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Stem cells are undifferentiated or partially differentiated cells that can proliferate indefinitely and give rise to various types of specialised cells. They are, therefore, very interesting for therapeutic purposes. In 2006, Shinya Yamanaka’s lab in Japan demonstrated that the introduction of four specific transcription factor genes, now known as Yamanaka factors, could convert differentiated, somatic cells into pluripotent stem cells (also known as iPS cells or iPSCs). For this discovery, Yamanaka was awarded the 2012 Nobel Prize along with Sir John Gurdon, honouring their findings that mature cells can be reprogrammed to become pluripotent.
The iPSC technology holds great promise in the field of regenerative medicine. iPSCs represent an invaluable source of cells, e.g. to replace lost, damaged or diseased cells. Specifically, iPSCs have significant potential in disease areas with high unmet medical need, e.g. neurodegenerative diseases such as Alzheimer’s, ALS or Huntington’s or conditions such as diabetes or age-related macular degeneration (AMD). In these indications, the application of iPSC-based models represents a paradigm shift in developing desperately needed new therapies.
Why iPSCs?
Compared to previous models, patient-derived iPSCs are more physiologically relevant and better suited for modelling disease pathophysiology and for understanding a drug’s mechanism of action. Therefore, iPSC-based high-throughput screening approaches provide unique opportunities as a tool for disease modelling and predicting drug efficacy. This is especially important in complex, age-related or genetic indications such as neuronal diseases. Moreover, patient-derived iPSCs may eventually be utilised to stratify patient populations for clinical trials - a key success factor for electing better and safer drugs for clinical development in disease areas with high unmet clinical need.
iPSCs at Evotec
Evotec has built one of the largest and most sophisticated iPSC platforms in the industry. The platform has been developed over recent years with the goal to industrialise iPSC-based drug screening in terms of throughput, reproducibility and robustness to reach the highest industrial standards, and to use iPSC-based cells in cell therapy approaches via the Company’s proprietary EVOcells platform.
While culturing and differentiating iPSC-derived cells in a reproducible manner at industry scale used to be a challenge in the past, Evotec has succeeded in establishing scalable and robust protocols that allow a stable production of specific disease-relevant cell types. This includes generation of a cell bank of fully validated iPSC lines, upscaling of iPSC culture and differentiation protocols to industry standards, as well as automation of iPSC-derived cultures - all meeting the highest quality control standards.
In addition to phenotypic screening, Evotec has developed more complex models, such as co-cultures of multiple cell types or microfluidic organs-on-a-chip approaches, which enable interaction between different cell types. These systems allow the modelling of human diseases under conditions that closely resemble the physiological environment.
Smart Partnerships
Evotec has entered into several long-term partnerships that leverage the Company’s iPSC platform to develop highly relevant disease models, e.g. with Bristol Myers Squibb (formerly Celgene) in neurodegeneration (2016), and with Centogene in rare diseases (2018).
In its TargetRD project in collaboration with Centre for Regenerative Therapies TU Dresden, Evotec is using the advances in iPSC technology to generate iPSC-derived Retinal Pigment Epithelium cells from patients with retinal degenerative diseases to accelerate drug discovery.
Read our DDup on iPSC-Based Drug Discovery
Read our DDup focused on iPSC-Based Drug Discovery and Retinal Disease
Learn more about biomanufacturing at Just-Evotec Biologics by downloading this presentation first presented at IFPAC in March 2021.
In this presentation, we touch on:
Tags: Presentations, Formulation & CMC, Biologics
Tags: Articles & Whitepapers, Biologics, Proteomics, Metabolomics & Biomarkers, Rare Diseases
The idea of targeting messenger RNAs for therapeutic purposes to shut off the translation of proteins dates back to 1978 when researchers discovered the first antisense oligonucleotide, an oligonucleotide complementary to the viral RNA of Rous sarcoma virus. It was capable of binding to the viral mRNA and thereby inhibiting viral replication and protein synthesis.
Meanwhile, a lot of short single-stranded antisense oligonucleotides made from natural or chemically modified DNA and RNA nucleotides have been developed. They all are designed to modify gene expression not only for inhibiting protein synthesis but also for altering RNA and/or reducing, restoring, and modifying protein expression through multiple molecular mechanisms such as splicing. Suppression of target expression is accomplished by binding of the antisense oligonucleotide to the target (pre)mRNA followed by degradation of this (pre)mRNA.
The pharmacology of targeted antisense therapy has provided the basis for translating it to the clinic. Chemical modifications of the oligonucleotides have enhanced the specificity, affinity and efficacy and reduced side effects. Optimisation of delivery and improved resistance to breakdown by nucleases, leading to precisely defined half-life, also have been accomplished. These improvements have brought research from bench to clinic. Additionally, the use of antisense oligonucleotides against long noncoding RNAs (lncRNAs), small interfering RNAs (siRNAs), micro RNAs (miRNAs), and ribozymes have also demonstrated preclinical and clinical responses in the treatment of deadly diseases like cancers.
Antisense oligonucleotides fill a position that is not or only insufficiently addressed by more traditional approaches. As an example, they can address targets undruggable by conventional strategies, e.g. targets that do not have a function or surface that can interact with small molecules or targets that are inaccessible for antibodies. They can also address challenging targets, e.g. targets that need to be addressed selectively as they possess high structural homology to other targets that should not be triggered to avoid unwanted side-effects.
Moreover, they have unique and well-characterized biodistribution and pharmacokinetics and can be manipulated by conjugation to targeting moieties. Also, there are many different administration routes, systemic treatments as well as local (e.g. intrathecal, intravitreal or inhalation) or ex vivo approaches to target cells in the cell therapy setting, e.g. to accomplish a transient target knockdown to improve the manufacturing process, the safety of the cell product or its efficacy.
Several antisense drugs have been approved, most against rare diseases such as Batten disease, cytomegalovirus retinitis, Duchenne muscular dystrophy, or spinal muscular atrophy. As of 2020, more than 50 antisense oligonucleotides were in clinical trials, including over two dozen in advanced clinical trials (phase II or III).
Evotec has considerable expertise in antisense therapy and in 2020 entered into a strategic partnership with antisense specialist Secarna Pharmaceuticals GmbH & Co. KG to build a co-owned antisense drug pipeline based on Secarna’s proprietary LNAplus™ platform. This third generation of LNAs allows to switch off gene expression of single disease-underlying genes in the cell.
The partnership aims to address a number of targets and complex indications, to establish a pipeline of co-owned antisense oligonucleotide therapies and to licence candidates to biopharmaceutical companies.
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In January 2021, researchers from Ruhr-Universität Bochum made headlines after publishing in Nature Communications that they had succeeded for the first time in enabling formerly paralyzed mice to walk. They had accomplished the feat by using gene therapy to transfer the gene for hyper-interleukin-6, a so-called designer cytokine, which does not occur in nature, to the brain of the animals. The gene was packed into Adeno-Associated Viruses (AAV) and the vector injected into the brain, where motoneurons and associated motion-related nerve cells started to produce this growth factor.
“Thus, gene therapy treatment of only a few cells stimulated the axonal regeneration of various nerve cells in the brain and several motor tracts in the spinal cord simultaneously,” said Dietmar Fischer, Professor at the Department for Cell Physiology at Ruhr-Universität Bochum and lead author of the study. “Ultimately, this enabled the previously paralyzed animals to start walking after two to three weeks. This came as a great surprise to us at the beginning, as it had never been shown to be possible before after full paraplegia.”
This breakthrough, which might end paraplegia in injured humans, is just one of many successes accomplished with gene therapy. The approach has come a long way. Its basic concept – modifying human genes by introducing genetic material – was first proposed in 1972. After premature first attempts in the 1980s failed, the science greatly improved and in 2003 China took the lead by approving Gendicine, a recombinant Ad-p53 gene therapy for the treatment of head and neck squamous cell carcinoma (HNSCC)—a cancer that accounts for about 10% of the 2.5 million annual new cancer patients in China.
It took another 9 years until the EU followed with the approval of Glybera, a treatment for patients who cannot produce enough of an enzyme that is crucial for breaking down fat, and in 2017 the first gene therapies were approved in the U.S.: Luxturna to treat RPE65 mutation-induced blindness and Kymriah, a therapy for the treatment of B-cell acute lymphoblastic leukemia (ALL) which uses genetically engineered T cells of the affected patients. Since then, further gene therapies have been approved, e.g. Zolgensma and Patisiran, and hundreds of clinical trials are under way to test gene therapy as a treatment for genetic disorders, cancer, and HIV/AIDS.
The gene therapy market was valued at approx. $ 500 m in 2018 but is expected to reach > $ 5 bn by 2025 with an impressive CAGR of about 34%.
Gene therapies can work through several mechanisms, the replacement of a disease-causing gene with a healthy copy, inactivation of a disease-causing gene that is not functioning properly and the introduction of a new or modified gene into the body to help treat a disease. The latter approach was used in the study to heal paraplegic mice.
There are various methods for administering gene therapeutics. The most common approaches are the use of viral vectors (mostly AAVs and lentiviruses) to transfer the genes directly to the patient, or the modification of patient-derived cells in the lab with subsequent transfer of the modified cells back into the patient. Most approaches use performing gene insertions in vivo and ex vivo, respectively, but non-viral delivery systems are also being used.
Evotec entered the gene therapy space in 2020 by establishing an alliance with Takeda, adding a team of 20 specialists by creating Evotec GT in Austria, where Takeda’s gene therapy operation GTCA (Gene Therapy Center Austria) is located.
Evotec GT is now an integral part of Evotec’s integrated drug discovery platform. Its services include
The services cover both in vivo and ex vivo gene therapy approaches. With this new unit, Evotec is now able to find the best potential drug candidate agnostic of modality for any given biology.
After more than a year into the COVID-19 pandemic, vaccines against the new coronavirus are all over the news. However, there is still a long way to go until people have been vaccinated worldwide, and as yet it is not clear how long the protection will last and whether the different vaccines will protect against re-infection and/or infection against mutated viruses.
Therefore, it is clear that even in 2021 and beyond millions of people will get infected by the virus and many thousands will become critically ill and require medical treatment.
Similar to vaccines, biopharmaceutical companies all over the world are trying to develop medications to combat Sars-CoV-2 infections: some are trying to repurpose existing drugs, others are developing small molecules or biologicals such as antibodies against a variety of targets – viral as well as cellular.
Evotec is also participating in this worldwide effort – but with a twist. The goal is to develop a monoclonal antibody that is not only effective, but can also be produced at low cost so that it is ideally suited to be administered even in the world’s poorest countries. And if all goes well, Evotec will also provide small, efficient manufacturing sites that can be operated all over the world.
Already in April last year, Evotec´s U.S. subsidiary Just - Evotec Biologics, Inc. entered into a partnership with Ology Bioservices, Inc. to evaluate and characterize antibodies against SARS-CoV-2. A few months later, in July, Just – Evotec Biologics was awarded up to $ 18.2 m by the U.S. Department of Defense for the development and manufacturing of monoclonal antibodies that might be able to prevent or treat COVID-19. And in September last year, the Bill & Melinda Gates Foundation joined in by granting another $1.9 million to develop and manufacture monoclonal antibodies at lowest possible cost of goods for the prevention of severe COVID-19 in vulnerable populations in low- and middle-income countries.
Just – acquired by Evotec in 2019 – was founded in 2015 in Seattle by former Amgen employees with the goal to make the entire manufacturing process of biotherapeutic drugs more efficient and affordable – not only by lowering development costs, but also by establishing smaller, more efficient manufacturing sites. The initial therapeutic focus was on anti-infectives, as infections constitute the biggest problems in poor countries that often don’t have enough money to purchase lifesaving drugs or to support their manufacturing, so lowering the costs of developing and producing anti-infectives are of great importance.
To accomplish this goal, Just is using artificial intelligence and an entirely data-driven drug discovery and development process. Its J.DESIGN technology platform integrates the discovery and optimization of drug candidates, process and product development, and manufacturing with the goal of providing a product that can be manufactured at low cost of goods. Using large, diverse data libraries and machine learning, the platform from the outset screens and designs biologics that can be developed and manufactured under the most favourable development conditions.
The know-how of the company comprises cell line development, upstream bioreactor design (fed-batch or continuous), and the development of downstream purification, analytical methods, final drug product, formulation, and long-term storage.
Just – Evotec Biologics also has developed a small, flexible, low-cost facility solution to biotherapeutics manufacturing called J.POD. This facility can be installed easily wherever production is needed.
As infectious diseases are on the rise across the globe and SARS-CoV-2 will unlikely be the last pandemic affecting the human population, the approach developed by Just - Evotec Biologics will become even more important in the future.
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