Gene therapy is a powerful developing technology that has the potential to address myriad diseases. For example, Huntington's disease, a neurodegenerative disorder, is caused by a mutation in a single gene, and if researchers could go into specific cells and correct that defect, theoretically those cells could regain normal function.

A major challenge, however, has been creating the right "delivery vehicles" that can carry genes and molecules into the cells that need treatment, while avoiding the cells that do not.

Now, a team led by Caltech researchers has developed a gene-delivery system that can specifically target brain cells while avoiding the liver. This is important because a gene therapy intended to treat a disorder in the brain, for example, could also have the side effect of creating a toxic immune response in the liver, hence the desire to find delivery vehicles that only go to their intended target. The findings were shown in both mouse and marmoset models, an important step towards translating the technology into humans.

A paper describing the new findings appears in the journal Nature Neuroscience on December 9. The research was led by Viviana Gradinaru (BS '05), professor of neuroscience and biological engineering, and director of the Center for Molecular and Cellular Neuroscience.

The key to this technology is the use of adeno-associated viruses, or AAVs, which have long been considered promising candidates for use as delivery vehicles. Over millions of years of evolution, viruses have evolved efficient ways to gain access into human cells, and for decades researchers have been developing methods to harness viruses' Trojan-Horse-like abilities for human benefit.

AAVs are made up of two major components: an outer shell, called a capsid, that is built from proteins; and the genetic material encased inside the capsid. To use recombinant AAVs for gene therapy, researchers remove the virus's genetic material from the capsid and replace it with the desired cargo, such as a particular gene or coding information for small therapeutic molecules.

"Recombinant AAVs are stripped of the ability to replicate, which leaves a powerful tool that is biologically designed to gain entrance into cells," says graduate student David Goertsen, a co-first author on the paper. "We can harness that natural biology to derive specialized tools for neuroscience research and gene therapy."

The shape and composition of the capsid is a critical part of how the AAV enters into a cell. Researchers in the Gradinaru lab have been working for almost a decade on engineering AAV capsids that cross the blood-brain barrier (BBB) and to develop methods to select for and against certain traits, resulting in viral vectors more specific to certain cell types within the brain.

In the new study, the team developed BBB-crossing capsids, with one in particular AAV.CAP-B10that is efficient at getting into brain cells, specifically neurons, while avoiding many systemic targets, including liver cells. Importantly, both neuronal specificity and decreased liver targeting was shown to occur not just in mice, a common research animal, but also in laboratory marmosets.

"With these new capsids, the research community can now test multiple gene therapy strategies in rodents and marmosets and build up evidence necessary to take such strategies to the clinic," says Gradinaru. "The neuronal tropism and decreased liver targeting we were able to engineer AAV capsids for are important features that could lead to safer and more effective treatment options for brain disorders."

The development of an AAV capsid variant that works well in non-human primates is a major step towards the translation of the technology for use in humans, as previous variants of AAV capsids have been unsuccessful in non-human primates. The Gradinaru lab's systematic in vivo approach, which uses a process called directed evolution to modify AAV capsids at multiple sites has been successful in producing variants that can cross the BBBs of different strains of mice and, as shown in this study, in marmosets.

"Results from this research show that introducing diversity at multiple locations on the AAV capsid surface can increase transgene expression efficiency and neuronal specificity," says Gradinaru. "The power of AAV engineering to confer novel tropisms and tissue specificity, as we show for the brain versus the liver, has broadened potential research and pre-clinical applications that could enable new therapeutic approaches for diseases of the brain."

The paper is titled "AAV capsid variants with brain-wide transgene expression and decreased liver targeting after intravenous delivery in mouse and marmoset." Goertsen; Nicholas Flytzanis (PhD '18), the former scientific director of the CLARITY, Optogenetics and Vector Engineering Research(CLOVER)Center of Caltech's Beckman Institute; and former Caltech postdoctoral scholar Nick Goeden are co-first authors. Additional coauthors are graduate student Miguel Chuapoco, and collaborators Alexander Cummins, Yijing Chen, Yingying Fan, Qiangge Zhang, Jitendra Sharma, Yangyang Duan, Liping Wang, Guoping Feng, Yu Chen, Nancy Ip, and James Pickel.

Funding was provided by the Defense Advanced Research Projects Agency, the National Institutes of Health, and the National Sciences and Engineering Research Council of Canada.

Flytzanis, Goeden, and Gradinaru are co-founders of Capsida Biotherapeutics, a Caltech-led startup company formed to develop AAV research into therapeutics.

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New Technology is One Step Closer to Targeted Gene Therapy - Caltech

In the summer of 2015, a 7-year-old named Hassan was admitted to the burn unit of the Ruhr University Childrens Hospital in Bochum, Germany, with red, oozing wounds from head to toe.

It wasnt a fire that took his skin. It was a bacterial infection, resulting from an incurable genetic disorder. Called junctional epidermolysis bullosa, the condition deprives the skin of a protein needed to hold its layers together and leads to large, painful lesions. For kids, its often fatal. And indeed, Hassans doctors told his parents, Syrian refugees who had fled to Germany, the young boy was dying.

The doctors tried one last thing to save him. They cut out a tiny, unblistered patch of skin from the childs groin and sent it to the laboratory of Michele de Luca, an Italian stem cell expert who heads the Center for Regenerative Medicine at the University of Modena and Reggio Emilia. De Lucas team used a viral vector to ferry into Hassans skin cells a functional version of the gene LAMB3, which codes for laminin, the protein that anchors the surface of the skin to the layers below.

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Then the scientists grew the modified cells into sheets big enough for Ruhr University plastic surgeons Tobias Hirsch and Maximilian Kueckelhaus to graft onto Hassans raw, bedridden body, which they did over the course of that October, November, and the following January.

It worked better than the boys doctors could have imagined. In 2017, de Luca, Hirsch, Kueckelhaus, and their colleagues reported that Hassan was doing well, living like a normal boy in his lab-grown skin. At the time though, there was still a big question on all their minds: How long would it last? Would the transgenic stem cells keep replenishing the skin or would they sputter out? Or worse could they trigger a cascade of cancer-causing reactions?

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Today, the same team is out with an update. Five years and five months after the initial intervention, Hassan is still, for the most part, thriving in fully functional skin that has grown with the now-teenager. He is attending school, and playing sports with his friends and siblings, though he avoids swimming due to blistering in the areas that werent replaced by the lab-grown skin. One of his favorite activities is a pedal-powered go kart. There are no signs his modified stem cells have lost their steam, and no traces of tumors to be found.

The encouraging follow-up data has been instrumental in moving forward a larger clinical trial of the approach, offering hope to the 500,000 epidermolysis bullosa patients worldwide currently living without treatment options.

We were astonished by the speedy recovery, Kueckelhaus, now at University Hospital Muenster, told STAT via email. But experience from skin transplantation in other settings made him and his colleagues wary of the grafts failing as the months and years wore on. Thankfully, wrote Kueckelhaus, those fears never materialized. We are very happy to be able to prove that none of these complications appeared and the genetically modified skin remains 100% stable. The chances are good that he will be able to live a relatively normal life.

Over the last five years, Hassans team of doctors and researchers has put his new skin through a battery of tests checking it for sensitivity to hot and cold, water retention, pigmentation and hemoglobin levels, and if it had developed all the structures youd expect healthy skin to have, including sweat glands and hair follicles. Across the board, the engineered skin appeared normal, without the need for moisturizers or medical ointments. The only flaw they found was that Hassans skin wasnt as sensitive to fine touch, especially in his lower right leg. This mild neuropathy they attributed not to the graft itself, but to how that limb was prepared doctors used a more aggressive technique that might have damaged the nerves there.

The team also used molecular techniques to trace the cells theyd grown in the lab as they divided and expanded over Hassans body. They found that all the different kinds of cells composing the boys new skin were being generated by a small pool of self-renewing stem cells called holoclone-forming cells, carrying the Italian teams genetic correction.

This was quite an insight into the biology of the epidermis, said de Luca. Its an insight he expects will have huge consequences for any efforts to advance similar gene therapies for treating other diseases affecting the skin. You have to have the holoclone-forming cells in your culture if you want to have long-lasting epidermis, he said.

The approach pioneered by de Lucas team will soon be headed for its biggest clinical test yet, after nearly a decade of fits and starts. They expect to begin recruiting for a multi-center Phase 2/3 trial sometime next year.

De Luca first successfully treated a junctional EB patient in 2005. But then a change to European Union laws governing cell and gene therapies forced his team to stop work while they found ways to comply with the new rules. It took years of paperwork, building a manufacturing facility, and spinning out a small biotech company called Holostem to be ready to begin clinical research again. Hassan came along right as they were gearing up for a Phase 1 trial, but data from the boys case, which was granted approval under a compassionate use provision, convinced regulators that the cell grafts could move to larger, more pivotal trials, according to de Luca.

We didnt cure the disease, he told STAT. But the skin has been restored, basically permanently. We did not observe a single blister in five years. The wound healing is normal, the skin is robust. From this point of view, the quality of life is not even comparable to what it was before.

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Syrian refugee is thriving five years after last-gasp gene therapy - STAT - STAT

The Cystic Fibrosis Foundationis funding three new early-stage research awards worth more than $1.8 million to bolster the development of potential gene therapies for cystic fibrosis (CF).

This funding will support critical early steps necessary for the development of genetic therapies for cystic fibrosis, William Skach, MD, executive vice-president and chief scientific officer of the CF Foundation, said in a press release. These promising programs are tackling difficult challenges such as efficient therapeutic delivery of diverse genetic cargos and evasion or modulation of the immune systems response to gene delivery vehicles.

Gene therapy works by adding a new gene or replacing or repairing a mutated gene inside cells in the body. To get gene therapy into the cells, it first must be packed into a carrier, usually a harmless virus. However, other carriers exist that may deliver gene therapy.

Carmine Therapeutics was awarded more than $766,000 to test one such alternative type of carrier. The company plans to use tiny particles, called vesicles, that naturally bud off from red blood cells to deliver a healthy copy of cystic fibrosis transmembrane conductance regulator (CFTR) the gene mutated in people with CF into lung cells. Unlike other carriers, which sometimes trigger an immune response, the vesicles are expected to be well-tolerated by the immune system, even upon repeat administration.

If a viral carrier must be used, the bodys immune response should be blocked to allow repeat administration. GenexGen was awarded close to $595,000 to develop a way to lessen the immune response to a viral carrier. The company is testing an approach that uses CRISPR a kind of molecular scissors that can cut pieces of DNA to target a certain gene that plays a key role in the immune system. The goal is to turn off that gene temporarily, thus allowing gene therapy to be delivered by a virus.

Finally, Specific Biologics was awarded more than $527,000 to test a CRISPR-based approach to make precise changes in DNA and thereby correct (edit) three common CFTR mutations in CF: G542X, R553X, and W1282X. Each of these mutations results in a stop codon in the middle of the gene and a shorter protein that ends up getting degraded by the cells. If successful, the approach is expected to work for any mutation.

The award will support preclinical testing of an inhaled medicine that uses tiny fat particles to help the gene-editing molecules enter the cells more easily.

The awards are part of the foundations Path to a Cure, an initiative whose goal is to accelerate the development of therapeutic strategies that address the root cause of CF.

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CF Foundation Funding Bolsters Gene Therapy Research - Cystic Fibrosis News Today

CHICAGO, Dec. 9, 2021 /PRNewswire/ -- In-depth analysis and data-driven insights on the impact of COVID-19 included in this Europe cell and gene therapy market report.

The Europe cell and gene therapy market is expected to grow at a CAGR of over 23% during the period 20202026.

Key Insights:

Key Offerings:

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Europe Cell and Gene Therapy Market Segmentation

Europe Cell and Gene Therapy Market by Product

Europe Cell and Gene Therapy Market by End-user

Europe Cell and Gene Therapy Market by Application

Europe Cell and Gene Therapy Market by Geography

The following factors are likely to contribute to the growth of the Europe cell and gene therapy market during the forecast period:

Europe Cell and Gene Therapy Market Vendor Landscape

Many regional vendors are also investing in the new therapy products in Europe. Many regional and local companies are posing a threat to global players due to their innovative and cost-effective products and technologies. This indicates that the market offers tremendous growth opportunities both for existing and future/emerging players. This is due to the presence of a large pool of target patient population with chronic diseases such as cancer, wound management, DFUs, CVDs, and other genetic diseases. The major players are focusing on strategic acquisitions, licensing, and collaboration agreements with emerging players to enter the cell and gene therapy market and to gain access to commercially launched products. They are also focusing on market expansion in existing and new markets to cater to the needs of a growing customer base, widen their product portfolios, and boost their production capabilities to gain traction from end-users.

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Prominent Vendors

Other Prominent Vendors

Emerging Investigational Vendors In Europe

Explore our healthcare and lifesciences profile to know more about the industry.

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Europe Cell and Gene Therapy Market Size to Reach Revenues of USD 2.9 Billion by 2026 - Arizton - PRNewswire

DUBLIN--(BUSINESS WIRE)--The "Global Gene Therapy Partnering Terms and Agreements 2010 to 2021" report has been added to ResearchAndMarkets.com's offering.

The Global Gene Therapy Partnering Agreements 2010-2021 report provides an understanding and access to the gene therapy partnering deals and agreements entered into by the worlds leading healthcare companies.

The report provides a detailed understanding and analysis of how and why companies enter gene therapy partnering deals. The majority of deals are early development stage whereby the licensee obtains a right or an option right to license the licensors gene therapy technology or product candidates. These deals tend to be multicomponent, starting with collaborative R&D, and commercialization of outcomes.

Understanding the flexibility of a prospective partner's negotiated deals provides critical insight into the negotiation process in terms of what you can expect to achieve during the negotiation of terms. Whilst many smaller companies will be seeking details of the payments clauses, the devil is in the detail in terms of how payments are triggered - contract documents provide this insight where press releases and databases do not.

This report contains a comprehensive listing of all gene therapy partnering deals announced since 2010 including financial terms where available including over 650 links to online deal records of actual gene therapy partnering deals as disclosed by the deal parties. In addition, where available, records include contract documents as submitted to the Securities Exchange Commission by companies and their partners.

In addition, a comprehensive appendix is provided organized by Gene Therapy partnering company A-Z, deal type definitions and Gene Therapy partnering agreements example. Each deal title links via Weblink to an online version of the deal record and where available, the contract document, providing easy access to each contract document on demand.

Report Scope

Global Gene Therapy Partnering Terms and Agreements includes:

In Global Gene Therapy Partnering Terms and Agreements, the available contracts are listed by:

Key Topics Covered:

Executive Summary

Chapter 1 - Introduction

Chapter 2 - Trends in Gene therapy dealmaking

2.1. Introduction

2.2. Gene therapy partnering over the years

2.3. Most active Gene therapy dealmakers

2.4. Gene therapy partnering by deal type

2.5. Gene therapy partnering by therapy area

2.6. Deal terms for Gene therapy partnering

2.6.1 Gene therapy partnering headline values

2.6.2 Gene therapy deal upfront payments

2.6.3 Gene therapy deal milestone payments

2.6.4 Gene therapy royalty rates

Chapter 3 - Leading Gene therapy deals

3.1. Introduction

3.2. Top Gene therapy deals by value

Chapter 4 - Most active Gene therapy dealmakers

4.1. Introduction

4.2. Most active Gene therapy dealmakers

4.3. Most active Gene therapy partnering company profiles

Chapter 5 - Gene therapy contracts dealmaking directory

5.1. Introduction

5.2. Gene therapy contracts dealmaking directory

Chapter 6 - Gene therapy dealmaking by technology type

Chapter 7 - Partnering resource center

7.1. Online partnering

7.2. Partnering events

7.3. Further reading on dealmaking

Appendices

Appendix 1 - Gene therapy deals by company A-Z

Appendix 2 - Gene therapy deals by stage of development

Appendix 3 - Gene therapy deals by deal type

Appendix 4 - Gene therapy deals by therapy area

Appendix 5 -Deal type definitions

Companies Mentioned

For more information about this report visit https://www.researchandmarkets.com/r/s8kgqs

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Global Gene Therapy Partnering Terms and Agreements Report 2021: Access to 650+ Online Deal Records of Actual Deals - ResearchAndMarkets.com -...

This webcast features: Chris Heger, PhD, Director of Applications Science, Bio-Techne.

Modern medicines call for modern technologies. Gene therapy is an exciting approach at work to cure diseases, where genetic material is delivered to a patient via a viral vector. This approach requires a doubly complex drug that contains both protein and oligonucleotides, and existing analytical tools just dont meet the quantitative needs of these complicated therapeutic agents.

In this webinar, hear how a variety of innovative analytical tools from Bio-Techne can support your gene therapy workflow from discovery to quality control and how they can address certain critical quality attributes of your therapeutic.

Learn how automated Simple WesternTM systems can streamline your Western blotting workflow, characterize capsid proteins by size (MW) or charge (pI) based techniques in complex sample types, and identify contaminant species with high sensitivity.

Learn how automated Maurice systems can also precisely characterize samples by size (MW) or charge (pI) using direct detection methods, how Micro-Flow Imaging (MFI) can assess particle contaminants in formulations, and how Ella (Simple PlexTM) can improve your ELISA-based protein detection methods.

Just fill out the form below to watch the recorded webcast now.

Link:
Modernize Your Gene Therapy Analytics with Automated Tools from Bio-Techne - BioProcess Insider

The past 40 years have ushered in the most advanced medicines the world has ever seen, with tremendous improvements in biomanufacturing technologies to enable their development. Advances in production technology have brought significant improvements in upstream productivity, which then caused bottlenecks in downstream processing. Although many bottlenecks have been resolved for most biologics, new modalities such as gene therapies and mRNA vaccines are driving the need for differentiated purification solutions. Meanwhile, pressures to increase efficiency and reduce costs continue to mount for all biologics.

Innovative fit-for-purpose purification solutions are essential to the successful expansion of advanced therapeutic modalities beyond niche indications. Astrea Bioseparations is leveraging its expertise in development of customized separation solutions with unique nanofiber technology to bring game-changing purification solutions to market for both traditional and next-generation biologics. Additionally, the company can help customers reduce the time and cost of process chromatography by providing economical, ready-to-use columns packed with high-performance resins.

Combining a partnering approach with a focus on tailored solutions will contribute to advances in downstream processing for current and future biologics.

Upstream Advances Drive Downstream InnovationImprovements in expression systems such as Chinese hamster ovary (CHO) and human embryonic kidney (HEK) cells and in growth media have increased upstream productivity dramatically for manufacturing engineered proteins and antibodies. With proteins reaching several grams per liter in culture today, productivity is far greater than was achievable for the first commercial biopharmaceuticals.

Expanding adoption of single-use (SU) systems eliminates costly and time-consuming cleaning and cleaning-validation procedures. And implementation of perfusion cell culture for continuous processing is boosting upstream productivity further.

Initially, the rapid increase in upstream titers outpaced available downstream purification technologies, especially for capture or affinity-based chromatography. Innovation in downstream bioprocess technologies improved performance substantially through application of membrane separation technologies, introduction of ready-to-use prepacked filters, development of continuous processing methodologies, and improvement of ligand and resin chemistries. For example, protein A binding capacities have increased from 20 mg/mL to 100mg/mL.

New Modalities Create New ChallengesFurther bioprocess improvements still need to be made, particularly considering the advent of complex next-generation therapies, such as multispecific and conjugated antibody products, oncolytic virus-based treatments, cell and gene (DNA and mRNA) therapies, and novel vaccines. Much process development work for these new modalities has focused on adapting methods and technologies originally designed for engineered protein and monoclonal antibody (MAb) products.

Chromatography resins optimized for MAbs are not as well suited to cells, viral vectors such as adenoassociated viruses (AAVs) and lentiviruses (LVs), plasmid DNA, mRNA, and exosomes. Conventional resins require oversized columns because the bead pores are difficult to access, so binding capacities are low. Diffusion is slow, resolution is low, and processing takes much longer than desired. Manufacturing footprints are consequentially larger as well.

Meanwhile, membrane adsorbers work well for simple flow-through applications in which capacity is less critical, but membranes have limited applicability for capture chromatography because of their limited surface area. Leveraging new materials designed for next-generation biologics is the only way to overcome the limitations of current downstream processes. Emerging technologies must be purpose-built for viral vector manufacturing and purification, for instance, to make gene therapies and viral vector vaccines more affordable.

A Nanofiber Purification SolutionAs a member of the Gamma Biosciences portfolio, Astrea Bioseparations has added Nanopareil technology to the bioseparations toolbox. Nanopareil separation solutions are based on functionalized nanofibers that deliver dramatic improvements in performance over that of legacy chromatography technologies. Based on composite electrospun cellulose nanofibers with uniform and consistent composition and pore sizes, the matrix is physically or chemically functionalized for different separation modalities: e.g., ion-exchange (IEX), hydrophobic interaction (HIC), affinity, and steric exclusion.

Nanofiber membranes have a high surface area (>1,000 m2/g) and are >80% porous. No internal diffusion is required for adsorption, so the binding kinetics are rapid, requiring just one-second residence time to obtain saturation capacities. The average effective pore size is ~1.5 m, and the open nature of the matrix allows for high flow rates at low pressures (<1bar). In addition, porosity and pore sizes can be tailored for specific applications by controlling the layer stacking of nanofibers within a mat. With large pores, high ligand densities, and rapid flow rates, high-capacity separations are possible in a relatively small footprint, with significantly reduced processing times and costs. This technology is scalable from laboratory to clinical manufacturing.

Our initial work is focused on nanofiber separation solutions for IEX (weak and strong anion and cation) chromatography operations in bindelute and flow-through modes. Proof-of-concept studies are in progress. For viruses, virus-like particles, AAV vectors, and plasmid DNA, we are reporting binding capacities >2.5 higher, cycle times >50 faster, and footprints 10 smaller than those possible with traditional resins.

Nanofiber separations should be applicable for all biologic drug modalities. In the AsiaPacific region, where the cost of protein A for capture chromatography is a significant barrier, this new technology could offer an attractive alternative for dramatically reducing biomanufacturing costs. In fact, with their improved efficiency and productivity, nanofiber solutions from Astrea Bioseparations and Nanopareil could be game changers for the biopharmaceutical industry.

Partnerships Cut Development Time and CostCollaboration always has been a key focus for Astrea Bioseparations. Decades of close work has been carried out with academics, researchers, industry associations, other partners, and colleagues to accelerate the development of next-generation chromatographic tools.

Significant deals include licensing of the Affimer (stefin A) platform from Avacta Life Sciences for applications in bioprocessing. That has expanded Astreas range of ligand discovery and development capabilities to include high-performance, engineered, proteinaceous ligands as superior alternatives to antibody-based ligands. Combined with the mimetic Chemical Combinatorial Library (CCL) platform, the Affimer platform significantly expands our capacity to discover, develop, and deliver custom affinity adsorbents for purification of biotherapeutics and advanced therapies.

Prepacked plastic columns help to eliminate not only the packing step (which requires specialized skills and experience), but also cleaning and cleaning validation work. Such columns thus accelerate process development and production operations.

Enabling the FutureNovel modalities such as cell and gene therapies present great potential to mitigate and possibly cure diseases that previously were untreatable. Current bioprocess approaches, however, have led to unsustainable costs that are limiting access to (and thus the value of) these important new medicines. More rapid and cost-effective processes are needed to expand the scope of the cell and gene therapy field beyond niche products to treatments for widespread diseases.

Development of novel, fit-for-purpose biomanufacturing technologies and strategies such as the downstream purification solutions advanced by Astrea Bioseparations and its partners will be essential to overcoming the poor performance of existing processes. New nanofiber materials could reduce the time and cost of purification dramatically for viral vector, plasmid DNA, and other large biologic drug substances.

Daniella Steel, PhD, is senior product manager of cell and gene therapiesat Astrea Bioseparations, Horizon Park, Barton Road, Comberton, Cambridge, CB23 7AJ, UK; https://www.astreabioseparations.com. Affimer is a registered trademark of Avacta Life Sciences. CCL is a registered trademark of Astrea Bioseparations.

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Cell and Gene Therapy Development Time and Cost Reduction - BioProcess Insider

The gene therapy era can be said to have begun in 1990, when the first gene therapy clinical trial took place. Some 3,000 clinical trials have followed that first study, a resounding affirmation of innovators increasing recognition of gene therapys breakthrough possibilities for treating a diverse range of disorders especially afflictions with limited or no established treatments.

Patients with Parkinsons disease (PD) are among the potential beneficiaries of gene therapy. Although there are currently numerous available treatments for PD, these merely target symptomatic relief, leaving disease onset or progression largely unmet and sometimes producing significant adverse effects. Those limitations underscore the need for novel therapeutic approaches.

Compared to conventional pharmacological and surgical approaches to treating PD, gene therapy has several potential advantages including preservation or restoration of dopaminergic neurons; addressing underlying pathophysiological imbalances, possibly resulting in less fluctuation in response and reduced risk of dyskinesias.

In vivo gene therapy the direct, vector-delivered, intra-cerebral injection of genetic material appears to hold great promise in PD. Its success depends on efficient uptake of the therapeutic gene by the target cells and on the genes expression capability. Viral vector-based in vivo gene therapy is less invasive than transplantation techniques, leaving the striatal circuitry undisturbed by cellular implants.

Challenges inherent in the promise of gene therapy

For all its promise, gene therapy for PD has several potential limitations, including:

The gene therapy regulatory environment

Gene therapy developers must navigate a continually evolving regulatory environment. In the United States, the National Institutes of Health Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules define recombinant and synthetic nucleic acids, and include further guidelines for human gene transfer. Gene therapies are regulated under the Food and Drug Administrations (FDA) Coordinated Framework for Regulation of Biotechnology. In recent years the FDA has issued several guidance documents to support the development of gene therapy, some of which are particularly relevant for PD.

Whereas the European Medicines Agency classifies gene therapy products as Advanced Therapeutic Medicinal Products (ATMPs), the European Union (EU) Directive 2001/83/EC articulates two conditions for ATMPs, both of which must be fulfilled simultaneously:

Gene therapy products can also be defined per directive 2001/18/EC as a genetically modified organism (GMO) or micro-organism (GMM). The assessment of risk of such GMOs is split into two major categorizations that dictate the respective directive that should be followed.

The route taken depends on the product and country in which the clinical trial is taking place. Generally:

In general, the EU and US guidance for gene therapy clinical trials are very similar, with a few exceptions. In the US, when human gene transfer occurs, the study protocol must be submitted to an institutional biosafety committee (IBC); most IBCs are local, though some sites use a central IBC. In the EU, gene therapy clinical trials that fall under the GMO/GMM definition must be submitted to additional country- or site-level GMO authorities or committee(s) and require a specific GMO dossier that necessitates careful preparation to enable a timely review process.

Study design considerations

As is typical in clinical development, most gene therapy clinical programmes start with open-label cohort studies to establish the appropriate dose before proceeding to proof of concept (POC). Given that many gene therapy studies are conducted in rare disease populations, often involving paediatric patients, historical controls and natural history studies are frequently used as dose comparators. In PD programmes, however, the FDA has been known to request placebo-controlled POC studies due to research demonstrating the magnitude of the placebo effect specifically in PD and in surgical studies, and to reduce the current trend of failed sham-controlled studies following successful open-label studies.

European regulators, in contrast, do not always follow this approach, citing concerns about the patient risk/benefit ratio due to increased patient burden, increased risk of sham neurosurgery, and ensuring that patients understand that surgery may not imply gene therapy.

There is no definitive answer to the question of whether placebo control is required for a POC study in PD. Early engagement with US and EU regulators is therefore critical to avoid delays in securing final protocol approval.Investigational medicinal product availability

Due to the limited number of vector manufacturing facilities and open slots, biotech companies are increasingly building their own facilities rather than depending on vendors. But regardless of where manufacturing occurs, vector availability is key.

That makes it important to consider the full chain of the vector from manufacturing, to transport and storage, to receipt, storage, preparation, and administration at the trial site, as well as return or destruction processes as necessary. Sites must also have their own standard operating procedures for GMO handling.

PD trial sponsors should therefore consider an investigational medicinal products commercialisation potential early in development planning, as a well-designed clinical trial can enable translation of vector manufacturing, transport, and site processes to commercial processes without the need for additional studies.Additional PD trial considerations

In addition to the above, sponsors need to consider the following factors when planning gene therapy trials in PD:

Long-term follow-up

Figure 1 outlines the interplay of long-term strategic, protocol, patient, and data quality considerations for gene therapy trials, which may require up to 15 years of follow-up. The key is to strike a balance between collecting long-term safety and efficacy data relevant for regulators and payers and reducing participants on-site burden and maximising patient retention.

A basket study a long-term study involving patients from more than one protocol requiring the same type of follow-up can help reduce the financial and logistical burden of a gene therapy clinical programme. However, a basket study may require other types of approval and safety follow-up as the therapy progresses to commercialisation.Future directions

As a potential treatment modality for PD, gene therapy is highly promising and constantly evolving, with numerous approaches for both disease-modifying and non-disease-modifying therapies. However, after numerous reports of clinical improvement in animal and Phase I studies, most double-blind Phase II studies thus far have been negative, raising some important questions:

Continued advancement of newer therapeutic techniques such as optogenetics, chemogenetics, and genome-editing technology may yield answers to some of these questions in the next few years. In the meantime, early engagement with regulators, patient advocates, and even payers can keep a clinical programme moving forward. This requires considerable upfront planning, though timeline pressures and patient needs may complicate even the most well-intentioned plans. Nevertheless, given the urgency of those needs, the promise of gene therapy for PD must be explored fully and expeditiously.

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Parkinson's disease and gene therapy: strategic and operational considerations - PharmaTimes

THOUSAND OAKS, Calif., Dec. 7, 2021 /PRNewswire/ --Capsida Biotherapeutics Inc., an industry-leading gene therapy platform company creating a new class of targeted, non-invasive gene therapies for patients with debilitating and life-threatening genetic disorders, today announced the appointment of Peter Anastasiou as the company's Chief Executive Officer (CEO) and the promotions of Capsida co-founders Nicholas Flytzanis, Ph.D., to Chief Scientific Officer (CSO) and Nick Goeden, Ph.D., to Chief Technology Officer (CTO).

Gene therapy is still in its infancy and has yet to achieve its full potential. First-generation gene therapies have been challenged by safety issues due to their inability to target cells and organs without also penetrating non-targeted cells and organs, especially the liver. Capsida's proprietary, targeted, non-invasive gene therapy technology allows more selective targeting of specific tissues and cells, overcoming many of the problems associated with first-generation gene therapies, specifically off-target cell and organ activity. In addition, it allows the gene therapy to be delivered non-invasively through intravenous (IV) administration. The company's already strong leadership team is poised to actualize the promise of gene therapy with the addition of Mr. Anastasiou and the promotions of Drs. Flytzanis and Goeden.

"I can't imagine a more exciting time to join this organization," said Mr. Anastasiou. "Capsida is enabling gene therapy to become what the industry, physicians, and patients have been dreaming it will be. Our patent-protected technology allows the targeting of cells and organs while limiting the negative impact on non-targeted areas, and can be applied across multiple therapeutic areas. Another important benefit of our technology is that we are able to deliver the gene therapy non-invasively through IV administration. I'm honored to lead this talented team to achieve Capsida's potential and to improve and even save patients' lives."

Mr. Anastasiou joins Capsida from Lundbeck, where he was an executive vice president and a member of the executive committee, reporting to the CEO. As the president of Lundbeck's U.S. and Canadian business operations, Mr. Anastasiou has built organizations from the ground up. He brings significant leadership experience managing diverse organizations and bringing them together to achieve common goals. He led as many as 1,200 employees and achieved net revenues of $1.5 billion. During his 12-year tenure at Lundbeck, Mr. Anastasiou held several progressive leadership positions, playing a pivotal role in developing and launching multiple products and building the company's cross-functional capabilities. Mr. Anastasiou serves on the Board of PhRMA and the global advisory board for the Healthcare Businesswomen's Association. Mr. Anastasiou begins his new role with Capsida on January 3, 2022.

"We're thrilled to welcome Peter as Capsida's new CEO," said Beth Seidenberg, M.D., founding managing director at Westlake Village BioPartners, one of the company's lead investors, and Capsida board member. "Peter has deep industry expertise, a broad network, and significant public company experience, which will be valuable as Capsida grows. In addition, his strong track record of success demonstrates he is a visionary leader who will be able to deliver on the promise of targeted non-invasive gene therapy to help underserved patients and achieve business success."

"During his tenure at Lundbeck, Peter has created significant shareholder value, creating and leading organizations and successful blockbuster product launches," said Clare Ozawa, Ph.D., managing director at Versant Ventures, one of Capsida's lead investors, and Capsida board member."Under Peter's leadership, we will continue to build Capsida as the industry's leading targeted, non-invasive gene therapy company with the ability to transform the lives of patients with life-threatening genetic disorders."

Prior to Lundbeck, Mr. Anastasiou held management roles at Neuronetics, Inc., Bristol-Meyers Squibb Company, and Eli Lilly and Company. He holds an MBA from the Kelley School of Business at Indiana University, and a B.A. in economics and management from Albion College.

Capsida co-founders Nicholas Flytzanis, Ph.D., promoted to CSO and Nick Goeden, Ph.D., promoted to CTO

In addition to Mr. Anastasiou's appointment, Capsida announced that Dr. Flytzanis has been promoted toCSO and Dr. Goeden has been promoted to CTO.

"The promotions of Drs. Flytzanis and Goeden are in recognition of the significant contributions they have made since co-foundingCapsida in 2019," said Mr. Anastasiou. "Their steadfast commitment to delivering on the promise of Capsida's differentiated, non-invasive gene therapy platform has been a key driver behind many of the company's early achievements."

"Drs. Flytzanis' and Goeden's strong scientific and technical expertise and know-how have already delivered results in the startup of Capsida based on Caltech'sbasic research on targeted non-invasive gene delivery to the brain," said Capsida co-founder Viviana Gradinaru, Ph.D. "Their promotions are timely as Capsida enters the phase of delivering from the lab and for the patients."

Prior to co-founding Capsida, Dr. Flytzanis served as scientific director of the CLOVER research center at the California Institute of Technology (Caltech), leading an interdisciplinary team to develop and disseminate emerging technologies focused on the cross-section of neurological research and gene therapy. His research spans the fields of tissue clearing and imaging, optogenetics and rodent behavior, and adeno-associated virus (AAV) engineering and gene therapy, with collaborations across multiple institutions. During his Ph.D., Dr. Flytzanis applied protein engineering and directed evolution across biological modalities, with a focus on developing AAVs as therapeutic tools for neurological disease.

Dr. Flytzanis holds a Ph.D. in biology from Caltech and a B.S. in biology from the Massachusetts Institute of Technology.

Prior to co-founding Capsida, Dr. Goeden led a team developing the novel adeno-associated virus (AAV) engineering technology underlying Capsida's biologically driven gene therapy platform. During his tenure as a postdoctoral fellow in Dr. Gradinaru's lab at Caltech, he developed high-throughput methods for screening combinatorial libraries to explore the AAV fitness landscape and engineered novel AAVs with high efficiency and specificity for the rodent and primate brain. During his Ph.D., Dr. Goeden developed a novel organ bioreactor to study real-time metabolomics in diseased states, exploring the relationship between gene expression and the pathophysiology of neurodevelopmental disorders.

Dr. Goeden holds a Ph.D. in neuroscience from The University of Southern California and a B.S. in biology from Caltech.

About Capsida Biotherapeutics

Capsida Biotherapeutics Inc. is an industry-leading gene therapy platform company creating a new class of targeted, non-invasive gene therapies for patients with debilitating and life-threatening genetic disorders. Capsida's technology allows for the targeted penetration of cells and organs, while limiting collateral impact on non-targeted cells and organs, especially the liver. This technology allows for the delivery of the gene therapy in a non-invasive way through intravenous administration. Capsida's technology is protected by a growing intellectual property portfolio which includes more than 30 patent applications and one issued U.S. patent 11,149,256. The company is exploring using the technology across a broad range of life-threatening genetic disorders. Its initial pipeline consists of multiple neurologic disease programs. The company has strategic collaborations with AbbVie and CRISPR, which provide independent validation of Capsida's technology and capabilities. Capsida is a multi-functional and fully integrated biotechnology company with proprietary adeno-associated virus (AAV) engineering, multi-modality cargo development and optimization, translational biology, process development and state-of-the-art manufacturing, and broad clinical development experience. Capsida's biologically driven, high-throughput AAV engineering and cargo optimization platform originated from groundbreaking research in the laboratory of Viviana Gradinaru, Ph.D., a neuroscience professor at the California Institute of Technology. Visit us at http://www.capsida.com to learn more.

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Capsida Biotherapeutics Poised to Capitalize on Industry-leading Gene Therapy Technology With New CEO, CSO, and CTO - BioSpace