Genome editing is rapidly progressing into a new treatment paradigm for a wide range of human diseases. Its ability to permanently modify the target sequence allows the potential to achieve long-lasting or curative effects. Like every innovation, the clinical use of genome editing technologies comes with its own challenges.
Speakers will address the most critical aspects to consider in the design and control of the different genome editing tools to improve specificity and avoid genotoxicities. As important differences are expected for in vivo vs ex vivo applications, both approaches will be covered.
Phillip Ramsey will provide an overview of genome editing platforms, on-target safety evaluation, off- target identification, and provide recommendations on how to assess these potential risks and how to minimize these risks from a CMC perspective.
Jonathan Phillips will present an overview of therapeutic CRISPR/Cas9 genome editing, using NTLA-2001 as an example with a focus on the assessment of mutagenicity (off-target) and chromosomal structural integrity, followed by a discussion of genetic safety considerations and approaches.
Cicera Lazarotto will discuss the risks of inadvertently introducing oncogenic off-target mutations and present sensitive analytical methods, such as GUIDE-seq, CHANGE-seq, and Digenome-seq, for defining the genome-wide activity of genome editors, to better understand the features that drive the genome-wide activity of engineered nucleases, and the frequency and location of resulting off-target mutations.
Cell, gene, and other novel therapies require carefully designed and well executed logistics solutions for supplying lifesaving medicine to patients. Biological material sourced and produced for autologous and allogeneic therapies must be strictly controlled for temperature, timeline, as well as chain of identity and custody. This complexity was expanded by the COVID pandemic which has caused disruption in supply of materials, as well as manufacturing and logistics processes. On the other hand, smart technologies, digital solutions, and innovative operation models have driven the rapid evolution of global CGT clinical and commercial distribution. This session will explore the following topics:
• Planning and ensuring manufacturing capacity to serve the patient/market need.
• Solving supply chain challenges for clinical and/or commercial cell therapy products.
• Case studies of digital solution (electronic system integration), smart technologies and operation model successfully applied in supply chain management.
Adeno-associated viral (AAV) vector-based gene therapy medicinal products hold curative promise for many disease indications. Although these products have been safely administered to hundreds of patients, recent safety issues have highlighted the need to close gaps in knowledge of product attributes and their potential impacts on safety and efficacy. The characterization and understanding of AAV-based gene therapies are improving, yet there remains much to be understood about the product quality attributes that impact safety and efficacy. For example, improved understanding of attributes that impact duration of transgene expression, as well as immunogenicity, and removal of impurities such as capsids lacking the desired therapeutic genetic material, is of importance going forward. In September, 2021, the US FDA held an advisory committee meeting to discuss safety issues observed for a range of AAV-based products. While the AdCom focused on clinical considerations, the aspects of product quality that may result in safety issues were not discussed in depth. In this session, presentations will address potential impacts of AAV gene therapy product quality attributes on safety and efficacy, innovative strategies and approaches for enhancing and optimizing vector performance, and limiting patient exposure to impurities. This will be followed by a discussion about where the industry is today with respect to characterizing AAV-based gene therapies, and where it is headed.
In recent years, cell and gene therapies have evolved rapidly into approved products for the treatment of both incurable genetic diseases as well as for the treatment of certain cancers. Emerging technologies such as the design of new experimental vectors, use of pluripotent and allogenic cells, improvements in efficacy and specificity of the delivery systems, and the greater understanding of the inflammatory response against these modalities are leading to the expansion of clinical applications in this space. This session will explore examples of emerging molecular and cellular approaches that are tackling the challenges with the current therapeutic options in gene and cell therapy and building the next generation of sophisticated approaches to treating diseases.
Potency is a critical quality attribute (CQA) for cell and gene therapy (CGT) medicinal products. Assays that measure potency are required for multiple purposes, including product release, stability, characterization, as well as assessing process comparability, batch-to-batch consistency, and structure-activity relationships. A quantitative assay where potency is analyzed relative to a reference standard and is relevant to the mechanism of action (MOA)/clinical response remains the golden standard, like protein biologics. The MOAs of several CGT medicinal products are not well understood or fully known and are often too complex with the many quality attributes involved to be modeled by a single in vitro assay. The small size of batches and their limited number, the frequent lack of reference standards, the need of multiple analytical methods and the rapid development of the manufacturing process create additional challenges. Several products are highly specific, for example AAV-based GT medicinal products with capsids targeting specific cell types and/or transgenes with tissue specific promoters. These products may require genetic engineering to create permissive cell lines to analyze their potency or rely on the use of in vivo assays. Given these challenges, potency is often assessed using a surrogacy- or a matrix of orthogonal assay-based approach. These assays should be developed early during product development and correlated as soon as possible with functional assays or pre-clinical and clinical studies.
This session will be focused on generating a robust discussion between the audience, presenters, and panel members. The objective is to explore various approaches to potency assay development and discuss potential strategies when Sponsors/Applicants are faced with difficulties in the establishment of robust potency assays for CGT medicinal products. Questions that will be discussed may include:
1. What are the regulatory requirements for potency testing CGT medicinal products at various development stages?
2. What are critical deficiencies observed by regulators when reviewing potency assays?
3. Some Sponsors/Applicants perform complex in vivo studies to confirm product potency, does this add value?
4. How do we re-evaluate the use of infectivity assays to measure AAV-based medicinal products potency?
The Cell Therapies products space is continuing to build on the potential for innovative treatments for unmet patient needs. Topics include cell products with unique manufacturing process, complex sourcing starting material, and assays with direct relevance to CQAs. This session will provide insights into early CMC development and points to consider for cell therapies.
Modern medicines call for modern technologies. Revolutionary cell and gene therapies offer significant promise to treat life-threatening diseases. Getting therapies to market quickly and efficiently requires accurate testing of critical quality attributes, including accurate viral vector analysis.
In this technical seminar, you'll learn how a variety of innovative analytical tools from Bio-Techne can help give you the automation and scalability you need on your road to discovery, along with consistent, high-quality data across labs and project phases. You'll discover how these next-generation analytical solutions are designed to easily fit into your current workflows and adapt to your changing needs.
This session will gather leaders from competent regulatory authorities spanning Canada, Europe, India, Israel, and the United States to discuss trends and topics critical to the successful development of cell and gene therapy products. Areas of focus include perspectives on global regulatory convergence, manufacturing and analytical challenges and recent and pending regulatory guidance.