Are we ready for the Million dollar pills offering one time cures to life-threatening diseases?

With FDA approval of the first gene therapy for SMA by Novartis and Bluebird Bio set to launch Zynteglo for transfusion-dependent beta-thalassemia, there are burgeoning excitement and optimism in the potential of gene and cell therapy. Scott Gottlieb, former FDA Commissioner said, “By 2025, we predict that the FDA will be approving 10 to 20 cell and gene therapy products a year based on an assessment of the current pipeline and the clinical success rates of these products”.

Gene therapies can offer an actual cure in a one-time treatment but are highly customized and expensive, leading to logistics, distribution and reimbursement challenges. They can be delivered in-vivo (modifying the gene inside the patient) or ex-vivo (modifying harvested cells outside the patients’ body and putting the modified cells back in). Cell therapies can be autologous (modifying patients’ own cells) or allogeneic (from unrelated donor tissues). Autologous therapies (the majority of the currently available set) are particularly difficult to manufacture and require a stringent chain of custody, a chain of condition (temperature control), chain of identity and fast turnaround times.

Key Considerations/ Essential performance parameters:

- Persistence of efficacy

- Potential for re-treatment

- Impact of host immunology on patient selection and drug efficacy

- Molecular characterization of specific delivery modalities

- Plug and play platform approaches

- Standards for product characterization to ensure consistency


Immunological factors can impact persistent expression and patients’ eligibility for treatment. Pre-existing neutralizing Abs due to natural viral infection or prior exposure to capsid can exclude a patient. Patients with high titer nAb response are excluded from redosing. Immune response to transduced cells can damage targeted liver and muscle tissue when receiving systemic gene/cell therapy. Excessive steroid use can lead to systemic immune suppression. Tina Liu and Kai Chan’s spinout from the George Church Lab, Ally Therapeutics, seeks to systematically solve the immune response issues limiting gene therapy today.

Molecular features — Concatemer state and integration mechanism can impact persistence due to the dilutional impact of tissue division and growth.

Manufacturing processes — Consistent supply of viral vectors is a huge bottleneck. Large scale optimized production needs harvesting and purification strategies and analytical tools to monitor quality attributes and close the vector production gap in the industry. Bluebird bio is having to delay the launch of Zynteglo to early 2020 due to manufacturing issues despite having obtained regulatory approval in Europe.

Commercial-scale manufacturing processes and facilities are extremely capital intensive; hence most companies rely on CMOs until clinical efficacy is proven. Companies like Bluebird Bio are pursuing both in-house and outsourced approach while others like Avexis have invested over $55M to build in house facilities. Both have pros and cons — investing in manufacturing before product characterization can lead to a manufacturing process that doesn’t produce the correct product but without it, it might be difficult to scale up later. Having a scalable manufacturing setup/ a trusted partner — both commercial scale and research is critical to maintaining continuity of the supply chain. TriLink biotechnologies acquired by Maravai Lifesciences, ABL, Millipore Sigma, Novacep, and Wuxi AppTec are the ‘Illumina/Paramit of Gene therapy’. Cobra Biologics (UK) produces and characterizes plasmids to reduce costs of AAV and lentiviral vectors while Octane biotech has developed Cocoon™ system, a patient-scale, closed, end-to-end, automated cell-therapy manufacturing system for MSC and CAR T. AskBio is taking a more integrated approach — capsid development, scaled manufacturing, and developing a portfolio of therapeutic programs to the feasibility stage before spinning them out.

We need industrial platforms that standardize with regard to suspension cell culture, versatile single-use technologies, and cutting-edge applications of automation concepts.

Engineering challenges — Robust design build test platforms are needed to build large, complex circuits for synthetic biology. Larger circuits run into delivery challenges as they need more genetic material. Using technologies pioneered in the George Church lab, Dyno Therapeutics’ AAV discovery platform enables multi-functional enhancement of AAV vector capsids such as immune system evasion and precision delivery to target tissues for specific disease applications.

AAVs are used in nearly 50% of ongoing 483 gene therapy trials. Most commonly used AAV capsids (e.g. AAV2, 5, 8 and 9) were identified either 1) as contaminants in lab stocks of adenovirus, or 2) through monkey tissue processing. These are not targeted specifically to any tissue, leading to inefficient and non-specific delivery, hence requiring extremely high doses and potentially resulting in toxicities (including inflammation), high manufacturing burdens and suboptimal efficacy.

MaxCyte has developed a scalable transfection system for high-performance delivery of biomolecules using Flow Electroporation™ Technology to safely and reproducibly modify primary human cells with high efficiency, low cytotoxicity, and at the scale required to treat patients. It is the leading non-viral delivery platform for cell-engineering in clinical use and is currently being used in 10+ clinical trials. Sqz Biotech is using high-speed cell deformation to inject target material into the cells.

Inducible promoters can help tune expression, operator sites can enable tighter control, RNA based switches can respond to small molecules and nucleic acids in mammalian cells, optimize tight “off” to stop production when not needed and highest “on” to maximize dynamic range

Cost — With Novartis’ Zolgensma just hitting the market at $2.125M, the issue of cost is top of mind for payers and patients. Novartis is pricing the drug at an annualized cost of $425,000 per year for five years. Bluebird Bio will price Zynteglo in Europe at €1.575 million ($1.77 million), amortized over five years and only if it works on transfusion-dependent beta-thalassemia patients. Payers will likely want to see data beyond clinical trials to justify long term product overage or high upfront payments. Value-based payment models will develop to align incentives.

Access — For cell therapies, specifically autologous cell therapies (which form the bulk of Cell therapies on market), timely access is a challenge. Novartis has faced issues delivering on their turnaround time of 21 days for Kymriah. In order to scale out, the process needs to be repeated consistently, closer to the patient instead of a centralized hub (to ensure faster delivery and higher efficacy). Several logistics and software solutions are seeking to optimize the supply chain, ensure the chain of custody and improve logistical efficiency. TrakCel’s cloud-based software delivers personalized processes and workflows for every participant in the supply chain to safely manage and scale the delivery of therapies. Co-founded by GE Ventures and Mayo Clinic, Vineti provides a compliant, validated, scalable solution to support personalized therapy workflows across clinical and commercial phases to improve operations, reduce risk and reduce time to regulatory approval.

Delivery — Suboptimal routes of delivery can hamper delivery to the right tissues (e.g. subretinal delivery to the retina). 4D Molecular Therapeutics uses a robust discovery platform, “Therapeutic Vector Evolution”, to create customized and proprietary gene delivery vehicles (novel AAV vectors) to deliver genes to specific tissues and cells in the body by the optimal route of administration.


Tissue substitutes: Currently most therapies are delivered only to muscle, liver, brain, and eye. An example is the intravitreal delivery of viral vectors instead of commonly used subretinal approaches.

Advanced cells: Modified T cells, mesenchymal stem cells, iPSCs, hemopoietic stem cells, adult progenitor cells.

Cell-based immunotherapies: CART, TCR, NK, TILs, MILs, dendritic vaccines.

Novel delivery vehicles: Viral vectors — Retrovirus, adenovirus, HSV, Vaccinia, AAV; Non-viral vectors — nanoparticles, nanospheres, transposons, electroporation. Alex Marson, an immunologist from UCSF, recently published in Nature, a technique to insert DNA into T cells without using viruses. When certain quantities of T cells, DNA, and the CRISPR “scissors” are mixed together and then exposed to an appropriate electrical field, T cells will take in these elements and integrate specified genetic sequences precisely at the site of a CRISPR-programmed cut in the genome. It has been used to repair a disease-causing mutation in children with a rare autoimmune condition, and to create customized T cells to kill human melanoma cells.

Genome editing: Nucleases — CRISPR/Cas9, ZFNs, TALEN, homologous recombination of AAV derived sequences — CRISPR Therapeutics.

Next-gen expression constructs: novel capsids, synthetic promoters to enhance specificity, strength and capacity, molecular kill switches for safety, temporal regulation or stimulus-induced regulation of gene expression. To control gene expression, design/optimize a promoter; to be environmentally responsive, design/optimize a gene regulatory circuit; to optimize for speed of response, design/optimize protein regulatory circuits.

Synthetic Biology: “Thermostat” to improve specificity and safety — Ability to spatially and temporally tune the therapy for optimal results at the patient level, dynamic dosing using environmentally responsive genetic circuits e.g. MeiraGTx. Opportunity to improve immunogenicity profile, tackle large market polygenic diseases like wet AMD, expand to a variety of indications and organ systems including the microbiome.

Beyond Oncology: Neurological diseases and autoimmune diseases are some of the next frontiers being targeted by cell/gene therapies.

Predictive Tools: Predictive tools for immunogenicity of viral or liposomal delivery systems to design vectors that will evade immune recognition, a better understanding of drug metabolism and decay of persistence in children or in specific organs/tissues, modeling pre-existing and adaptive immune responses to specific therapies.


In 2018, $9.7B was invested in gene therapy and $7.6B in cell therapy development. Currently, there are over 300 therapies in development, over half of them in oncology. This is a fast-growing market with proven clinical success, favorable regulatory tailwinds and increasing investment flowing into the sector. Interesting investment opportunities will emerge in novel delivery mechanisms — cells, viruses, nonviral vectors, tissue substitutes; advances in gene editing and regulation technologies — CRISPR, promoters, molecular kill switches, environmentally responsive regulatory mechanisms; and predictive tools to predict immune response, and persistence of drug levels and efficacy. With autoimmune and neurology already emerging as attractive indications, the market offers the potential for expansion beyond oncology. Investment in infrastructure technologies will be critical to manufacture, commercialize and distribute cell and gene therapies at scale.

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