared to patients with the endometrioid subtype. We found that the uterine serous carcinoma-type patients actually did better than the endometrioid patients, OConnor said.

There is currently only one first-line chemotherapy for uterine serous carcinoma: carboplatin, Narla noted. This type of uterine cancer has a short progression, and its a particularly lethal form, so we want to find a drug that will work earlier on in disease progression and find a molecular way to target the cancer. We believe we may have that here, he said.

The research team is now planning to begin a clinical trial of gemcitabine in patients with uterine serous carcinoma. They also plan to extend this work to other cancers that harbor the PP2A mutations, including lung, colon and ovarian cancer.

Additional authors include Sarah E. Taylor of Case Western Reserve University; Kathryn M. Miller and Dmitriy Zamarin of Memorial Sloan Kettering Cancer Center; Fallon K. Noto of Hera BioLabs, Inc.; Lauren Hurst, Terrance J. Haanen, Tahra K. Suhan, Kaitlin P. Zawacki, Jonida Trako, Arathi Mohan, Jaya Sangodkhar and Analisa DiFeo of the University of Michigan.

The research was supported by grants from the National Institutes of Health (R01 CA-181654, R01 CA-240993, T32 CA-009676), and funding provided by the Rogel Cancer Center.

OConnor and Narla are named inventors on a U.S. provisional patent application concerning compositions and methods for treating high grade subtypes of uterine cancer. OConnor, Suhan, Zawacki and Sangodkar are consultants for RAPPTA Therapeutics. Narla is chief scientific officer of, reports receiving commercial research support from and has ownership interest in RAPPTA Therapeutics and is an adviser to Hera BioLabs. Zamarin reports research support to his institution from Astra Zeneca, Plexxikon, and Genentech, and personal/consultancy fees from Synlogic Therapeutics, GSK, Genentech, Xencor, Memgen, Immunos, Celldex, Calidi, and Agenus, and is an investor on a patent related to use of oncolytic Newcastle Disease Virus for cancer therapy.

Paper cited: Targeting ribonucleotide reductase induces synthetic lethality in PP2A-deficient uterine serous carcinoma, Cancer Research. DOI: 10.1158/0008-5472.CAN-21-1987

Link:
Researchers zero in on therapeutic target for aggressive uterine cancer - Michigan Medicine

Generation Bios shares were briefly halted Tuesday morning on the release of mouse data that complicated its search for a viable target for hemophilia A to take into the clinic.

The biotech, which joined the public markets with an IPO that had proceeds of $230 million in June 2020, announced in a Securities and Exchange Commission filing that data from early preclinical mouse studies did not translate into nonhuman primates.

This one is in the weeds, but Generation's previous research in mouse models found that their candidate demonstrated peak mean human factor VIII expression of 205% of normal. Factor VIII is an essential blood-clotting protein and a key biomarker for patients with hemophilia. New gene therapies are trying to correct deficiency of that protein to prevent bleeding episodes.

However, once the candidate was administered to nonhuman primates, that peak mean human factor VIII expression dropped to just 2%. That result is now sending Generation back to the drawing board to come up with a new candidate that might work in humans.

RELATED:Generation Bio tees up $125M IPO to push next-gen gene therapies

After trading on Generations shares resumed, the price plummeted more than 55% to $6.22, compared to a prior close of $13.60.

Generation had promised to pick its clinical candidates over the course of 2020, with IND-enabling studies planned for this year. Applications to the FDA for human testing were expected in 2022.

That timeline will be pushed backway back. The company now plans to provide updates to its pipeline program sometime in 2022 and timing for IND submissions will come in the future.

This is a cautionary tale for the hot IPO arena that has seen biotechs leap to the public markets based purely on preclinical data.

Nevertheless, Chief Scientific Officer Matthew Stanton, Ph.D., said the company has learned plenty about its platform in collecting the animal study data, specifically around manufacturing capabilities and production processes.

RELATED:Generation Bio grabs a $110M round to ramp up work on next-gen gene therapies

We are working to translate the improved potency and decreased variability that we have observed in mice to [nonhuman primates], Stanton said.

Back in January, Generation said its candidate had been successfully delivered to the liver of nonhuman primates. At the time, Stanton referred to data on the demonstration of translation from mice to nonhuman primates as important proof points for our platform.

Generation is aiming to exceed the limits of conventional gene therapies, CEO Geoff McDonough, M.D., said in a Tuesday statement. The companys gene therapy technology is based on a non-viral genetic medicine platform.

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Generation Bio shares halved as hemophilia gene therapy hunt goes back to square one - FierceBiotech