Tisagenlecleucel

The University of Pennsylvania has spun out multiple life sciences companies over the years, including Interius BioTherapeutics / iStock, f11photo The Philadelphia market has gained recognition not only for its cell and gene therapy sector but also its real estate scene and talent pool. Vittoria Biotherapeutics, Interius BioTherapeutics and Chamber of Commerce for Greater Philadelphia executives share why the area is a life sciences hot spot. As a life sciences hub within the Pharm Country hotbed , the Philadelphia market has much to offer, although it wasn’t always that way. Just ask Nick Siciliano, CEO, co-founder and director of Philadelphia-based Vittoria Biotherapeutics. He told BioSpace that Philadelphia’s life sciences scene has grown tremendously during his 20-year career in the city and is more sophisticated than it’s ever been. “You have a stable of entrepreneurs and life science executives that I think are committed now to bringing Philadelphia up to par with the Bostons, the Bay Areas,” said Siciliano, whose clinical-stage immunotherapy company develops cell therapies for hard-to-treat diseases. “They’re committed to building companies here. The technology that we’ve seen just in the last decade has been inspirational coming out of some of these institutions for what I believe are going to be transformative modalities in medicine—cell therapy, gene therapy, etc.” The supporting infrastructure has also noticeably changed during Siciliano’s 20-year career. As an example, he noted the growth of incubator University City Science Center. Established in 1963 as a research park, the nonprofit eventually partnered with Wexford Science & Technology and Ventas to create uCity Square , a mixed-use development that takes up 11 city blocks and is home to over 200 life sciences companies. The Science Center has full or partial ownership in six buildings there. Philadelphia’s life sciences businesses and jobs have grown significantly in the past five to 10 years, according to Claire Greenwood, senior vice president of economic competitiveness at the Chamber of Commerce for Greater Philadelphia and executive director of the chamber’s CEO Council for Growth. A 2024 chamber report reflects that growth. It noted that more than 5,000 people work in biotech in Philadelphia, an eight times increase from a decade ago, while lab space square footage inside the city has increased by 150% since 2018. Also noteworthy: According to the chamber , Greater Philadelphia—which it defines as an 11-county region across northern Delaware, southern New Jersey and southeastern Pennsylvania—has over 1,200 life sciences establishments, including more than 450 biotech research and development and manufacturing companies. Cell and Gene Therapy Remains Key Part of Identity The Philadelphia market is best known for its innovative cell and gene therapy sector, which has more than 60 companies and institutions in Greater Philadelphia, according to the chamber’s report. The report also noted that the sector represents over 7,000 jobs and $1 billion in estimated wages. Notable milestones include development of Kymriah and Luxturna , which in 2017 were the first FDA-approved cell and gene therapies. The Philadelphia market goes beyond cell and gene therapy, however. mRNA technology is a growing area, according to Greenwood and Cushman & Wakefield. The commercial real estate services firm’s 2024  research noted, “Pioneered in Philadelphia, mRNA technology presents a budding future for Philadelphia’s life sciences ecosystem.” An April 2024 Colliers life sciences report had similar findings, noting that the Philadelphia market remains on the forefront of gene, cell and mRNA research and development. Real Estate Scene Earns Recognition The Colliers report also named the area as the No. 4 life sciences market based on 2020 to 2023 venture capital funding, fiscal year 2023 National Institutes of Health funding, 2022 biomed degree completions, size of real estate inventory and space absorbed—the rate at which property is leased or sold—over the past three years. Regarding real estate specifically, Philadelphia has started coming into its own, noted Dora Mitchell, senior vice president of operations and chief of staff at Interius BioTherapeutics, a Philadelphia-based clinical-stage biotech that’s developing genetic medicines. Mitchell told BioSpace that five or six years ago, she likely would have said, “Where are all the developers at?” Now, she said, the city has an excellent mix of space available, including larger and customizable offerings. Greenwood told BioSpace she’s seen significant real estate investment in the past three to four years. Because of that, she said, the issue of not having the space needed to serve the industry is no longer part of the dialogue. She noted that there’s a lot of new capacity either online or coming online, whether companies are looking for manufacturing facilities or traditional lab and office workspaces. According to the Colliers report, there is 2.5 million square feet under construction in the Philadelphia market, where the vacancy rate is 7.7%. As to the cost of office space, a key factor for life sciences companies, Mitchell noted that rent in Philadelphia is a fraction of what it is in Boston. That aligns with Cushman & Wakefield research, which stated that the cost per square foot is $53.53 in the Philadelphia market, compared to $90.39 in the Boston market. Proximity to Resources Benefits Companies A key advantage of the Philadelphia life sciences scene, according to Greenwood, Mitchell and Siciliano, is proximity to resources, including universities and contract development and manufacturing organizations (CDMOs). Siciliano noted that companies can get in front of third-party manufacturing groups, academic collaborators and other industry service providers all in an afternoon. Philadelphia universities include the University of Pennsylvania, which has spun out multiple life sciences companies, including Interius, whose co-founders are Saar Gill, an associate professor of medicine at Penn, and Bruce Peacock, who also co-founded Vittoria and has worked in biotech for over 35 years. Mitchell had high praise for Peacock’s contributions to Philadelphia’s biotech scene. “We all need to put a monument of that man out in Philly somewhere,” she said. Regarding proximity to resources, Mitchell noted that Interius is walking distance from the University of Pennsylvania, which houses Gill’s research lab, and near the Philadelphia College of Pharmacy, which is part of Saint Joseph’s University. Expand the perimeter, she said, and there’s also Drexel University , Temple University and Thomas Jefferson University. These institutions offer life sciences companies talent and the opportunity to collaborate, she noted. Mitchell also shared that Interius is just 10 minutes away from its contract manufacturing organization. “The benefit that that has brought to our program is just immeasurable,” she said. “Our folks can jump in a car and be right there, troubleshoot together.” Talent Pool Draws Praise As to the talent pool itself, a June 2024 CBRE  report noted that in 2023, the Philadelphia market ranked No. 8 for research and development talent and No. 7 for manufacturing talent. Cushman & Wakefield’s research found that total life sciences employment in the market is 50,300, with the 10-year growth rate at 20.7%. Regarding who’s in that talent pool, Siciliano noted that there are great scientists coming out of the universities. Mitchell agreed, sharing that academic institutions offer individuals who are at the forefront of clinical science. She also highlighted Philadelphia’s manufacturing professionals; nearby New Jersey’s Big Pharma employees, who include R&D and commercialization talent; and CDMOs’ process development professionals. “The combination of all of these inputs, I think, is unique,” Mitchell said. “And I don’t know that you can really replicate that anywhere else.” On the Wish List: More Resident Capital One area where there’s room for improvement, according to Mitchell, is resident capital—having more venture capital firms located in Philadelphia. “There is a benefit to an up-and-coming life sciences community if there is resident capital there, because then you really naturally have more opportunity to bump into each other, to have these sort of organic discussions and ideas flourish in a less sort of deliberate sort of way,” she said. Siciliano agreed there’s not a strong presence of resident capital in the area, noting, “We go to a biotech event here in Philadelphia, we’re not going to be rubbing shoulders with the men and women that run some of the biggest VC funds, where you get that in Boston, you’ll get that in the Bay Area.” He said that should change. “I think as the sector continues to grow here, and more companies are successful, you’ll start to see more and more venture funds set up shop here,” Siciliano said. Interested in more career insights?  Subscribe to  Career Insider  to receive our quarterly life sciences job market reports, career advice and more.

In 2023, the global market for AAV (Adeno-associated virus) therapies reached $1.5 billion, with projections suggesting growth to $22.3 billion by 2029, underscoring the rapid development of AAV therapies. Currently, eight AAV gene therapies have been approved worldwide, with over 900 pipeline projects in progress, highlighting both the swift expansion and widespread research interest in AAV gene therapies. AAV gene therapy holds a central position in the field due to its efficient, safe, and durable gene delivery capabilities. With recent advances in understanding the biological properties of AAV, gene engineering techniques, and accumulated clinical trial data, AAV gene therapies are entering a period of rapid global growth. Global Transaction Status of AAV Therapies in Patsnap SynapseMechanism of Action of AAV VectorsAs an effective gene therapy vector, AAV operates through a complex sequence of steps, from binding and entry at the cell surface to eventual gene expression and protein synthesis. AAV binds to specific receptors on the host cell surface via surface proteins, a process crucial for the virus's targeted infection. For example, AAV2 primarily recognizes and attaches to heparan sulfate proteoglycans (HSPG) on host cells, which aids in cellular attachment and entry. This binding facilitates virus adsorption and triggers intracellular signaling pathways, leading AAV to enter the cell through receptor-mediated endocytosis. Schematic representation of AAV genome1AAV binds to specific receptors on the host cell surface through its surface proteins, a critical process for the virus’s selective infection. For instance, AAV2 primarily attaches to heparan sulfate proteoglycans (HSPG) on the host cell surface, which facilitates cellular recognition and attachment. This binding not only aids in viral adhesion but also activates intracellular signaling pathways, triggering receptor-mediated endocytosis that allows AAV to enter the cell. Endocytosis typically relies on clathrin or other mechanisms like caveolin or micropinocytosis, assisting viral particles in reaching the cell interior. Once AAV particles enter through endocytosis, they are enclosed in endosomes. The acidic environment within the endosomes induces major structural changes in the viral capsid, exposing a phospholipase A2 (PLA2) catalytic domain. This exposure enables viral particles to escape into the cytoplasm. The escape process can vary based on cell type and AAV serotype, with different serotypes exhibiting varying cellular affinities, allowing enhanced transduction efficiency in specific tissues or cell types through appropriate serotype selection. Gene replacement and supplementation therapy2Once in the cytoplasm, AAV particles use the cell's microtubule transport system to approach the nucleus. This process occurs through interactions with microtubules and motor proteins such as dynein and kinesin. The microtubule transport system plays a crucial role in intracellular directional movement, efficiently transporting AAV particles to the vicinity of the nucleus to prepare for nuclear entry. When AAV particles near the nucleus, they interact with nuclear pore complexes (NPCs) and are transported through NPCs into the nucleus. NPCs are large molecular channels on the nuclear membrane that regulate nuclear transport. The nuclear import of AAV is a tightly regulated process, involving interactions between various cellular factors and viral proteins. NPCs consist of multiple protein subunits forming a channel approximately 100 nanometers in diameter. These subunits include nucleoporins, which are essential to NPC structure and function. FG repeat sequences in nucleoporins (phenylalanine-glycine repeats) form a selective filter, allowing only specific proteins and macromolecular complexes to pass through and enter the nucleus. A timeline of cell and gene therapy approvals to date and their target indications3Some research indicates that AAV particles may enter the nucleus intact through NPCs. This process depends on interactions between viral capsid proteins, particularly VP1 and VP2, and FG repeat sequences in nucleoporins. After entering the nucleus, the viral particles undergo uncoating to release their single-stranded DNA genome. Another view suggests that AAV particles may partially uncoat in the cytoplasm, releasing portions of viral DNA. These exposed DNA fragments then enter the nucleus through NPCs and undergo further uncoating and processing. Regardless of the mechanism, once inside the nucleus, AAV’s DNA must be unpackaged for subsequent processing. This involves the breakdown and removal of viral capsid proteins, potentially facilitated by host cell proteases and other enzymes, exposing the single-stranded DNA genome. Upon entry, the single-stranded DNA genome undergoes secondary structural changes to form double-stranded DNA, either through host DNA repair mechanisms or replication-aiding factors within the viral genome. In double-stranded form, the AAV genome utilizes inverted terminal repeats (ITRs) for inter- or intramolecular genomic recombination. This recombination stabilizes the AAV genome as episomal DNA (non-integrating circular DNA), enabling sustained gene expression in non-dividing cells. The ITR sequences within the AAV genome drive this recombination process, forming a circular, episomal genome that can persist in the nucleus, promoting continuous transgene expression and protein synthesis. AAV vector design2Market Drivers for AAV TechnologyMany genetic disorders currently lack effective treatments, particularly those caused by single-gene mutations, such as cystic fibrosis, Huntington's disease, spinal muscular atrophy (SMA), and Duchenne muscular dystrophy (DMD). AAV (Adeno-Associated Virus) technology brings new hope for treating these conditions by restoring or improving patients’ physiological functions through gene replacement or gene editing. Although rare disease patient populations are relatively small individually, they are substantial in total. Statistics show there are over 7,000 rare diseases worldwide, affecting millions of people. The application of AAV technology in rare disease treatment offers more therapeutic options for these patients, driving market demand growth. Large-scale production of AAV vectors has long been a challenge in gene therapy. Recently, improvements in production processes, such as the use of suspension cultures and bioreactors, and new manufacturing technologies (like TESSA™ technology), have significantly enhanced AAV vector yield and purity, reducing production costs and advancing AAV commercialization. The main targets of AAV technologyThe U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) provide accelerated approval pathways for gene therapy products. These policies aim to speed up the market availability of innovative therapies to meet urgent patient needs, thus promoting the development of AAV technology. Companies in gene therapy are accelerating research and commercialization through partnerships and alliances to share resources and technologies. For example, Sarepta Therapeutics collaborates with various research institutions and pharmaceutical companies to advance the application of AAV technology in DMD treatment. Traditional gene therapy products are often personalized and customized, resulting in high production costs and long timelines. Recent innovations, such as using universal CAR-T cells and AAV vectors, have enabled the development of “off-the-shelf” therapies. These can be produced in bulk in advance and applied to broader patient groups, lowering costs and improving accessibility. Main Diseases Targeted by AAV Vector ApplicationsRegional Analysis of AAV Technology DevelopmentNorth America and Europe lead globally in AAV technology research and applications, supported by strong research institutions, biotechnology companies, and comprehensive policy frameworks with significant market potential. The U.S. and the EU facilitate rapid AAV product approvals through FDA and EMA’s accelerated pathways, playing a key role in innovation and commercialization in gene therapy. Main Development Areas of AAV TechnologyIn Asia, particularly China and Japan, there is rapid growth as an important hub for AAV development. The Chinese government supports gene therapy research and industrialization through various policies, while Japan promotes clinical applications of AAV products with its advanced technology and favorable market environment. Other regions, such as Australia, the Middle East, and Africa, though still in early stages, show promising development potential. International collaborations and policy support are gradually advancing AAV technology development in these areas. Market Competitive Landscape for AAV TechnologyMain Research and Development Institutions for AAV TechnologySarepta Therapeutics Sarepta Therapeutics is a leading biopharmaceutical company dedicated to developing and commercializing innovative therapies for rare diseases, particularly in the gene therapy field. The company has made significant progress with AAV gene therapies, notably in Duchenne muscular dystrophy (DMD) and limb-girdle muscular dystrophy (LGMD). Its AAV-based gene therapy product SRP-9001 (Elevidys) has undergone several clinical trials and received FDA accelerated approval in 2023 for treating DMD in children aged 4-5 with dystrophin gene mutations. Despite Phase III trials not achieving their primary endpoint, the therapy demonstrated clinically meaningful benefits, generating $200.4 million in sales in 2023. Sarepta is also developing other DMD therapies, such as Amondys 45 and Vyondys 53, targeting exon-skipping therapies for exons 45 and 53. In LGMD, Sarepta’s SRP-9003 has entered clinical trials, showing promising safety and efficacy. Spark Therapeutics Spark Therapeutics is a biotechnology leader in gene therapy, particularly for ophthalmic diseases. Its landmark product Luxturna (voretigene neparvovec-rzyl) is FDA-approved to treat Leber congenital amaurosis (LCA) due to RPE65 mutations. Luxturna, the first approved "in vivo" gene therapy, delivers a functional RPE65 gene to retinal cells through a single intravitreal injection, restoring visual function. This approval marked a significant milestone in gene therapy, offering new hope for patients with inherited vision loss. Spark is also developing gene therapies for other genetic diseases, including hemophilia A, lysosomal storage disorders, and neurodegenerative diseases, demonstrating its extensive capabilities and innovation in the gene therapy landscape. uniQure Based in the Netherlands, uniQure is a biotechnology company focused on developing AAV-based gene therapies, achieving notable success in rare and neurological disorders. Key products include Glybera, the world's first approved gene therapy, for lipoprotein lipase deficiency (LPLD). Despite being withdrawn in 2017 due to high costs and limited market acceptance, it showcased the potential of AAV-based therapies. uniQure’s AMT-130 targets Huntington's disease (HD), using AAV5 to deliver a microRNA that silences the Huntington (HTT) gene, thus slowing disease progression. In August 2023, Phase I/II clinical trial results highlighted its potential in reducing disease progression. Additionally, Hemgenix (etranacogene dezaparvovec), an AAV5-based gene therapy for hemophilia B, received FDA approval in November 2022, marking it as the first approved AAV gene therapy for hemophilia B. Oxford BioMedica Headquartered in the UK, Oxford BioMedica is a gene therapy company specializing in lentiviral and AAV vector development, with products targeting genetic diseases and cancer. Established in 1995, Oxford BioMedica has become a global player in cell and gene therapy, largely due to its Lentiviral Vector (LVV) platform. This technology efficiently delivers therapeutic genes into target cells and is applicable for treating neurodegenerative diseases, ophthalmic disorders, and cancers. Oxford BioMedica collaborated with Novartis to develop Kymriah (tisagenlecleucel), the first approved CAR-T cell therapy for B-cell acute lymphoblastic leukemia. The company is also developing gene therapies, such as AXO-Lenti-PD for Parkinson’s disease and BI 3720931 for cystic fibrosis, through partnerships with other organizations. SummaryAAV, as a non-replicating, non-enveloped, single-stranded DNA virus, offers advantages like high safety, long-term expression, and broad application potential in gene therapy. Its stability, minimal host cell impact, and ability to deliver therapeutic genes with sustained expression make AAV vectors promising for durable therapeutic effects. Once in the cell nucleus, AAV sheds its capsid and releases its single-stranded genome, which converts into a double-stranded DNA template, allowing transgene transcription and translation to express the therapeutic gene. There are 13 natural serotypes of AAV (AAV1-13) and over 200 variants, each with distinct tissue tropisms, making it possible to target different tissues. Significant progress in AAV gene therapy has been made in clinical applications, treatment effectiveness, and therapy innovation. With ongoing advancements, AAV gene therapy is positioned to redefine the future of gene-based treatments, offering more therapeutic options and hope to patients worldwide. How to obtain the latest research advancements in the field of biopharmaceuticals? In the Synapse database, you can keep abreast of the latest research and development advances in drugs, targets, indications, organizations, etc., anywhere and anytime, on a daily or weekly basis. Click on the image below to embark on a brand new journey of drug discovery! Refrence  1.Dhungel BP, Winburn I, Pereira CDF, Huang K, Chhabra A, Rasko JEJ. Understanding AAV vector immunogenicity: from particle to patient. Theranostics. 2024 Jan 20;14(3):1260-1288. doi: 10.7150/thno.89380. PMID: 38323309; PMCID: PMC10845199.2.Ling Q, Herstine JA, Bradbury A, Gray SJ. AAV-based in vivo gene therapy for neurological disorders. Nat Rev Drug Discov. 2023 Oct;22(10):789-806. doi: 10.1038/s41573-023-00766-7. Epub 2023 Sep 1. PMID: 37658167.3.Jiang Z, Dalby PA. Challenges in scaling up AAV-based gene therapy manufacturing. Trends Biotechnol. 2023 Oct;41(10):1268-1281. doi: 10.1016/j.tibtech.2023.04.002. Epub 2023 Apr 30. PMID: 37127491.