Adeno-associated viral (AAV) vectors remain the tool of choice for today’s gene therapy manufacturers – but as demand increases, the limitations of traditional manufacturing methods may severely impact progress of the field. This article discusses a case study on the development of a novel gene therapy for motor neuron disease (MND) and Parkinson’s disease (PD), before discussing how next generation technologies can help overcome manufacturing challenges and accelerate the development of novel gene therapies.
A novel gene therapy for MND & PD
Innervate Therapeutics is a biotechnology company focused on developing glial cell -derived neurotrophic factor (GDNF) gene therapies to achieve neuro-restoration and neuroprotection in diseases including PD and MND.
GDNF, a protein derived from the glial cells in the brain, is a neurotrophic factor for dopaminergic, serotonergic, noradrenergic, cholinergic, and motor neurons. When GDNF is introduced to dopaminergic cells in animal models of PD the cells recover their motor function and re-innervate the tissue. Similarly, when applied to sick or dying motor neurons in models of MND they also recover. Therefore, GDNF is an exciting molecule for the potential treatment of a range of neurodegenerative diseases.
In 2012, Professor Gill ran a clinical trial infusing this protein into the striatum, via a port on the side of the patients’ head. His team observed regeneration of the dopaminergic neurons (Figure 1), demonstrated by increased 18F-Dopa uptake after 24 months. With this improvement in PET signal came clinical benefit, and patients experienced substantial improvements in motor function. However, delivering GDNF as a protein means that patients must travel every month to receive their infusion, which can be burdensome. The next step is to instead deliver GDNF as a gene therapy.
GDNF gene therapy for PD
The major advantage of a gene therapy approach to treating PD with GDNF is that it would only require a single surgical administration of the therapy, after which regeneration could proceed and the benefits would be maintained.
For this to be effective, it would first require a viral vector with highly efficient gene transfer to the target tissue (Figure 2). In this instance, Professor Gill’s team chose AAV5, as it transfers efficiently to neurons. It would also require long-term expression with regulated release of GDNF, since constant expression of a neurotrophin such as GDNF would downregulate receptors over time. Therefore a mechanism for intermittent release is critical to provide a long lasting and effective therapy.
Innervate Therapeutics is engaging with international gene therapy experts to solve these issues and optimize the AAV vector construct for intermittent release of GDNF. They have developed a strategy for delivering the therapy throughout the striatum, using a posterior trajectory to give homogeneous coverage of key target structures, and through an exclusive license agreement with Neurochase Ltd for use of their devices and technology, they’ve secured a means of scaling this delivery and delivering it safely to large patient populations.
Innervate Therapeutics will continue to further the development of gene therapies against PD. Meanwhile, their current lead therapeutic candidate targets a different neurological disorder; motor neuron disease.
Innervate Therapeutics’ primary product, INN-MND-001, is focused on MND, also known as Amyotrophic lateral sclerosis (ALS). This is a progressive and lethal motor neuron disorder with median survival ranging from 20 to 48 months. There are approximately 450,000 people with ALS worldwide, of which only 10% of cases are familial. Some of these are caused by known mutations, such as SOD1, FUS, and C9ORF72, whilst the majority have an unknown cause. Riluzole is the only drug licensed for the treatment of MND in the US and UK and has a modest impact on survival.
There is therefore an urgent unmet need for treatments against both the familial and non-familial forms of ALS, and GDNF is a particularly promising option, as it effectively protects and restores motor neuron function irrespective of the underlying cause.
Innervate Therapeutics expects their GDNF/AAV to be the first treatment that can both halt, and potentially reverse, the effects of familial and non-familial ALS. The neuroprotective effects of GDNF on motor neurons have been demonstrated in preclinical trials infusing GDNF/AAV into motor neurons either at the terminals in the muscle, in the spinal cord, or in the motor cortex.
Drug delivery will be key to the success of this treatment and Innervate Therapeutics has developed a means of delivering therapies directly to the motor cortex. They infuse the AAV/GDNF underneath the motor cortex and drive it up into the motor cortex with an inert artificial cerebral spinal fluid. In this way, the complex pleated sheet which forms the motor cortex can be covered with the vector and because it is axonally transported, the vector will then travel down the spinal cord and into secondary motor neurons. Therefore, a single delivery to the motor cortex can potentially preserve primary and secondary motor neurons as well as recover dying neurons.
Innervate Therapeutics chose to work with OXGENE to develop this treatment. OXGENE engineered and produced research grade plasmids and then AAV for Innervate Therapeutics and these materials are now being used for preclinical large animal (sheep) studies assessing toxicity and distribution. Most of the proof-of-concept work is now completed and Innervate hope to begin a Phase 1 study in the latter part of 2022. The first-in-human study will include 3 patients who will be monitored for a period of 12 months following treatment. Innervate Therapeutics is very hopeful that this work will offer one of the first treatments for this debilitating degenerative disease.
Executing the INN-MND-001 development plan
Innervate Therapeutics engaged OXGENE to produce purified AAV/GDNF vectors for preclinical studies, and OXGENE also aimed to demonstrate the process scalability of this vector production to help Innervate Therapeutics prepare for larger scale manufacture.
Generation of rAAV vectors containing human glial cell-derived neutrophic factor (hGDNF) for pre-clinical studies
A process overview of the project can be seen in Figure 3. Everything begins with plasmid construction, and all of OXGENE’s plasmids are based on their proprietary SnapFast™ plasmid system, which enables faster and easier cloning, as well as improved gene expression and safety profile.
When the GDNF project began, OXGENE discussed which promoter and target gene sequence variant to use with the team at Innervate. A few versions of the cloning strategies were explored until both parties were happy with the plan, and confident they had achieved optimal design for the construct.
After cloning the plasmid, the OXGENE team then carried out small scale production of rAAV5-GDNF. Following this, they scaled up production to 1-liter and 10-liter scales, establishing a standard scaling up and production process for viral production at these scales. OXGENE also worked with Innervate to adjust process parameters to account for their specific serotype and transgene, as well as meeting any other specific process requirements.
Once the product was produced and purified, it required testing. OXGENE has developed a standard panel of analytics for the preclinical materials that it produces, and it is also possible to perform additional assays at the client’s request.
OXGENE’s plasmid system
Further information about OXGENE’s optimized XAAV plasmid system for AAV production can be seen in Figure 4. To increase the productivity of AAV and the packaging efficiency of the AAV particles, OXGENE designed and tested multiple configurations of Rep/Cap plasmids. The chosen configuration shown in Figure 4 significantly increased both the production yield of AAV vectors through triple transfection, and the percentage of full capsids. This represents a significant improvement for AAV plasmid systems.
OXGENE has also developed a simplified, smaller helper plasmid. This provides two benefits. Firstly, it doesn’t contain any additional adenovirus late gene sequences, making it regulatory-friendly. Secondly, because the helper plasmid is smaller, it results in higher plasmid production yield.
Finally, OXGENE has developed a clonal HEK293 cell line for AAV production. OXGENE went through a high throughput, fully traceable cell line development process to specifically select a clonal HEK293 cell line that is particularly effective for AAV production. This cell line has already been banked at GMP and tested comprehensively.
Figure 5A shows production titers of the upstream production from different scales in the GDNF project. This project started in small-scale shake flasks and production was performed in biological triplicate. Across the scales, production titer is very consistent at between 1.5 and 2.0E+11 viral genome per mL before concentration and purification.
After upstream production at 1-liter and 10-liter scale, OXGENE performed downstream concentration and purification (Figure 5B). The crude lysate materials from upstream production go through tangential filtration concentration first, and then affinity chromatography as a further concentration and purification step. After the purification step comes buffer exchange if the formulation buffer is different from the elution buffer, and sterile filtration was performed before the product was handed over to Innervate Therapeutics.
The graph on the left of Figure 5B shows the titers throughout the downstream processes. From the crude lysate to post-TFF materials, titers were increased by ∼10-fold after AAVX purification, titers were increased a further 10- to 50-fold depending on the process.
Looking to the graph on the right of Figure 5B, the total viral genome that had been produced and retained throughout the process was calculated with the data from the 10-liter production. For the final product, one 10-liter production yielded a total viral genome titer of above 1.0E+15 . The overall recovery of the downstream process is above 50%, a good overall recovery and yield.
OXGENE also measured total particle titers using ELISA for AAV5 particles and calculated the percentage of full capsids. The full/empty particle ratio was 35% and more than 50% of full particles for the 1-liter and 10-liter productions, respectively. Endotoxin levels were tested in the end products and were well below the threshold required by FDA recommendations. The purity of the final products was also assessed using SDS-PAGE page. These are the standard analytics that OXGENE runs for research grade materials for preclinical study, but other testing such as infectivity assays or electron microscopy imaging can also be performed as required.
This concludes the project between OXGENE and Innervate Therapeutics, and both companies are eager to see what the in vivo data currently being generated will show.
OXGENE & WuXi Advanced Therapies: supporting innovators from discovery to commercial stages
Previously, OXGENE mainly supported clients in the research phase and could only provide materials for preclinical research. However, in March 2021 OXGENE was acquired by WuXi AppTec to become part of WuXi Advanced Therapies. WuXi Advanced Therapies is a Contract Testing, Development and Manufacturing Organization (CTDMO). Together, OXGENE and WuXi Advanced Therapies have more than 1,100 employees and can provide end-to-end support to cell and gene therapy companies from preclinical discovery and development to clinical and commercial manufacture and testing through eight sites across three countries and regions (Figure 6).
Next generation AAV manufacturing strategies: TESSA technology
There is incredible potential for gene therapy to be transformative for patients suffering from truly debilitating conditions. AAV is the prominent vector of choice in the gene therapy space and is commonly manufactured by introducing plasmids into cells by transfection to produce AAV particles.
OXGENE has been working to improve the plasmid system. But at the same time, it is important to look at the global need for AAV and recognize that this platform likely will not allow the field to have the level of productivity that it needs in the future. With this in mind, OXGENE is also working to develop entirely new ways of manufacturing AAV – resulting in the Tetracycline Enabled Self-silencing Adenovirus (TESSA) platform.
TESSA represents a scalable way of manufacturing AAV that does not require plasmids and improves the yield of AAV. Another important point is that this approach improves the quality of the particles themselves. In theory, improving the quality will allow a lower quantity of AAV to be used to get the same therapeutic effect, which offers significant advantages from both a safety and Cost of Goods perspective.
The TESSA platform uses a modified adenoviral vector. In nature, as the name suggests, AAV takes advantage of adenovirus to replicate itself, and the quality of the resulting AAV produced is very high. The numbers of AAV particles containing the AAV genome is also very high, with close to perfect packaging of particles. However, this result is not achieved when using plasmid transfection to produce AAV. The helper genes from adenovirus are introduced into the cells, but generally, the level of productivity and particle quality is not comparable.
By using adenovirus to make AAV it is possible to harness what has already evolved naturally to achieve the best yields and quality possible. Adenovirus is an incredible machine for putting the cell into the right environment for manufacturing adenoviral particles, or in this case also AAV particles, and completely takes over the cell. After about three days of infection, ~90% of the RNA in the cell is derived from the adenovirus genome.
This approach has been used previously, and the main challenge is that it produces roughly equal levels of adenovirus and AAV, resulting in contamination issues. An expensive and lengthy purification processes is then required to remove the adenovirus. OXGENE set out to solve this issue.
Solving the adenovirus contamination question
The adenovirus lifecycle can be divided into two parts (Figure 7). The early parts of the lifecycle, dubbed the early phase, produce a series of genes that are involved in the lifecycle of both adenovirus and AAV, and are fundamentally required by both. The late part of the lifecycle is only required by adenovirus and produces a series of structural proteins which make up the particle itself.
To make AAV, the aim is to capture and harness the early part of the lifecycle, but turn off the late part of the lifecycle. This is the principle behind the development of TESSA technology.
TESSA technology regulates the late part of the lifecycle in a way that allows for switching it on and off. Adding doxycycline to the virus allows you to turn on all the late genes of the adenovirus and produce it, scale it up, and grow it like any other adenovirus. The success of some of the recent COVID vaccines show that it is possible to scale up adenovirus to very large quantities relatively quickly.
Making AAV is done in the absence of doxycycline. This approach closes down all of the late genes of the adenovirus lifecycle but allows expression of the early genes required for AAV replication. The cells can be infected with this adenovirus, but they will only manufacture AAV, without contaminating adenovirus.
TESSA: supporting data
As shown in Figure 8A, TESSA modification reduces adenoviral particle formation to baseline. Figure 8B represents this visually – the right hand set of images shows that after 2 days of infecting cells with a wildtype adenovirus, the cells that have been infected go green. By day nine the monolayer is entirely decimated. This is because the adenovirus has come back out of the cells, reinfected adjacent cells, and killed them over the nine-day window. The adenoviral lifecycle is about three days; hence this represents multiple rounds of replication.
On the left side, on day 2 when TESSA technology has been added, the cells turn green. However, because the virus then shuts down the late genes, there are no structural proteins being produced. Day nine looks essentially the same as day two because the virus is not coming back out of the cells, and therefore not killing the cells and infecting adjacent ones.
TESSA 2.0: removing plasmid dependency
Next, OXGENE’s goal was to remove the dependency on plasmids and integrate the components of the AAV system into the adenovirus. Creating adenoviral vectors encoding both Rep and Cap has not previously been achieved because they are toxic to the adenovirus, but through vector engineering OXGENE is now able express all the different isoforms of Rep and Cap in the right stoichiometries required for manufacturing AAV.
The data in Figure 9 is from a 1-liter bioreactor and shows very good yields of AAV2 and good productivity per cell. This particular production run resulted in very high packaging efficiency in terms of the empty to full ratio, well above what is typically seen with plasmid systems. This has been additionally demonstrated for all standard serotypes of AAV.
OXGENE also wanted to confirm the quality of the AAV being produced, as they observed improvements in both particle quality and efficiency of infection for different serotypes of AAV. A study of TESSA-produced AAV2 used to infect HEK293 or U87 cells demonstrated more efficient transduction than plasmid-produced AAV2. This is particularly notable for AAV2, which showed the biggest increase, as it is a difficult serotype to produce via the plasmid transfection method.
Figure 10 shows productivity data for other serotypes using TESSA-RepCap for AAV1, 4, 5, and 6. Productivities in some instances are in the low millions per cell, which has previously only been seen in some baculovirus systems for certain serotypes. It should be noted that this is against the standard Rep/Cap that is used across the industry, and not OXGENE’s reconfigured plasmids described earlier, so the numbers will be slightly different between these two datasets. However, as the majority of the industry is using a standard RepCap plasmid, it is nonetheless a fair comparison.
OXGENE also observed similar improvements in the particle quality for other serotypes, particularly AAV4 (Figure 11). While some of these improvements are small, a trend emerges towards an improved particle quality when derived from the TESSA 2.0 approach.
Finally, OXGENE discuss the safety aspects of TESSA technology, as an adenoviral vector is clearly very different from a plasmid-based system. The adenoviral vectors used in TESSA are E1/E3 deleted, and in the UK they are in the same Biosafety Laboratory (BSL) category as plasmids, i.e. category 1. The technology itself reduces the amount of contaminating adenovirus in AAV production to close to baseline. It is also a replication incompetent virus and so will cripple its own replication in the absence of doxycycline in the system.
OXGENE has now shown via next generation sequencing and other assays that TESSA modifications are very stable over extensive passage, far beyond what would be required in a GMP manufacturing run. The Rep/Cap components are split apart, and the chances of getting recombination to create wild type AAV from the TESSA system are extremely low. Most of the standard genetics of AAV have been removed from the system, resulting in a safe and stable platform.
To summarize, TESSA Technology:
Significantly increases AAV particle yields for all serotypes tested
Increases particle infectivity for multiple serotypes
Reduces adenoviral contamination by 99.9999999–100%
Is safe, efficient and removes the dependency on transfection
Offers significant improvements in scalability and process robustness, and uniform infection of cells
Is not restricted by cell density or volume
Enabling the next generation of gene therapies
Gene therapy holds the potential to transform treatment options for many patients – but to support and accelerate new therapies from initial concept, through the clinic and into commercialization, reliable and efficient AAV vector production is a crucial goal. By offering optimized AAV vector construction and production, OXGENE and WuXi Advanced Therapies can support innovators from discovery all the way to the commercial stage. Finally, next generation AAV manufacturing approaches like TESSA technology can move the field past transient transfection and prepare the industry to better meet the ever-growing need for AAV.
Ask the experts
Charlotte Barker, Editor at BioInsights, speaks to (from left to right): Steven Gill, Founder and Director, Neurochase and Innervate Therapeutics; Qian Lui, Head of Biomanufacturing Services, OXGENE; and Ryan Cawood Chief Scientific Officer, OXGENE & WuXi Advanced Therapies
Q Steve, what advice would you give to another company like Innervate looking to find a partner for preclinical viral vector manufacture?
SG: I think many startups like ours are probably at the stage where they haven’t necessarily got the in-house Chemistry, Manufacturing and Controls (CMC) expertise. They also often don’t have a lot of money as they start up.
If you are looking for a Contract Development and Manufacturing Organization (CDMO), you need to choose the right one, right at the beginning. That means one that has a highly experienced team and track record of high-quality production. But also, importantly, one that has established pathways for you to then scale to GMP production, and can provide various options. Understanding that you can actually take your product forward with the same group is quite important.
The other thing that seems to be a burden for us when looking ahead at some other projects is the production times. When are there going to be slots available for you? They might be many months apart. Looking ahead at what you might expect down the line is important.
The other thing is cost. Is there is a way in which you can build a relationship that means the costs can be either deferred, or based on your success down the line to some extent, rather than being entirely upfront? It is really difficult to get going, and you carry quite a high risk as you start.
Q What are the advantages of partnering with a company like OXGENE early on in your therapeutic development?
SG: Again, you have got to get your product right at the beginning, get the best advice, and have that pathway in place. Choose the CDMO with the right track record; someone you’ve got confidence in being able to take you all the way through. If you make a mistake in the production at the beginning, and your company is totally dependent on that, that can be hugely costly to you and may cause your production to fall down. You may work through one product at a preclinical stage and find you simply can’t translate it into a proper GMP product within a reasonable timeframe down the line.
Having all the information in front of you when you start is really helpful, and dealing with people with experience in this is the most important thing.
Q What are the key things to consider when taking the next step to GMP plasmid supply and viral vector manufacture for clinical trials? What would you advise therapeutic companies to consider when looking for a manufacturing partner?
RC: Plasmids, although relatively simple molecules, are quite challenging to make. Track record is something you want to be able to look at.
Also consider the yields you are trying to achieve. For some of these systemic treatments you are going to need extremely large quantities of plasmids, so being able to work with a partner that can deliver multi-gram quantities is obviously very important.
Additionally, plasmids are relatively simple, and viral vectors are arguably an order of magnitude more complex. What you want when you are talking about viral vector manufacture is someone with experience who has done it before.
There are a lot of aspects to the viral vector itself that are important. This is perhaps where it moves away from the way in which it’s been made from a laboratory perspective, and more towards the technologies that are being used. If you use a good technology to manufacture a viral vector it can significantly impact the treatment benefit and the way in which it behaves within a patient.
Therefore, it is a combination of looking at skills and expertise, but also the technologies that are being used.
QL: In addition to what Ryan mentioned, if a therapeutic company is considering GMP manufacture of either plasmid or viral vectors, they also need to make sure the CDMO has a reliable supply chain. That this is another guarantee for a quick turnaround time.
Another part is an integrated quality control and testing scheme. You need to make sure the CDMO has the capability to fully quality control the product and the facility itself, and make sure that it is in line with the regulatory requirements, and also that the processes are regulatory compliant. Ideally, the CDMO could also support any regulatory submissions for the customers.
Q Qian, what are the most important features a viral vector system to deliver gene therapies needs to provide? What would make a vector system stand out from all the others?
QL: We are supporting a lot of therapeutic companies who are developing their own products and we consider safety a crucial feature, because we know that is what the therapeutic companies and also the regulatory authorities consider as the priority as well. This is achieved through smart vector design and process control, and also a thorough testing scheme.
Equally important is the efficacy of the viral vectors. This again is achieved by vector design optimization and also manufacturing technology upgrades.
Q Last but not least is cost effectiveness. It was mentioned earlier that going to GMP standard manufacturing for a vector or plasmid can increase costs. Manufacturing technology upgrades and process development to optimize the yield are definitely helpful in reducing the cost for manufacturing. Something else that can be helpful for cost effectiveness is an end-to-end logistics model – this means the same facility can manufacture from plasmid to viral vector, or if it is a CAR T therapy they could do the cell part as well.
RC: Picking the viral vector is really about picking the right viral vector for the condition that you are trying to treat. Some viral vectors are pro-inflammatory, such as herpes viral vectors. They have been used for successful treatment of melanoma for that very reason; they are immunogenic. But if you are picking a vector to try and stealthily deliver a gene to correct a genetic disorder you certainly don’t want a pro-inflammatory vector, so you might use AAV.
It is also a matter of how you are trying to deliver it. Are you modifying cells ex vivo or are you delivering the vector directly into the patient? If you are delivering it into the patient, have they seen these vectors before? Are they pre-immune to them, and how? What is the dosage you are going to need to deliver to get therapeutic benefit, or are you delivering very small doses for something like ocular disorders?
It is a matter of picking the right vector for the right tissue and the right condition. There is no one-size-fits-all in terms of viral vector biology. It is certainly a scientific endeavor, but I don’t think there is any single magic bullet.
Q The presentation made the urgency of patient need for new gene therapies very clear. How can we accelerate the development of these groundbreaking treatments and get them to patients sooner?
RC: The industry has exploded since 2012, and a lot of the effort has gone into trying to get these vectors into patients as soon as possible.
Something we want to bear in mind is that it is one thing to get these things into the patient as soon as possible, but not if the ultimate end product is then unaffordable. It is a careful balance between speed and the cost of these vectors.
The cost has historically been very high because the technologies used were invented 20 years ago in some cases. Manufacturing technologies are now catching up, which is certainly helping to produce these vectors more consistently. It is also obviously slowing down progress if the production methods are not particularly consistent.
The analytics are also being developed quite rapidly. A lot of the analytical assays we needed to get these things properly qualified to be used consistently in patients didn’t really exist five to ten years ago. It is a matter of us all pushing together to try and standardize the manufacturing approaches, standardize the analytics, standardize the testing, and really streamline the entire workflow from the very concept of the vector all the way through to GMP release.
Q Qian, how can integrated Contract Testing, Development and Manufacturing Organizations (CTDMOs) like WuXi Advanced Therapies support the acceleration that Ryan spoke about?
QL: It will be very helpful if CTDMOs like WuXi Advanced Therapies can get involved from an early stage, for example in the development process of the drug. From the design and discovery phase we can start to help our customer, and then go through with them and use our manufacturing technology to achieve an optimized manufacturing platform, including good productivity and good robustness.
In this way we are providing an end-to-end service like I mentioned earlier. This logistics model would be cost effective for the customers and also guarantees the best outcomes, from small scale to larger scale or commercial scale manufacture. It is really important that the manufacturer or CDMO goes through the whole process with the therapeutic company, and becomes like a partner. It is also important for the CTDMOs themselves to keep developing and optimizing their manufacturing technologies.
Q Steve, what do you think the impact of technologies like TESSA will be for smaller therapeutic companies like Innervate?
SG: From a small biotech’s position, we want to get into the clinic and develop our therapy quickly, cost effectively and safely. TESSA sounds like it will tick all the boxes for people like us.
Efficacy is also key, and again that is down to being able to develop the appropriate type of capsid that has high transfection and very specific tissue targeting. All of this is important, and all of these things seem to be coming together now as this whole area is picking up.
Q Ryan, the number of new gene therapies entering clinical trials is growing year on year. What do you consider the major technological infrastructure or medical advances driving this growth, and what is making genetic medicine such a promising approach to treating hitherto incurable conditions?
RC: It is interesting. If you are in a revolution, do you ever realize you are in a revolution? I think sometimes the answer is probably no.
If we think back ten years ago, we literally had one patient treated with CAR T-cell therapy. CRISPR had not been used in any mammalian cells, and AAV hadn’t shown any clinical efficacy. Just ten years ago.
Look at where we are now. We have got every different CRISPR enzyme under the sun that can edit pretty much any genetic loci of the cell. We’ve got CART therapies as well as a number of other different cell therapies that are actually curing patients of previously completely intractable conditions. AAV is showing efficacy from hemophilia to retinal conditions.
It is all so incredibly exciting. We have gone from having a relatively modest toolkit to being able to do things we only dreamt we might be able to achieve.
There has been a fundamental shift in our capabilities to treat human disease, and the weapons we have to improve human health have been transformed in the last decade. Long may that continue.
Steven Gill, Founder and Director, Neurochase and Innervate Therapeutics
Professor Steven Gill is an Honorary Professor of Neurosurgery at the University of Bristol and formerly a Consultant Neurosurgeon at Southmead Hospital, Bristol. He is a world Leading expert in drug delivery to the Central Nervous System and has pioneered Deep Brain Stimulation of novel targets in the brain to treat Parkinson’s disease and tremor. Professor Gill carried out the first clinical trial infusing GDNF directly into the brain and demonstrated reversal of Parkinson’s disease. He has patented multiple inventions including the RNS drug delivery system and the Prestige Cervical Disk. He founded Neurochase and Innervate Therapeutics in 2020.
Qian Liu, Head of Biomanufacturing Services, OXGENE
Dr Qian Liu has a background in cell and molecular biology. She joined OXGENE in July 2017 as a Cell Line Engineering Scientist. She joined OXGENE in July 2017 as a Cell Line Engineering Scientist, and now leads all of OXGENE’s biomanufacturing services. Prior to joining OXGENE, Qian was a postdoctoral researcher in the field of Regenerative Medicine, involved in bioartificial liver development and investigating the mechanisms of stem cell differentiation in Loughborough University and the University of Nottingham, respectively.
Ryan Cawood, Chief Scientific Officer, OXGENE and WuXi Advanced Therapies
Dr Ryan Cawood is the Chief Scientific Officer, OXGENE and WuXi Advanced Therapies. Ryan founded Oxford Genetics in 2011, after earning a first class degree in genetics and a PhD from Oxford University. The idea behind the company was to simplify and standardise the process of DNA engineering using a proprietary DNA plasmid platform called SnapFast™ that allowed researchers – for the first time – to assemble complex sections of DNA as simply as molecular building blocks. Ryan used his background in genetic engineering and virology to guide and grow the business through a series of strategic changes that explored how further development of the SnapFast™ platform through in house research and development could help overcome multiple challenges in the development of new biologics. When OXGENE became a WuXi Advanced Therapies company in March 2021, Ryan became CSO of WuXi Advanced Therapies.