What is hot in multi-billion dollar RNAi, Gene therapy and CAR-T biotech?

There were two biotech buyouts this week. Celgene bought CAR-T player Juno Therapeutics for $9 billion and Sanofi buying blood disorder biotech Bioverativ for $11 billion.

Kite Pharmaceuticals, CAR-T company, got acquired late in 2017 by Gilead for $12 billion. Both Juno and Kite had been billed as CAR-T platform play.

CAR-T acquisitions provide near-term revenue growth.

It would take about $3 billion for Editas, Sangamo, and CRISPR in genome editing or Arrowhead and Dicerna in RNAi to be acquired at this time.

What is CAR-T? A cure for many types of cancer

Chimeric antigen receptors (CARs, also known as chimeric immunoreceptors, chimeric T cell receptors, artificial T cell receptors or CAR-T) are engineered receptors which graft an arbitrary specificity onto an immune effector cell (T cell). Typically, these receptors are used to graft the specificity of a monoclonal antibody onto a T cell, with transfer of their coding sequence facilitated by retroviral vectors. The receptors are called chimeric because they are composed of parts from different sources.

A CAR therapy for cancer, using a technique called adoptive cell transfer, has been approved by the US Food and Drug Administration for use against acute lymphoblastic leukemia. T cells are removed from a patient and modified so that they express receptors specific to the patient’s particular cancer. The T cells, which can then recognize and kill the cancer cells, are reintroduced into the patient. Modification of T-cells sourced from donors other than the patient are also under investigation.

Gene Silencing RNA-i could cure many diseases

The gene-silencing strategy, in the form of RNA interference, has shown promise against an uncommon neurodegenerative disease called hereditary ATTR amyloidosis.

There are several gene-silencing drugs in late-stage development and dozens of companies working in the space—and it feels like we could be close to a tipping point.

Several companies talk about RNAi platforms that will allow a rapid proliferation of treatments by just adjusting the targeting.

New Modular RNAi research

Previous studies have identified relevant genes and signaling pathways that are hampered in human disorders as potential candidates for therapeutics. Developing nucleic acid-based tools to manipulate gene expression, such as short interfering RNAs (siRNAs), opens up opportunities for personalized medicine. Yet, although major progress has been made in developing siRNA targeted delivery carriers, mainly by utilizing monoclonal antibodies (mAbs) for targeting their clinical translation has not occurred. This is in part because of the massive development and production requirements and the high batch-to-batch variability of current technologies, which rely on chemical conjugation. Here we present a self-assembled modular platform that enables the construction of a theoretically unlimited repertoire of siRNA targeted carriers. The self-assembly of the platform is based on a membrane-anchored lipoprotein that is incorporated into siRNA-loaded lipid nanoparticles that interact with the antibody crystallizable fragment (Fc) domain. We show that a simple switch of eight different mAbs redirects the specific uptake of siRNAs by diverse leukocyte subsets in vivo. The therapeutic potential of the platform is demonstrated in an inflammatory bowel disease model by targeting colon macrophages to reduce inflammatory symptoms, and in a Mantle Cell Lymphoma xenograft model by targeting cancer cells to induce cell death and improve survival. This modular delivery platform represents a milestone in the development of precision medicine.

Nature Nanotechnology – A modular platform for targeted RNAi therapeutics

13 pages of supplemental material

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