Science Pool

Learn more about the advantages of human iPSC-derived cardiomyocytes including:

• Predictive and physiological cell model
• Applicable for drug development, preclinical research, and cardiac safety assessment
• Quantity, consistency and efficiency for HTS

Learn more about in Vitro iPSC research services at Evotec including:

• Robust differentiation protocols or adaptation of client protocols
• High-quality production of iPSC-derived cells at large scale
• Disease-relevant phenotypic read-outs for exploratory research and compound profiling/HTS
• Proprietary iPSC patent portfolio in tissue and disease modeling

Learn more about Multi-Omic Analysis of Induced Biotherapeutic Protein Production in CHO Cells Reveals Substantial Shifts in Energy Allocation in this presentation from PEGS Boston - Optimizing Protein Expression from May 2021. 

In this presentation, we focus on:

• Experimental design
• Data processing and analysis in transcriptomics
• Multivariate 'omic analysis
• CHO clone screenings

For more than a decade, Evotec has been closing strategic R&D collaborations in the area of induced pluripotent stem cells (iPSC), both with academic and industry partners.

The scope ranges from broad, long-term alliances to targeted research-driven collaborations. These partnerships support Evotec’s growing iPSC activities, strengthen the capabilities, and thus comprise a strong foundation for success within Evotec’s iPSC Lighthouse.

A brief overview of key references for iPSC partnerships is provided below.

Industry partnerships

In 2006, Evotec and CHDI Foundation, Inc. (“CHDI”) closed a strategic collaboration to advance drugs for the treatment of Huntington´s disease. The partnership builds on Evotec’s integrated neuroscience platform and its iPSC platform, among others, and was extended in 2018.

In 2016, Evotec and Celgene (now Bristol Myers Squibb) signed a broad R&D collaboration to develop disease-modifying treatments for neurodegenerative disorders based on Evotec's unique iPSC platform. The platform allows for systematic drug screening in patient-derived disease models. The partnership was expanded to include additional cell lines in 2018 and new cell types in 2019. Following the acquisition of Celgene by Bristol Myers Squibb, the agreement with Evotec was again expanded to further broaden the number of cell lines in 2020.

In 2020, Evotec formed an alliance with Sartorius and Curexsys to advance an iPSC-based exosome approach. The collaboration combines Evotec’s iPSC platform with Curexsys’ proprietary exosome isolation technology, while Sartorius will support Curexsys in setting up a GMP-compliant and scalable manufacturing platform.

Scientific collaborations

The first iPSC partnership was a collaboration with the Harvard Stem Cell Institute ('HSCI') in 2013 to identify compounds which prevent or halt the loss of motor neurons, a key symptom of amyotrophic lateral sclerosis ('ALS').

In 2017, Evotec entered into a research collaboration with the Center for Regenerative Therapies TU Dresden ("CRTD") to discover novel small molecule candidates for retinal diseases. Gola of the collaboration is to combine CRTD's expertise in stem cell-based retinal disease modelling with Evotec´s iPSC technology platform to generate promising drug candidates for potential clinical development.

In 2018, Evotec and Centogene signed an agreement for a global drug discovery collaboration to develop novel small molecules in rare hereditary metabolic diseases, which are generated by a joint high-throughput platform.

The collaboration was expanded into Gaucher´s disease in 2020, leveraging Evotec’s iPSC platform and broad drug discovery and development capabilities and Centogene´s proprietary rare disease platform, including iPSC lines, to generate novel treatment approaches for this orphan drug indication.

In 2021, Evotec and the Medical Center Hamburg-Eppendorf (“UKE”) signed a partnership for the development of a novel, innovative first-in-class cell therapy based on Engineered Heart Tissue for the treatment of heart failure. The goal is to produce human, clinical-grade heart muscle cells (cardiomyocytes) for implantation.

Evotec is continuously looking to expand its iPSC portfolio through industry and academic partnerships both within existing disease areas but also to expand into new disease areas. Reach out to us for questions around collaborations and partnerships.

CONTACT US

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:

• Historic manufacturing practices
• Macro trends impacting affordability
• Speed and flexible capacity solutions
• New plan design principles

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.

Learn more:

Antisense Oligonucleotides
Gene Therapy

Curing paraplegia

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.”

The development of gene therapy

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%.

How does gene therapy work?

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´s gene therapy strategy

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 design of state-of-the-art viral AAV vectors,
• the generation of AAV material for research and non-clinical studies, 
• in vitroand in vivo proof of concept studies for target validation including screening of drug candidates, as well as
• the design, execution and interpretation of non-clinical gene therapy studies.

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.

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