Category Archives: Gene Medicine

There is no one-size-fits-all algorithm for AI that enables drug developers to apply it and quickly identify whatever features they seek. Finding an answer to this dilemma has great implications for the field of precision medicine.

Currently, researchers are selecting best-of-breed algorithms in a modular approach to build customized analytics engines that answer specific questions in a way that is both unbiased and reproducible.

We still dont have a gold standard in terms of implementing and applying reproducible AI/ML approaches, said Zeeshan Ahmed, Ph.D., assistant professor of medicine at Robert Wood Johnson Medical School, Rutgers Biomedical and Health Sciences, in an interview with BioSpace.

As yet, there has been very little effort to organize and understand the many computing approaches in this field.

Key AI/ML Objectives for Precision Medicine

A review published in Briefings in Bioinformatics is among the first. Ahmed and colleagues examined five years of literature in whole-genome or whole exome sequencing to identify 32 of the most frequently used AI/ML algorithms and approaches used to deliver precision medicine insights.

The team compared scientific objectives, methodologies, data sources, ethics and gaps for each of those approaches.

For AI/ML to be more useful for drug developers, several things are required. Chief among them, Ahmed said, are:

During cases, when data is of high volume, it is important to ensure the right balance between training and actual datasets to avoid overfitting, Ahmed noted.

For AI/ML to be most useful, the data should be standardized to enable more accurate searches. Ensuring the data uses the same terms to refer to the same elements helps ensure that all the relevant information can be identified and analyzed.

There should be a method to correct errors in the data, too. Data that is entered by hand, for instance, may well have inaccuracies. The study data also should span multiple diseases and distinct populations to reflect the broad way in which diseases, conditions and symptoms present.

The Role of AI/ML in COVID-19 Drug Repurposing

Recent research in Biomedicine & Pharmacotherapy, conducted by Kyung Hyun Choi from the Jeju National University in Korea and colleagues noted the value of ML and deep learning in drug repurposing for COVID-19 therapeutics. Those methods helped them distinguish between drug targets and gene products that affect target activity.

Each type of analysis had its own group of algorithms, Choi explained in the paper. Types of analyses used for machine learning included k-nearest neighbors (a non-supervised learning method), random forest and support vector machine, among others.

Deep learning techniques included artificial neural networks, convolutional neural networks and long short-term memory. AI algorithms were used for link prediction, node prediction or graph prediction and other tasks.

In applying AI/ML to research, Choi and colleagues wrote, The limitationsinclude the inconsistencyin biological networks, as well as challenges associated with various networks that can lead to bias in the outcome. To overcome those issues, he recommended using heterogeneous data from multiple sources to enhance the reliability of analyses.

Another study published in Current Drug Targets last year reviews ML tools used to identify biologically active compounds from among millions of candidates.

It found, among other things, that the support vector machine (SVM) algorithm was more effective than others in indicating the classification model best used for human intestinal absorption predictions. However, the quantitative structure-activity relationship (QSAR) model predicted flavonoid inhibitory effects in specific indications. Clearly, the choice of algorithm matters.

Decoding the Black Box

Until a few years ago, AI often was considered a black box that ingested data and expelled findings without providing researchers with the details needed to understand how those results were derived.

Youre learning how thousands of inputs connect to hundreds or thousands of outputs, David Longo, co-founder and CEO of Ordaos, told BioSpace. Machine learning algorithms learn the intrinsic relationships between for example amino acids and motifs and domainsin a nonlinear, complex way, so theres still a kind of black box element to AL/ML, depending on how you construct it.

Generally, modern AI/ML algorithms allow some degree of insight into how individual algorithms reach their conclusions.

For example, Ordaos, which develops mini-proteins, provides a trace-back of every single amino acid that was changed and how that affected the properties that come out of that protein, Longo said. For researchers, thats a huge benefit.

Innovation in the field of AI/ML today is not necessarily around creating new individual components, but putting them together in interesting ways, Longo continued.

He cited Ordaos multitask learning model as an example.

Traditionally, ML models were developed by training the algorithm in a specific area a structure predictor would just train on structures and, with a few more steps, create a model. Using that model for another, slightly different purpose, required retraining. Ordaos model, in contrast, learns from multiple tasks simultaneously, somewhat countering Ahmeds view of algorithm specificity.

Selecting the Right Algorithms

AI/ML analytic approaches have the potential to help develop enhanced, systems-level understanding of disease mechanisms and treatment impacts, and can replace the homogeneity of existing genetic and statistical approaches with heterogeneity. Realizing that value, however, requires selecting the right algorithms for the job.

It is important to measure and avoid algorithmic bias, Ahmed said. Classifying tasks based on available predictor variables is a key step to correctly address the problem of choosing a suitable AI/ML algorithm.

In my lab, Ahmed said, We practice AI/ML-driven personalized medicine. We are generating AI/ML-ready datasets based on clinical and multi-omics/genomics profiles and are developing automated pipelines to analyze and perform predictive analysis.

Furthermore, we are addressing ethical issues, which involve protecting health information associated with multi-omics/genomic datasets, he continued.

The analytics trend is shifting from generating big data to analyzing and interpreting that data and using it predictively. For those predictions to be accurate, the underlying assumptions also must be accurate, and that requires selecting the right algorithms for the questions.

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Leveraging Best-of-Breed Algorithms for Accuracy in Precision Medicine - BioSpace

Getting from point A to point B has never been easier thanks to digital maps on our smartphones. With the swipe of a finger, we can plan a route to the grocery store, scope out a hiking trail or pick a perfect vacation destination. Soon, biomedical researchers will have a similar tool to easily navigate the vast network of cells in the human body.

The Human BioMolecular Atlas Program, or HuBMAP, is an international consortium of researchers with a shared goal of developing a global atlas of healthy cells in the human body. Once completed, the resource will be made freely available to drug developers and clinical researchers who could use it to shape the development of specialized medical treatments.

The idea behind HuBMAP is akin to the National Institutes of Healths Human Genome Project, which sequenced every single gene in the human body. Completed almost 20 years ago, the massive undertaking kickstarted a renaissance in clinical research and laid the groundwork for innovative approaches to gene-based therapies. But instead of collecting genetic information on the whole organism level, HuBMAP goes deeper with the goal of mapping gene expression, proteins, metabolites and other information in different types of cells across various organs and tissues.

The next step of turning this vast wealth of data into a user-friendly tool is managed by bioinformaticians at the University of Pittsburgh, the Pittsburgh Supercomputing Center (PSC), Carnegie Mellon University and Stanford University. The teams recently received $20 million in renewed funding from the NIH to continue these efforts.

Creating an ecosystem that can connect all the different pieces of data into a single large knowledge resource is a tough job, but thats what this team has special expertise in. We are good at integrating all kinds of various pieces of software and making them run, said co-lead of the Pittsburgh HuBMAP Infrastructure and Engagement Component Jonathan Silverstein, a professor in theDepartment of Biomedical Informaticsat Pitt.

The team, led by Silverstein, who is also a chief research informatics officer at Pitt and UPMCsInstitute for Precision Medicine, and PSCs Scientific Director Phil Blood, will embark on a long journey of annotating vast amounts of molecular-level data from thousands of tissue samples collected in over 60 institutions across the country. A locally maintained and developed hybrid cloud infrastructure for data integration and software development is being used to mold the resulting library of genetic and protein signatures of healthy cells into a comprehensive map.

The HuBMAP Computational Tools Component, led by Matthew Ruffalo of Carnegie Mellons Computational Biology Department, has developed computational pipelines for processing these molecular datasets, allowing for efficient data integration across data types, tissues and more.

The team is also involved in projects aimed at creating an atlas of aging and senescent cells (SenNet) and building a framework for studying molecular markers of breast cancer.

In addition to research, the HuBMAP and SenNet consortia are really helping to shape the ecosystem and the culture around projects that this work will impact, said Kay Metis, SenNet program manager at Pitt. This project has the potential to impact Alzheimers and aging research and make a big difference to the direction of medical research going forward. I love being part of the effort to contribute to the social impact of what a project of this scale can accomplish.

The expertise in molecular biology and clinical data, combined with experience in managing research consortiums and deep knowledge of software integration, along with computing resources provided by the PSC, makes Pittsburgh uniquely capable of handling a complex task such as HuBMAP.

I came to Pitt because it is a place with great depth of interest and scientific expertise and people here are open to building collaborations, not only across Pittsburgh but worldwide. We have created a team that is unbounded not only on the clinical and biological data side, but also on the technology side, Silverstein said.

Ana Gorelova, image by Getty

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Pitt researchers are leading the way toward a Google Maps of cells - University of Pittsburgh

Nanotechnology, nicknamed "the manufacturing technology of the twenty-first century," allows us to manufacture a vast range of sophisticated molecular devices by manipulating matter on an atomic and molecular scale. These nanomaterials possess the ideal properties of strength, ductility, reactivity, conductance, and capacity at the atomic, molecular, and supramolecular levels to create useable devices and systems in a length range of 1-100 nm. The materials' physical, chemical, and mechanical characteristics differ fundamentally and profoundly at the nanoscale from those of individual atoms, molecules, or bulk material, which enables the most efficient atom alignment in a very tiny space. Nanotechnology allows us to build various intricate nanostructured materials by manipulating matter at the atomic and molecular scale in terms of strength, ductility, reactivity, conductance, and capacity [1,2].

"Nanomedicine" is the science and technology used to diagnose, treat, and prevent diseases. It is also used for pain management and to safeguard and improve people's health through nanosized molecules, biotechnology, genetic engineering, complex mechanical systems, and nanorobots [3]. Nanoscale devices are a thousand times more microscopic than human cells, being comparable to biomolecules like enzymes and their respective receptors in size. Because of this property, nanosized devices can interact with receptors on the cell walls, as well as within the cells. By obtaining entry into different parts of the body, they can help pick up the disease, as well as allow delivery oftreatment to areas of the body that one can never imagine being accessible. Human physiology comprises multiple biological nano-machines. Biological processes that can lead to cancer also occur at the nanoscale. Nanotechnology offers scientists the opportunity to experiment on macromolecules in real time and at the earliest stage of disease, even when very few cells are affected. This helps in the early and accurate detection of cancer.

In a nutshell, the utility of the nanoscale materials for cancer is due to the qualities such as the ability to be functionalized and tailored to human biological systems (compatibility), the ability to offer therapy or act as a therapeutic agent, the ability to act as a diagnostic tool, the capability to penetrate various physiological barriers such as the blood-brain barrier, the capability to accumulate passively in the tumor, and the ability to aggressively target malignant cells.

Nanotechnology in cancer management has yielded various promising outcomes, including drug administration, gene therapy, monitoring and diagnostics, medication carriage, biomarker tracing, medicines, and histopathological imaging. Quantum dots (QDs) and gold nanoparticles are employed at the molecular level to diagnose cancer. Molecular diagnostic techniques based on these nanoparticles, such as biomarker discovery, can properly and quickly diagnose tumors. Nanotechnology therapeutics, such as nanoscale drug delivery, will ensure that malignant tissues are specifically targeted while reducing complications. Because of their biological nature, nanomaterials can cross cell walls with ease. Because of their active and passive targeting, nanomaterials have been used in cancer treatment for many years. This research looks at its applications in cancer diagnosis and therapy, emphasizing the technology's benefits and limitations [3-5]. The various uses of nanotechnology have been enumerated in the Table 1.

Early cancer detection is half the problem solved in the battle against cancer. X-ray, ultrasonography, CT, magnetic resonance imaging (MRI), and PET scan are the imaging techniques routinely used to diagnose cancer. Morphological changes in tissues or cells (histopathology or cytology) help in the final confirmation of cancer. These techniques detect cancer only after visible changes in tissues, by which time the cancer might have proliferated and caused metastasis. Another limitation of conventional imaging techniques is their failure to distinguish benign from malignant tumors. Also, cytology and histopathology cannot be employed as independent, sensitive tests to detect cancer at an early stage. With innovative molecular contrast media and materials, nanotechnology offers quicker and more accurate initial diagnosis, along with an ongoing assessment of cancer patient care [6].

Although nanoparticles are yet to be employed in actual cancer detection, they are currently being used in a range of medical screening tests. Gold nanoparticles are among the most commonly used in home test strips. A significant advantage of using nanoparticles for the detection of cancer is that they have a large surface area to volume ratio in comparison to their larger counterparts. This property ensures antibodies, aptamers, small molecules, fluorescent probes, polyethylene glycol (PEG), and other molecules cover the nanoparticle densely. This presents multiple binding ligands for cancer cells (multivalent effect of nanotools) and therefore increases the specificity and sensitivity of the bioassay [7,8]. Applications of nanotechnology in diagnosis are for the detection of extracellular biomarkers for cancer and for in vivo imaging. A good nanoprobe must have a long circulating time, specificity to the cancer tissue, and no toxicity to nearby tissue [9,10].

Detection of Biomarkers

Nanodevices have been studied to detect blood biomarkers and toxicity to healthy tissues nearby. These biomarkers include cancer-associated circulating tumor cells, associated proteins or cell surface proteins, carbohydrates or circulating tumor nucleic acids, and tumor-shed exosomes. Though it is well known that these biomarkers help to detect cancer at apreliminary stage, they also help to monitor the therapy and recurrence. They have limitations such as low concentrations in body fluids, variations in their levels and timings in different patients, and difficult prospective studies. These hurdles are overcome by nanotechnology, which offers high specificity and sensitivity. High sensitivity, specificity, and multiplexed measurements are all possible with nano-enabled sensors. To further illuminate a problem, next-generation gadgets combine capture with genetic analysis [11-15].

Imaging Using Nanotechnology

Nanotechnology uses nanoprobes that will accumulate selectively in tumor cells by passive or active targeting. The challenges faced are the interaction of nanoparticles with blood proteins, their clearance by the reticuloendothelial system, and targeting of tumors.Passive targeting suggests apreference for collecting the nanoparticles in the solid tumors due to extravasation from the blood vessels. This is made possible by the defective angiogenesis of the tumorwherein the new blood vessels do not have tight junctions in their endothelial cells and allow the leaking out of nanoparticles up to 150 nm in size, leading to a preferential accumulation of nanoparticles in the tumor tissue. This phenomenon is called enhanced permeability and retention (EPR).Active targeting involves the recognition of nanoparticles by the tumor cell surface receptors. This will enhance the sensitivity of in vivo tumor detection. For early detection of cancer, active targeting will give better results than passive targeting [16-18].

This can be classified as delivery of chemotherapy, immunotherapy, radiotherapy, and gene therapy, and delivery of chemotherapy is aimed at improving the pharmacokinetics and reducing drug toxicity by selective targeting and delivery to cancer tissues. This is primarily based on passive targeting, which employs the EPReffect described earlier [16]. Nanocarriers increase the half-life of the drugs. Immunotherapy is a promising new front in cancer treatment based on understanding the tumor-host interaction. Nanotechnology is being investigated to deliver immunostimulatory or immunomodulatory molecules. It can be used as an adjuvant to other therapies [19-21].

Role of Nanotechnology in Radiotherapy

Thistechnology involves targeted delivery of radioisotopes, targeted delivery of radiosensitizer, reduced side effects of radiotherapy by decreasing distribution to healthy tissues, and combining radiotherapy with chemotherapy to achieve synergism but avoid side effects, andadministering image-guided radiotherapy improves precision and accuracy while reducing exposure to surrounding normal tissues[22,23].

Gene Therapy Using Nanotechnology

There is a tremendous interest in the research in gene therapy for cancer, but the results are still falling short of clinical application. Despite a wide array of therapies aimed at gene modulation, such as gene silencing, anti-sense therapy, RNAinterference, and gene and genome editing, finding a way to deliver these effects is challenging. Nanoparticles are used as carriers for gene therapy, with advantages such as easy construction and functionalizing and low immunogenicity and toxicity. Gene-targeted delivery using nanoparticles has great future potential. Gene therapy is still in its infancy but is very promising [24].

Nanodelivery Systems

Quantum dots: Semiconductor nanocrystal quantum dots (QDs) have outstanding physical properties. Probes based on quantum dots have achieved promising cellular and in vivo molecular imaging developments. Increasing research is proving that technology based on quantum dots may become an encouraging approach in cancer research[4]. Biocompatible QDs were launched for mapping cancer cells in vitro in 1998. Scientists used these to create QD-based probes for cancer imaging that were conjugated with cancer-specific ligands, antibodies, or peptides. QD-immunohistochemistry (IHC) has more sensitivity and specificity than traditional immunohistochemistry (IHC) and can accomplish measurements of even low levels, offering considerably higher information for individualized management. Imaging utilizing quantum dots has emerged as a promising technology for early cancer detection[25,26].

Nanoshells and gold nanoparticles/gold nanoshells (AuNSs) are an excellent example of how combining nanoscience and biomedicine can solve a biological problem. They have an adjustable surface plasmon resonance, which can be set to the near-infrared to achieve optimal penetration of tissues. During laser irradiation, AuNSs' highly effective light-to-heat transition induces thermal destruction of the tumor without harming healthy tissues. AuNSs can even be used as a carrier for a wide range of diagnostic and therapeutic substances[27].

Dendrimers: These are novel nanoarchitectures with distinguishing characteristics such as a spherical three-dimensional shape, a monodispersed uni-micellar nature, and a nanometric size range. The biocompatibility of dendrimers has been employed to deliver powerful medications such as doxorubicin. This nanostructure targets malignant cells by attaching ligands to their surfaces. Dendrimers have been intensively investigated for targeting and delivering cancer therapeutics and magnetic resonance imaging contrast agents. The gold coating on its surface significantly reduced their toxicity without significantly affecting their size. It also served as an anchor for attaching high-affinity targeting molecules to tumor cells [28].

Liposomal nanoparticles (Figure 1): These have a role in delivery to a specific target spot, reducing biodistribution toxicity because of the surface-modifiable lipid composition, and have a structure similar to cell membranes. Liposome-based theranostics (particles constructed for the simultaneous delivery of therapeutic and diagnostic moieties) have the advantage of targeting specific cancer cells.Liposomes are more stable in the bloodstream and increase the solubility of the drug. They also act as sustained release preparations and protect the drug from degradation and pH changes, thereby increasing the drug's circulating half-life. Liposomes help to overcome multidrug resistance. Drugs such as doxorubicin, daunorubicin, mitoxantrone, paclitaxel, cytarabine, and irinotecanare used with liposome delivery [29-31].

Polymeric micelles: Micelles are usually spherical particles with a diameter of 10-100 nm, which are self-structured and have a hydrophilic covering shell and a hydrophobic core, suspended in an aqueous medium. Hydrophobic medicines can be contained in the micelle's core. A variety of molecules having the ability to bind to receptors, such as aptamers, peptides, antibodies, polysaccharides, and folic acid, are used to cover the surface of the micelle in active tumor cell targeting. Enzymes, ultrasound, temperature changes, pH gradients, and oxidationare used as stimuli in micelle drug delivery systems. Various physical and chemical triggers are used as stimuli in micelle drug delivery systems. pH-sensitive polymer micelle is released by lowering pH. A co-delivery system transports genetics, as well as anticancer medicines. Although paclitaxel is a powerful microtubule growth inhibitor, it has poor solubility, which causes fast drug aggregation and capillary embolisms. Such medicines' solubility can beraised to 0.0015-2 mg/ml by encapsulating them in micelles. Polymeric micelles are now being tested for use in nanotherapy [32].

Carbon nanotubes (CNTs): Carbon from burned graphite is used to create hollow cylinders known as carbon nanotubes (CNTs). They possess distinct physical and chemical characteristics that make them interesting candidates as carriers of biomolecules and drug delivery transporters. They have a special role in transporting anticancer drugs with a small molecular size. Wu et al. formed amedicine carrier system using multi-walled CNTs (MWCNTs) and the 10-hydroxycamptothecin (HCPT) anticancer compound. As a spacer between MWCNTs and HCPT, they employed hydrophilic diamine trimethylene glycol. In vitro and in vivo, their HCPT-MWCNT conjugates showed significantly increased anticancer efficacy when compared to traditional HCPTformulations. These conjugates were able to circulate in the blood longer and were collected precisely at the tumor site [33,34].

Limitations

Manufacturing costs, extensibility, safety, and the intricacy of nanosystems must all be assessed and balanced against possible benefits. The physicochemical properties of nanoparticles in biological systems determine their biocompatibility and toxicity. As a result, stringent manufacturing and delineation of nanomaterials for delivery of anticancer drugs are essential to reduce nanocarrier toxicity to surrounding cells. Another barrier to medication delivery is ensuring public health safety, as issues with nanoparticles do not have an immediate impact. The use of nanocarriers in cancer treatment may result in unforeseen consequences. Hypothetical possibilities of environmental pollution causing cardiopulmonary morbidity and mortality, production of reactive oxygen species causing inflammation and toxicity, and neuronal or dermal translocations are a few possibilities that worry scientists. Nanotoxicology, a branch of nanomedicine, has arisen as a critical topic of study, paving the way for evaluating nanoparticle toxicity [35-37].

Nanotechnology has been one of the recent advancements of science that not only has revolutionized the engineering field but also is now making its impact in the medical and paramedical field. Scientists have been successful in knowing the properties and characteristics of these nanomaterials and optimizing them for use in the healthcare industry. Although some nanoparticles have failed to convert to the clinic, other new and intriguing nanoparticles are now in research and show great potential, indicating that new treatment options may be available soon. Nanomaterials are highly versatile, with several benefits that can enhance cancer therapies and diagnostics.

These are particularly useful as drug delivery systems due to their tiny size and unique binding properties. Drugs such as doxorubicin, daunorubicin, mitoxantrone, paclitaxel, cytarabine, irinotecan, and amphotericin B are already being conjugated with liposomes for their delivery in current clinical practices. Doxorubicin, cytarabine, vincristine, daunorubicin, mitoxantrone, and paclitaxel, in particular, are key components of cancer chemotherapy. Even in the diagnosis of cancer for imaging and detection of tumor markers, particles such as nanoshells, dendrimers, and gold nanoparticles are currently in use.

Limitations of this novel technology include manufacturing expenses, extensibility, intricacy, health safety, and potential toxicity. These are being overcome adequately by extensive research and clinical trials, and nanomedicine is becoming one of the largest industries in the world. A useful collection of research tools and clinically practical gadgets will be made available in the near future thanks to advancements in nanomedicine. Pharmaceutical companies will use in vivo imaging, novel therapeutics, and enhanced drug delivery technologies in their new commercial applications. In the future, neuro-electronic interfaces and cell healing technology may change medicine and the medical industry when used to treat brain tumors.

Continued here:
The Application of Nanotechnology and Nanomaterials in Cancer Diagnosis and Treatment: A Review - Cureus

Smart Immune Bolsters Management Team with Medical and Technical Appointments

Dr Frederic Lehmann, MD, appointed Chief Medical Officer and Dr Pierre Heimendinger, PharmD, appointed Chief Technical Officer

Dr Pierre Heimendinger and Dr Frederic Lehmann, CTO and CMO of Smart Immune.

PARIS, France, September 13, 2022 Smart Immune SAS, a clinical-stage biotechnology company developing ProTcell, a thymus-empowered T-cell therapy platform to fully and rapidly re-arm the immune system, announced today that it has appointed Dr Frederic Lehmann as Chief Medical Officer and Dr Pierre Heimendinger as Chief Technical Officer. They bring extensive experience and strong industrial track records in the fields of immune-oncology and cell and gene therapy.

Karine Rossignol, PharmD, Co-founder and Chief Executive Officer of Smart Immune, said: "I am thrilled to be expanding our management team with such seasoned and respected executives. Dr Frederic Lehmann and Dr Pierre Heimendinger have both made impressive contributions to the field of allogeneic T-cell medicine, bringing innovation from bench to bedside. Frederics experience in clinical trial design and Pierres in cell therapy process development will be instrumental in getting the Company ready for the registration phase. I am confident that their knowledge and commitment will raise the development of our ProTcell platform to a new level and expedite patient access to our technology. We are excited to welcome them to Smart Immune!"

As the former Head of Clinical Development and Medical Affairs and Vice President of Celyad Oncology, Dr Frederic Lehmann defined the strategic vision and contributed to securing a number of autologous and allogeneic engineered T-cell therapy IND candidates. He also spent 12 years at GSK in several roles including Head of the Early Clinical Development Business Unit for Cancer Immunotherapeutics in the companys Vaccine Division. Frederic takes over as Chief Medical Officer from Smart Immunes Co-founder Marina Cavazzana, MD, PhD, who will transition to the role of Strategic Clinical Development Advisor.

Dr Frederic Lehmann, Chief Medical Officer of Smart Immune, commented: I am honored to be joining such an outstanding organization and its founding team, true pioneers in T-cell progenitors, to give rise to long-lasting cellular therapy fighting cancer and infection. I strongly believe in Smart Immunes potential, and I am very pleased to be appointed Chief Medical Officer at this exciting time. I am fully committed to help enable delivery of this unique therapeutic approach to patients with unmet need.

As Chief Technical Officer, Dr Pierre Heimendinger will oversee the development of Smart Immunes ProTcell platform, most notably ensuring the stability and safety of the ProTcell products as they progress through Phase I/II clinical trials. Pierre brings over 30 years of experience in process automation of allogeneic and autologous CAR-Treg, Treg, viral vectors and vaccines. Prior to joining Smart Immune, he held key managerial roles overseeing production, pharmaceutical development and quality control departments at multiple pharma and biotech companies such as Aventis-Pasteur (Sanofi), Octapharma, Transgene, TxCell, and most recently, Sangamo Therapeutics. Pierre holds a PharmD from the Mrieux Institute in France.

Dr Pierre Heimendinger, Chief Technical Officer of Smart Immune, commented: Smart Immunes developments in T-cell therapy will be completely transformative to the field as we strive to re-arm the immune system for patients fighting cancer and infection, enabling a truly off-the-shelf approach, and making the ProTcell cell therapy accessible for patients when it is needed and wherever it is needed. I am delighted to be working with such a groundbreaking and innovative company at a pivotal time in its growth and development and am thankful to Karine and the rest of the Smart Immune team for such a warm welcome.

Ends

About Smart Immune

Smart Immune is a clinical-stage biotechnology company developing ProTcell, a thymus-empowered T-cell therapy platform to fully and rapidly re-arm the immune system, enabling next-generation allogeneic T-cell therapies for all. The company was founded in 2017 to help patients with life-threatening diseases such as high-risk blood cancers and primary immunodeficiencies.

Smart Immunes ProTcell platform, which is already in Phase I/II clinical trials, enables the recovery of a complete immune repertoire in patients fighting cancer and infection. ProTcell introduces potent, allogeneic T-cell progenitors which are then differentiated by the thymus into fully functional T-cells an off the shelf T-cell medicine.

Smart Immunes partners include Memorial Sloan Kettering in New York and Greater Paris University Hospitals (AP-HP). The company is headquartered at Paris Biotech Sant, 29 rue du Faubourg St Jacques, France.

https://www.smart-immune.com/

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smartimmune@consilium-comms.com

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Smart Immune Bolsters Management Team with Medical and Technical Appointments - GlobeNewswire

Kaaja R, Laivuori H, Laakso M, Tikkanen M, Ylikorkala O. Evidence of a state of increased insulin resistance in preeclampsia. Metabolism. 1999;48(7):8926.

CAS PubMed Article Google Scholar

Bramham K, Villa P, Joslin J, Laivuori H, Hmlinen E, Kajantie E, et al. Predisposition to superimposed preeclampsia in women with chronic hypertension: endothelial, renal, cardiac, and placental factors in a prospective longitudinal cohort. Hypertens Pregnancy. 2020;39(3):32635.

CAS PubMed Article Google Scholar

Leach R, Romero R, Kim Y, Chaiworapongsa T, Kilburn B, Das S, et al. Pre-eclampsia and expression of heparin-binding EGF-like growth factor. Lancet (London). 2002;360(9341):12159.

CAS Article Google Scholar

Ness R, Sibai B. Shared and disparate components of the pathophysiologies of fetal growth restriction and preeclampsia. Am J Obstet Gynecol. 2006;195(1):409.

PubMed Article Google Scholar

Mol BWJ, Roberts CT, Thangaratinam S, Magee LA, de Groot CJM, Hofmeyr GJ. Pre-eclampsia. Lancet. 2016;387(10022):9991011.

PubMed Article Google Scholar

Kolkova Z, Holubekova V, Grendar M, Nachajova M, Zubor P, Pribulova T, et al. Association of circulating miRNA expression with preeclampsia, its onset, and severity. Diagnostics (Basel). 2021;11(3):476.

CAS Article Google Scholar

Poon L, Shennan A, Hyett J, Kapur A, Hadar E, Divakar H, et al. The International Federation of Gynecology and Obstetrics (FIGO) initiative on pre-eclampsia: a pragmatic guide for first-trimester screening and prevention. Int J Gynaecol Obstet. 2019;145(S1):133.

PubMed PubMed Central Article Google Scholar

Karumanchi SA. Angiogenic factors in preeclampsia: from diagnosis to therapy. Hypertension. 2016;67(6):10729.

CAS PubMed Article Google Scholar

Dechend R, Luft FC. Angiogenesis factors and preeclampsia. Nat Med. 2008;14(11):11878.

CAS PubMed Article Google Scholar

Cim N, Kurdoglu M, Ege S, Yoruk I, Yaman G, Yildizhan R. An analysis on the roles of angiogenesis-related factors including serum vitamin D, soluble endoglin (sEng), soluble fms-like tyrosine kinase 1 (sFlt1), and vascular endothelial growth factor (VEGF) in the diagnosis and severity of late-onset preeclampsia. J Matern Fetal Neonatal Med. 2017;30(13):16027.

CAS PubMed Article Google Scholar

Sung KU, Roh JA, Eoh KJ, Kim EH. Maternal serum placental growth factor and pregnancy-associated plasma protein A measured in the first trimester as parameters of subsequent pre-eclampsia and small-for-gestational-age infants: a prospective observational study. Obstet Gynecol Sci. 2017;60(2):15462.

PubMed PubMed Central Article Google Scholar

Saleh L, Tahitu SIM, Danser AHJ, van den Meiracker AH, Visser W. The predictive value of the sFlt-1/PlGF ratio on short-term absence of preeclampsia and maternal and fetal or neonatal complications in twin pregnancies. Pregnancy Hypertens. 2018;14:2227.

PubMed Article Google Scholar

Lou WZ, Jiang F, Hu J, Chen XX, Song YN, Zhou XY, et al. Maternal serum angiogenic factor sFlt-1 to PlGF ratio in preeclampsia: a useful marker for differential diagnosis and prognosis evaluation in Chinese women. Dis Markers. 2019;2019:6270187.

PubMed PubMed Central Article CAS Google Scholar

Bartel D. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136(2):21533.

CAS PubMed PubMed Central Article Google Scholar

Wang X, Qian T, Bao S, Zhao H, Chen H, Xing Z, et al. Circulating exosomal miR-363-5p inhibits lymph node metastasis by downregulating PDGFB and serves as a potential noninvasive biomarker for breast cancer. Mol Oncol. 2021;15(9):246679.

PubMed PubMed Central Article CAS Google Scholar

Bao S, Hu T, Liu J, Su J, Sun J, Ming Y, et al. Genomic instability-derived plasma extracellular vesicle-microRNA signature as a minimally invasive predictor of risk and unfavorable prognosis in breast cancer. J Nanobiotechnology. 2021;19(1):22.

CAS PubMed PubMed Central Article Google Scholar

Gebert LFR, MacRae IJ. Regulation of microRNA function in animals. Nat Rev Mol Cell Biol. 2019;20(1):2137.

CAS PubMed PubMed Central Article Google Scholar

Gantier MP, McCoy CE, Rusinova I, Saulep D, Wang D, Xu D, et al. Analysis of microRNA turnover in mammalian cells following Dicer1 ablation. Nucleic Acids Res. 2011;39(13):5692703.

CAS PubMed PubMed Central Article Google Scholar

Sayed AS, Xia K, Salma U, Yang T, Peng J. Diagnosis, prognosis and therapeutic role of circulating miRNAs in cardiovascular diseases. Heart Lung Circ. 2014;23(6):50310.

PubMed Article Google Scholar

Xu P, Zhao Y, Liu M, Wang Y, Wang H, Li Y, et al. Variations of microRNAs in human placentas and plasma from preeclamptic pregnancy. Hypertension (Dallas, Tex: 1979). 2014;63(6):127684.

CAS Article Google Scholar

Murphy M, Casselman R, Tayade C, Smith G. Differential expression of plasma microRNA in preeclamptic patients at delivery and 1 year postpartum. Am J Obstet Gynecol. 2015;213(3):367.e1-9.

CAS Article Google Scholar

Zheng W, Chen A, Yang H, Hong L. MicroRNA-27a inhibits trophoblast cell migration and invasion by targeting SMAD2: potential role in preeclampsia. Exp Ther Med. 2020;20(3):22629.

CAS PubMed PubMed Central Google Scholar

Cui J, Chen X, Lin S, Li L, Fan J, Hou H, et al. MiR-101-containing extracellular vesicles bind to BRD4 and enhance proliferation and migration of trophoblasts in preeclampsia. Stem Cell Res Ther. 2020;11(1):231.

CAS PubMed PubMed Central Article Google Scholar

Licini C, Avellini C, Picchiassi E, Mensa E, Fantone S, Ramini D, et al. Pre-eclampsia predictive ability of maternal miR-125b: a clinical and experimental study. Transl Res. 2021;228:1327.

CAS PubMed Article Google Scholar

Wang D, Na Q, Song GY, Wang L. Human umbilical cord mesenchymal stem cell-derived exosome-mediated transfer of microRNA-133b boosts trophoblast cell proliferation, migration and invasion in preeclampsia by restricting SGK1. Cell Cycle. 2020;19(15):186983.

CAS PubMed PubMed Central Article Google Scholar

Zhou W, She G, Yang K, Zhang B, Liu J, Yu B. MiR-384 inhibits proliferation and migration of trophoblast cells via targeting PTBP3. Pregnancy Hypertens. 2020;21:1328.

PubMed Article Google Scholar

Awamleh Z, Gloor GB, Han VKM. Placental microRNAs in pregnancies with early onset intrauterine growth restriction and preeclampsia: potential impact on gene expression and pathophysiology. BMC Med Genomics. 2019;12(1):91 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE114349).

PubMed PubMed Central Article CAS Google Scholar

Brookes S, Martin E, Smeester L, Boggess K, Grace M, Fry R. GEO https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE84260. 2016.

Wyatt S, Kraus F, Roh C, Elchalal U, Nelson D, Sadovsky Y. The correlation between sampling site and gene expression in the term human placenta. Placenta. 2005;26(5):3729.

CAS PubMed Article Google Scholar

Huang HY, Lin YC, Li J, Huang KY, Shrestha S, Hong HC, et al. miRTarBase 2020: updates to the experimentally validated microRNA-target interaction database. Nucleic Acids Res. 2020;48(D1):D14854.

CAS PubMed Google Scholar

Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019;10(1):1523.

PubMed PubMed Central Article CAS Google Scholar

Gestational Hypertension and Preeclampsia: ACOG Practice Bulletin. Obstet Gynecol.2020;135(6):e23760.

Magee LA, Nicolaides KH, von Dadelszen P. Preeclampsia. N Engl J Med. 2022;386(19):181732.

CAS PubMed Article Google Scholar

Phipps EA, Thadhani R, Benzing T, Karumanchi SA. Pre-eclampsia: pathogenesis, novel diagnostics and therapies. Nat Rev Nephrol. 2019;15(5):27589.

PubMed PubMed Central Article Google Scholar

Roberge S, Bujold E, Nicolaides KH. Aspirin for the prevention of preterm and term preeclampsia: systematic review and metaanalysis. Am J Obstet Gynecol. 2018;218(3):28793 (e1).

CAS PubMed Article Google Scholar

Fox R, Kitt J, Leeson P, Aye CYL, Lewandowski AJ. Preeclampsia: risk factors, diagnosis, management, and the cardiovascular impact on the offspring. J Clin Med. 2019;8(10):1625.

CAS PubMed Central Article Google Scholar

Rasmussen M, Reddy M, Nolan R, Camunas-Soler J, Khodursky A, Scheller NM, et al. RNA profiles reveal signatures of future health and disease in pregnancy. Nature. 2022;601(7893):4227.

CAS PubMed PubMed Central Article Google Scholar

Rudov A, Balduini W, Carloni S, Perrone S, Buonocore G, Albertini MC. Involvement of miRNAs in placental alterations mediated by oxidative stress. Oxid Med Cell Longev. 2014;2014:103068.

PubMed PubMed Central Article CAS Google Scholar

Mouillet JF, Ouyang Y, Coyne CB, Sadovsky Y. MicroRNAs in placental health and disease. Am J Obstet Gynecol. 2015;213(4 Suppl):S16372.

CAS PubMed PubMed Central Article Google Scholar

Gong S, Gaccioli F, Dopierala J, Sovio U, Cook E, Volders PJ, et al. The RNA landscape of the human placenta in health and disease. Nat Commun. 2021;12(1):2639.

CAS PubMed PubMed Central Article Google Scholar

Fu G, Brkic J, Hayder H, Peng C. MicroRNAs in human placental development and pregnancy complications. Int J Mol Sci. 2013;14(3):551944.

CAS PubMed PubMed Central Article Google Scholar

Luo SS, Ishibashi O, Ishikawa G, Ishikawa T, Katayama A, Mishima T, et al. Human villous trophoblasts express and secrete placenta-specific microRNAs into maternal circulation via exosomes. Biol Reprod. 2009;81(4):71729.

CAS PubMed Article Google Scholar

Makarova JA, Shkurnikov MU, Wicklein D, Lange T, Samatov TR, Turchinovich AA, et al. Intracellular and extracellular microRNA: an update on localization and biological role. Prog Histochem Cytochem. 2016;51(34):3349.

PubMed Article Google Scholar

Hromadnikova I, Dvorakova L, Kotlabova K, Krofta L. The prediction of gestational hypertension, preeclampsia and fetal growth restriction via the first trimester screening of plasma exosomal C19MC microRNAs. Int J Mol Sci. 2019;20(12):2972.

CAS PubMed Central Article Google Scholar

Luizon MR, Conceicao I, Viana-Mattioli S, Caldeira-Dias M, Cavalli RC, Sandrim VC. Circulating microRNAs in the second trimester from pregnant women who subsequently developed preeclampsia: potential candidates as predictive biomarkers and pathway analysis for target genes of miR-204-5p. Front Physiol. 2021;12:678184.

PubMed PubMed Central Article Google Scholar

Niu ZR, Han T, Sun XL, Luan LX, Gou WL, Zhu XM. MicroRNA-30a-3p is overexpressed in the placentas of patients with preeclampsia and affects trophoblast invasion and apoptosis by its effects on IGF-1. Am J Obstet Gynecol. 2018;218(2):249 e1-e12.

Article CAS Google Scholar

Hromadnikova I, Kotlabova K, Ivankova K, Krofta L. First trimester screening of circulating C19MC microRNAs and the evaluation of their potential to predict the onset of preeclampsia and IUGR. PLoS ONE. 2017;12(2):e0171756.

PubMed PubMed Central Article CAS Google Scholar

Mi C, Ye B, Gao Z, Du J, Li R, Huang D. BHLHE40 plays a pathological role in pre-eclampsia through upregulating SNX16 by transcriptional inhibition of miR-196a-5p. Mol Hum Reprod. 2020;26(7):53248.

CAS PubMed Article Google Scholar

Enquobahrie DA, Abetew DF, Sorensen TK, Willoughby D, Chidambaram K, Williams MA. Placental microRNA expression in pregnancies complicated by preeclampsia. Am J Obstet Gynecol. 2011;204(2):178 e12-21.

Article CAS Google Scholar

Bao S, Zhou T, Yan C, Bao J, Yang F, Chao S, et al. GEO https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE206988. 2022.

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A blood-based miRNA signature for early non-invasive diagnosis of preeclampsia - BMC Medicine - BMC Medicine

LONDON and MONTREAL, July 21, 2022 (GLOBE NEWSWIRE) -- DalCor Pharmaceuticals announced the results of the dal-GenE Phase 3 cardiovascular precision medicine outcomes trial with publication of Pharmacogenetics-guided dalcetrapib therapy after an acute coronary syndrome: the dal-GenE trial in the European Heart Journal.1

The dal-GenE (DAL-301) trial was initiated to determine the ability of dalcetrapib to reduce cardiovascular (CV) morbidity and mortality in a population experiencing an acute coronary syndrome (ACS) within 1-3 months before randomization (N=6147) and identified as carrying the AA genotype at variant rs1967309 in the adenylate cyclase type 9 (ADCY9) gene, as determined by the cobas ADCY9 genotype test. This AA genotype is carried by approximately 20% of the total population and up to 40% in people of African descent. Eligible patients were optimally treated for CV risk factors. The prespecified primary endpoint was time-to-first event for the composite of CV death, resuscitated cardiac arrest, non-fatal myocardial infarction (MI) or non-fatal stroke.

In the dal-GenE trial, treatment with dalcetrapib in the intent-to-treat (ITT) analysis did not demonstrate a statistically significant result, with the composite primary endpoint event occurring in 9.5% of the patients in the dalcetrapib group, as compared with 10.6% in the placebo group (hazard ratio (HR) 0.88; 95% CI 0.75-1.03; p=0.12).

However:

Pre-COVID-19, the clinical efficacy of dalcetrapib seen in the dal-GenE study was also consistent with that of the retrospective analysis conducted in patients with the rs1967309 AA genotype in the dal-OUTCOMES study3. The totality of these data validates the pharmacogenetic hypothesis that dalcetrapib can safely improve, beyond the current standard of care, the prognosis of ACS patients with the rs1967309 AA genotype. DalCor is working closely with Health Authorities to determine the path forward for the approval of dalcetrapib for the treatment of patients with the rs1967309 AA genotype following an ACS event.

About DalCorDalCor is a biopharmaceutical company with a focus on addressing cardiovascular disease, the greatest global healthcare burden. Our purpose is to deliver the first pharmacogenomic precision medicine in cardiovascular disease that specifically targets patients with the ADCY9 AA genotype. For more information, please visit dalcorpharma.com.

About dal-GenEdal-GenE was a double-blind, parallel-group, placebo-controlled, randomized trial comparing orally administered dalcetrapib 600 mg once daily with placebo in a 1:1 ratio in patients with an acute coronary syndrome within 1 to 3 months and the AA genotype at variant rs1967309 in the ADCY9 gene. A total of 6147 patients were randomly assigned to receive dalcetrapib 600 mg or placebo daily.

The primary endpoint was the time from randomization to first occurrence of cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction, or non-fatal stroke.

Participants were enrolled across 630 investigational sites located in North America, South America, Europe, Middle East, South Africa, Australia, and New Zealand. Patients were eligible if they were at least 45 years of age, recently hospitalized for an acute coronary syndrome within the previous 1 to 3 months, clinically stable, treated with guidelines-based management of LDL- cholesterol at a minimum to a target level less than 2.6 mmol/L, and confirmed in a central laboratory to have the AA genotype at variant rs1967309 in the ADCY9 gene.

About DalcetrapibDalcetrapib is potentially the first pharmacogenomic precision medicine in cardiovascular disease developed for patients with the ADCY9 AA genotype. A companion diagnostic test, developed in conjunction with Roche Molecular Systems, identifies patients with the ADCY9 AA genotype who may potentially benefit from dalcetrapib treatment. DalCor obtained global rights to develop, manufacture and commercialize dalcetrapib under a license and collaboration agreement with Roche.

References

Media Contact:Clare EvansIris Communication+1 403 888 6869clare.evans@iriscommunication.net

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dal-GenE Phase 3 Cardiovascular Precision Medicine Outcomes

Should you find a link that does not work within any Guidance document, Rule or other document posted on the FDA Web site, please try searching for the document using the document title. If you need further assistance, please go to Contact FDA.

Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products; Draft Guidance for Industry3/2022

Human Gene Therapy Products Incorporating Human Genome Editing; Draft Guidance for Industry3/2022

Policy for Certain REMS Requirements During the Tocilizumab Shortage Related to the COVID-19 Public Health Emergency; Guidance for Industry and Health Care Professionals12/2021

Interpreting Sameness of Gene Therapy Products Under the Orphan Drug Regulations; Guidance for Industry9/2021

Studying Multiple Versions of a Cellular or Gene Therapy Product in an Early-Phase Clinical Trial; Draft Guidance for Industry9/2021

Manufacturing Considerations for Licensed and Investigational Cellular and Gene Therapy Products During COVID-19 Public Health Emergency; Guidance for Industry1/2021

Human Gene Therapy for Neurodegenerative Diseases; Draft Guidance for Industry1/2021

Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs); Guidance for Industry1/2020

Long Term Follow-up After Administration of Human Gene Therapy Products; Guidance for Industry1/2020

Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus During Product Manufacture and Patient Follow-up; Guidance for Industry1/2020

Human Gene Therapy for Hemophilia; Guidance for Industry1/2020

Human Gene Therapy for Rare Diseases; Guidance for Industry1/2020

Human Gene Therapy for Retinal Disorders; Guidance for Industry1/2020

Evaluation of Devices Used with Regenerative Medicine Advanced Therapies;Guidance for Industry2/2019

Expedited Programs for Regenerative Medicine Therapies for Serious Conditions;Guidance for Industry2/2019

Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use; Guidance for Industry and Food and Drug Administration StaffUpdated: 12/2017

Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception; Guidance for Industry11/2017

Deviation Reporting for Human Cells, Tissues, and Cellular and Tissue-Based Products Regulated Solely Under Section 361 of the Public Health Service Act and 21 CFR Part 1271; Guidance for Industry9/2017

Recommendations for Microbial Vectors Used for Gene Therapy; Guidance for Industry9/2016

Design and Analysis of Shedding Studies for Virus or Bacteria-Based Gene Therapy and Oncolytic Products; Guidance for Industry8/2015

Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products; Guidance for Industry6/2015

Determining the Need for and Content of Environmental Assessments for Gene Therapies, Vectored Vaccines, and Related Recombinant Viral or Microbial Products; Guidance for Industry3/2015

Guidance for Industry: BLA for Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic and Immunologic Reconstitution in Patients with Disorders Affecting the Hematopoietic System3/2014. (This guidance finalizes the draft guidance of the same title dated June 2013.)

IND Applications for Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic and Immunologic Reconstitution in Patients with Disorders Affecting the Hematopoietic System - Guidance for Industry and FDA Staff3/2014. (This guidance finalizes the draft guidance of the same title dated June 2013.)

Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products(This guidance finalizes the draft guidance entitled Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products dated November 2012) 11/2013

Guidance for Industry: Preparation of IDEs and INDs for Products Intended to Repair or Replace Knee Cartilage12/2011. (This guidance finalizes the draft guidance of the same title dated July 2007.)

Guidance for Industry: Clinical Considerations for Therapeutic Cancer Vaccines10/2011. (This guidance finalizes the draft guidance of the same title dated September 2009.)

Guidance for Industry: Potency Tests for Cellular and Gene Therapy Products1/2011. (This guidance finalizes the draft document of the same name, dated October 2008.)

Guidance for Industry: Cellular Therapy for Cardiac Disease(This guidance finalizes the draft guidance entitled Guidance for Industry: Somatic Cell Therapy for Cardiac Disease dated March 2009 (April 2, 2009, 74 FR 14992). 10/2010.

Guidance for Industry: Considerations for Allogeneic Pancreatic Islet Cell Products9/2009

Guidance for FDA Reviewers and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs)4/2008

Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products; Guidance for Industry8/2007

Guidance for Industry: Guidance for Human Somatic Cell Therapy and Gene Therapy3/1998

12/10/2021

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Cellular & Gene Therapy Guidances | FDA

Failed efforts do not overshadow fields progress, resolve.

The recent news of Biogen and Ionis Pharmaceuticals ending a clinical trial for their amyotrophic lateral sclerosis drug candidate and Roches failed Phase III study in Huntingtons disease (HD) are hard to bear for many families holding on to hope in the face of devastating diseases with limited options. Their drug development journeys underscore the highly challenging nature of tackling rare diseases. As a geneticist, Ive seen firsthand the difficulties these patients endure. But even in the face of what might seem like failure, there is great progress. New thinking, research, and discoveries are only made possible by those who bravely forge new paths to gain a better understanding of the human body, even when that risk entails failure. Success will come.

The silver lining? Our strategy is sound. There is no doubt that genetic medicines work at addressing root causality in monogenic rare diseases like HD.

Back in the mid-1980s, a group of scientists came together at Alta Ski Resort to investigate whether it was possible to detect increased mutations in the survivors of the Hiroshima and Nagasaki bombings. The conclusion was that current methods were insufficient, yet the meeting spurred an energized response around genetic sequencing that resulted in the federal government funding the multibillion-dollar, multinational, and multiyear project to sequence all six billion letters of the diploid human genome, which resulted in the publication of the draft sequence of the human genome in 2001, years earlier than expected.

In less than four decades since, we have unraveled the blueprint of human life, cataloged the vast majority of mutations in the genetic code, implemented global infrastructure to provide rapid and inexpensive genetic testing to patients and physicians, and have a first wave of genetic medicines saving human lives. This is breathtaking progress.

However, there is still much work to do, with numerous challenges centered on improving the delivery, selectivity, and tolerability of these genetic medicines. We know the medicines work; it is just a matter of getting the therapy to the tissue where the disease manifests, dialing in the selectivity for the gene of interest, and engineering out toxicities.

With HD, patients receive an injection into the spinal cord, but in order for enough of a relatively large genetic medicine to penetrate into the deep brain structures to be effective, the high concentrations of the drug injected at the surface of the brain may result in neurotoxicity.

Rapid advancements in the areas of delivery, selectivity, and tolerability are happening. For delivery, innovations are allowing us to deliver genetic medicines across the blood-brain barrier to allow uniform exposures across all brain regions and not setting up toxic gradientswhich has been difficult for large molecules. This method avoids the brain surface toxicity. Since HD is a disease that involves the whole body, delivering a solution systemically via the bloodstream may address the whole-body manifestations of the disease. These new delivery devices are also noninvasive, using either ultrasound or emerging tech, and allow effective administration in a previously impossible manner.

For selectivity, emerging technologies can identify and engage with only the targeted mutated gene. Weve essentially reverse engineered nature so that the genetic-medicine-to-gene-target interface wont tolerate any mismatches. The treatment is viewed by the body as a complementary sequence to the mutant gene, yet one that contains a biologically inert chemistry that ensures no off-target engagement. The end result will be clean, highly effective, and well-tolerated medicines.

Because many of these therapies are delivered systemically, they can trigger an immune reaction that renders the medicine intolerable, yet even on this front, we are seeing advancements. By using the bodys own intelligent design, scientists have copied the existing framework and then improved upon it using synthetic strategies that allow for greater tolerance, thereby preventing the normally useful immune response from derailing healing.

We are in the most exciting time in the history of medicine, bar none. The science is dazzling. Patients should feel very optimistic. Cures are coming not in decades, but in a matter of years. The innovation thats happening today will be the breakthrough therapies of tomorrow. If you are looking for a silver lining, here it is.

Dietrich Stephan, CEO, Chairman, and Founder, NeuBase Therapeutics

See more here:
The Silver Lining Of Innovation in Genetic Medicine - Pharmaceutical Executive

The Center for Biologics Evaluation and Research (CBER) of the U.S. Food and Drug Administration (FDA) updated its Guidance Agenda in June 2022,1which provides that the agency plans to issue 18 guidance documents in 2022, including eight guidance documents on tissues and advanced therapies. In this alert, we highlight some key considerations from three draft guidance documents on human gene therapy products that incorporate gene editing (GE) components, chimeric antigen receptor (CAR) T cell products, and regenerative medicine therapies that can benefit biopharmaceutical developers and sponsors. Recognizing the challenges of developing such complex, multi-component biologic drug products, including unanticipated risks associated with on-target and off-target activities, these draft guidance documents describe the FDA's recommendations for preclinical and clinical testing, chemistry, manufacturing, and controls (CMC), as well as information that should be included in investigational new drug (IND) applications to ensure proper identity, potency/strength, quality, and purity of the investigational drug products. FDA recommends sponsors of such complex products to communicate with the Office of Tissues and Advanced Therapies (OTAT) in CBER early in product development before submission of an IND, to discuss the product-specific considerations in preparation for transitioning to the clinical phase.

FDA expects detailed information and data IND applications before sponsors can transition to clinical testing. We recommend biopharmaceutical developers and sponsors review the applicable FDA draft guidance documents early in their product development process to identify these needs. Work closely with both FDA regulatory counsel and intellectual property/patent counsel to ensure there is sufficient data to support an IND application, including adequate testing and quality control measures, and that CMC, preclinical, and clinical development plans are coordinated with intellectual property and patent strategies to ensure robust protection of their intellectual property and to maximize the benefits of their patents and FDA regulatory exclusivities. We also encourage interested persons to submit comments to shape the policies proposed in FDA's draft guidance documents prior to finalization.

Draft Guidance for Industry: Human Gene Therapy Products Incorporating Genome Editing2

Draft Guidance for Industry: Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products3

Draft Guidance for Industry: Voluntary Consensus Standards Recognition Program for Regenerative Medicine Therapies4

Stakeholders have until September 14, 2022, to submit comments to this draft guidance to ensure they are considered by FDA before finalization of the guidance.

For More Information

For questions regarding FDA strategy, approval, and regulatory compliance, please contact any member of Wilson Sonsini'sFDA regulatory, healthcare, and consumer productspractice. For questions regarding intellectual property and patent counseling, please contact any member of Wilson Sonsini'spatents and innovationspractice.

Andrea Chamblee,Paul Gadiock, andEva Yincontributed to the preparation of this Wilson Sonsini Alert.

[1] FDA, Guidance Agenda: Guidance Documents CBER is Planning to Publish During Calendar Year 2022 (Updated June 2022), available at https://www.fda.gov/media/120341/download.

[2] FDA, Draft Guidance for Industry: Human Gene Therapy Products Incorporating Genome Editing (March 2022), available at https://www.fda.gov/media/156894/download.

[3] FDA, Draft Guidance for Industry: Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products, available at https://www.fda.gov/media/156896/download.

[4] FDA, Draft Guidance for Industry: Voluntary Consensus Standards Recognition Program for Regenerative Medicine Therapies (June 2022), available at https://www.fda.gov/media/159237/download.

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FDA Issues Draft Guidance to Facilitate Development of Human Gene Therapy, CAR T Cell, and Regenerative Medicine Products - Wilson Sonsini Goodrich...

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The family is cautiously optimistic about the improvements they are seeing in Michael, 4, since the gene therapy three months ago

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Doctors and researchers at The Hospital for Sick Children in Toronto have conducted one of the first individualized gene therapies as part of a single-patient clinical trial.

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There is hope that this success will begin to carve a path for precision child health care and more patients will have the opportunity to receive individualized care and treatments for a wide range of conditions.

David Malkin, lead of the Precision Child Health initiative, director of the Cancer Genetics Program, and the CIBC Childrens Foundation Chair in Child Health Research at SickKids, said the idea behind precision medicine is to use the unique features of an individual to make diagnosis more precise and to predict approaches and outcomes to treatments.

The concept is that we take all information, from the postal code to the genetic code, so it is more than medicine, its overall health and everything that encompasses, said Malkin.

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This groundbreaking individualized gene therapy procedure was years in the making.

After fundraising over $3.5 million to develop the therapy, successfully testing it in mice, and finally getting Health Canada approval, Toronto-born four-year-old Michael Pirovolakis received the procedure in March to hopefully slow the progression of his ultra-rare genetic condition, SPG50.

In April 2019, Michael was diagnosed with the progressive neurodegenerative disorder spastic paraplegia type 50 or SPG50. This condition, which is caused by variants in a gene called AP4M1, causes developmental delays, speech impairment, seizures, and progressive paralysis of the arms and legs. Over the course of a few years, children lose the ability to walk and use their hands, and eventually lose their mental capacity. It is also likely to be fatal.

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Michael is currently the only known patient with the condition in Canada. It is estimated that there are around 80 other children with SPG50 around the world, making it an ultra-rare disease.

Having a child with an ultra-rare disease is difficult, said Terry Pirovolakis, Michaels father. Someone has to be watching him at all times because he doesnt understand that climbing up on the couch or opening the fridge door could be unsafe.

We love him more than anything, you know, but it is difficult, he said.

Upon diagnosis, the treatment options for SPG50 were extremely limited. So, Terry and his wife Georgia started the charity CureSPG50 to raise money to develop a gene therapy that would help their son and others with SPG50.

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Gene therapies are usually used to treat conditions caused by genetic mutations, said Jim Dowling, staff physician in the Division of Neurology and senior scientist in the Genetics & Genome Biology program at SickKids.

The idea is that through some delivery mechanism, a gene is added back to an individual, he said.

Currently, the standard way of delivery is to replace the DNA of a virus, most commonly an adeno-associated virus (AAV), with the healthy DNA of the mutated gene. An AAV is used because people do not get sick when they are exposed to it, said Dowling.

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The virus is then given to the patient in a way that is specific to their condition. Sometimes this is through an IV, sometimes into the muscle, or even into the eyeball. For SPG50, gene therapy is given into the spinal fluid so it can easily access the brain.

There are risks associated with the gene therapy procedure, specifically if the patient may develop cancer.

It was exciting that we can give Michael a better life, but scary at the same time because the last thing I ever want to do is hurt my child, said Terry

What was especially unique about Michaels gene therapy was that it was designed specifically for him and his condition, said Dowling, who led Michaels clinical trial.

This type of individualized treatment is what the doctors behind the Precision Child Health initiative at SickKids have been working towards.

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Currently, the precision child health team is gathering case studies that show the use of individualized medicine, like Michaels gene therapy, to create a plan on how to go from the discovery of disease to medical intervention.

They hope that they will soon be able to give the same specialized treatment that Michael received to many more children with many different types of conditions.

Terry said that he and his family are cautiously optimistic about the improvements they are seeing in Michael since the gene therapy three months ago. He is doing well and there are small signs that his symptoms may be improving.

We wouldnt have gotten here without the amazing people helping us along the way, said Terry. I want to thank everybody for just truly being there for us.

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Michael will hopefully not be the only child that receives gene therapy to treat SPG50.

Currently, another batch of treatment is being made with the hope of having 10 doses to give to other kids, said Terry. If all goes to plan and the U.S. Food and Drug Administration (FDA) approves the treatment, in October there will be another clinical trial in Texas.

Terry said this plan relies on CureSPG50 raising another quarter of a million dollars per child. The money is needed to cover a five-year study and hospital costs.

Our goal is to save as many kids as we humanly can, said Terry. I hope we can raise enough money to eradicate this disease.

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Canadian family raised $3.5M to develop individualized gene therapy for son's rare condition - National Post