ACCELERATING CGT DEVELOPMENT IN UK

"UK innovation strategies to lead in cell & gene therapy"

Jonathan Appleby
Chief Scientific Officer from Cell and Gene Therapy Catapult.

Catapult is a network subsidized by the UK government, they are a not for profit supporting from academics startups to scale up companies and manufacturing. They collaborate with the therapy developers to bring their technologies to the market place. Jonathan had shown an overview of the catapult, their capabilities and objectives.

He also shared an overview of the MRC/LifeArc Viral Vector Innovation Hubs as an example of coordinated action. They have been awarded with a grant to support academic focused manufacturing capability, to help transition from therapeutic targets from the university into clinical proof of concept.

Moreover he addressed the skills gap as one of the challenges for the growing industry. In the whole industry there is no much people, and there is the bottle neck. In order to collaborate to solve this issue, Catapult support through its network the creation of this organizational network called Advanced Therapies Apprenticeship Community (ATAC) and the Advanced Therapies Skills training Network (ATSTN). The National Training Centers are also part of Catapult and trainee numbers of life sciences professionals throughout the year.

Catapult is also involved in accelerating clinical adoption and patient access by ensuring the NHS has the infrastructure and training to deliver cutting-edge treatments to patients at scale. The last message was to share about the important UK position in the global ATMP manufacturing Industry.

"CAR-T Therapy in Practice: Clinical and Manufacturing Challenges"

Christof Scheid
Head from Cell Therapy at University of Cologne, Germany.

CART show unprecedented clinical responses, however the durability remains a challenge, but a rapid availability is necessary to bring a treatment alternative to patients.

Dr. Christof is treating Multiple Myeloma patients with cell therapy. He shared that many conventional treatments are not so effective. Therefore, new therapeutic targets need to be developed. His group has developed the KarMMa (EMA approved), a B Cell Maturation Antigen (BCMA)-direct CAR-T Cell Therapy. It is known that increase in BCMA levels is associated with disease progression and poorer outcome, and it has become a prime target at the moment. It is specific for tumor cells and we can live without B cells. He shared results of the first clinical trials, and it was shown a response of 82% with the highest cell numbers, and about third of the patients had complete remission. Christof said: “These are very exciting response figures that are totally unprecedented in this have to treat population, and this explains our excitement to get involved with this highly complex agents”. However, after one year, many patients showed a decrease in response, therefore is not yet a cure, is still a work in progress.

He shared also the practical difficult involved in Cell therapy such as, cost of the treatment for the patients, logistics, and timing, especially related to manufacturing processes.

"Regulatory considerations for CGT products with the MHRA (UK) and EU National Competent Authorities."

Adeyemi Afuwape
Associate Director, CMC Regulatory Affairs (ATMP/Biologics) at ProPharma Group.

In his interesting talk, he had discussed the Nonclinical and CMC package required for CGT products. It was also presented the available expedited regulatory programs. And at last he showed the procedural steps for CTA submission.

"IP in Cell and Gene Therapy"

Kirsty Simpson
Partner at Venner Shipley. Kirsty is a UK and European Patent Attorney.

Kirsty started by sharing how the industry of gene & cell therapy in booming in UK. Patents applications in Gene Therapy has been increasing in the last years. Also, that has been a lot of contentious matters at the European Patent Office (EPO) related to gene therapy in recent years.

In her talk, Kirsty explained how IP (intellectual property) works in the companies, and what defines the IP strategies. She also highlighted the importance of IP in some recent CGT deals that would not have been possible without a strong intellectual property portfolio.

"Enhancements in gene therapy workflows"

Rouba Najjar
Senior Product Manager at GenScript.

Rouba Najjar gave us a short overview on CRISPR Technology, its advances and applications, which includes genome engineering and virus diagnostics.

It was discussed the impact factors and technical challenges of using CRISPR in research. A good quality gRNA, the different types of nucleases used, the challenges on delivery mechanism for therapy and the cell type used for therapy, all need to be take in consideration when applying CRISPR technology.

She emphasizes the ribonucleoprotein (RNP) complex delivery. Complexing a CRISPR nuclease with the guide RNA, commonly referred to as the ribonucleoprotein (RNP) complex, can enhance gene editing performance, while reducing common challenges observed with other delivery systems, including viral- and plasmid-based.

The RNP delivery is more benefic due:

• Highest editing efficiency
• Enhanced Specificity
• Reduced insertional mutagenesis
• Reduced toxicity
• Reduced host immune response
• Proved platform for genome editing of cells with low transcription and translation activity
• Flexibility with multiple cell contexts successful editing, such an embryonic, pluripotent and tissue stem cells.

GenScript has a range of Cas nucleases, and has developed the product line GenCRISPR™ Ultra Cas9 Nuclease, with three different grades, the RUO, basic GMP and GMP grade. Basically, GenScript offers one nuclease for each step of the workflow (from discovery to market).

"Parallel CAR T-Cell Immunotherapy of Solid Tumours"

John Maher
a clinical immunologist who leads the "CAR Mechanics" research group within King's College London.

Dr. John shared details about the core technology that his group (“CAR Mechanics Team) had developed years ago, and that lead them to spinout to this company Leucid Bio from Kings College London.

He started by describing the 3 generations of CAR-T. He noticed that the third generation contains two costimulatory domains in cis in linear design, but Leucid Bio has developed a Leucid:pCAR with costimulatory domains in both trans and cis, being the molecules in close proximity. They developed many families of pCAR, and he gave emphases to NKG2D receptor and its ligand. NKG2D receptor is expressed on Natural Killer (NK) cells, T-cells and macrophages. It is an activating receptor that triggers cell killing. The importance of this receptor is that it ligand is expressed in 80% of human tumour cells.

"The resolution of complex eye diseases using multi-pathway targeting AAV gene therapies"

Emily Warner
Senior scientists at Ikarovec.

Dr. Emily started her talk by pointing the support that GenScript has been doing in their research with gene synthesis, plasmid construction and antibody synthesis. Ikarovec Ltd. was awarded £2.5M seed-funding and a £0.5M Innovate UK grant in 2020 for the pre-clinical development of products targeting common, complex eye disorders. Multi-modal treatments allow for the targeting of multiple pathways in complex, chronic eye disorders. Ikarovec focuses on novel approaches to boost efficacy and offer long-term protection against sight loss. Adding to the milestones, Ikarovec already filed four patents and the company is on track for IND enabling studies to begin in 4Q22.

The lead asset from Ikarovec is a multi-cistronic gene therapy for Diabetic Macular Oedema (DMO). It has a complex disease pathway with growing younger patient population. Moreover, it is a leading cause of sight loss in <65s. It is a complication of retinopathy, which affects over 100 million people. As consequence it causes severe vision loss and blindness. A protein called VEGF has a role in the DMO and the available treatment focused on regular injections of anti-VEGF into eye which has a 40% effectivity in patients. Therefore, there is an urgent medical need for safer, cheaper and more effective treatment. Actually, VEGF is not the only pathway involved, but it is much more complex, because of that therapies should target multiple pathways to be fully effective.

The solution that Ikarovec brings, is a Tricistronic Construct for gene therapy. It involves the expression of a Protein A (anti-neovascularisation & anti-vascular leakage), Protein B (anti-inflamatory, retinoprotective), and Protein C ( anti-vascular leakage, anti-fibrotic), as a “fire and forget” approach. All the three genes are packaged in one vector, driven by one promoter, internally cleaved and secreted as functional proteins. She shared some preliminary data from in vitro studies.

"PureSpring Therapeutics, transferring academic innovation to a successful gene therapy biotech"

Key note speaker: Moin Saleem
Professor of Pediatric Renal Medicine, and founder of PureSprings Therapeutics.

At his talk he had shared that kidney disease is a huge unmet need (>840m patients suffering from kidney disease globally), therefore the key importance to understand and target the biology of kidney diseases. As founder of PureSpring therapeutics, the first kidney gene therapy company (spin out of the University of Bristol), he showed that innovation in both technology and in manipulating biological pathways are possible, and are essential to bring a cure to patients. The big challenge from PureSpring was to introduce therapies to the kidney, via de glomerular podocyte with AAV technology, and if successful, it be in the future a potential curative therapy for a number of major kidney conditions.

Moreover, he discussed the market size in renal medicine for this type of therapy and how will dose influence the likelihood of successful market approval.