A. C. Matin

Stanford School of Medicine, California

Title: mRNA-based systemically delivered directed gene therapy using nanomaterials

---

Biography

Dr. Matin has been a full professor in Stanford Medical School for several years and is affiliated

with several programs, including the Stanford Cancer Research Institute; he elected to become

emeritus, July 1, ‘21. His research contributions are numerous, including discovery of new drugs,

therapeutic enzymes, and their improvement as well as their specific targeting to cancer (and other

diseases). He did his Ph. D. at UCLA, spent some years in the Netherlands (State University of

Groningen), where he directed a research group, before joining Stanford. He is recipient of

numerous awards and honors

Abstract

The presentation focuses on systemically administered targeted gene therapy using mRNA

instead of DNA; why the former is superior for this purpose will be discussed. Lipid nanoparticles

(LNPs) and, more recently, extracellular vesicles (EVs, aka exosomes) have proven effective

vectors. An example of LNP-mediated directed mRNA delivery is that of Cas9 gene for editing of

PTEN by the CRISPR/Cas system. Also, an mRNA-LNP drug, NTLA-2001, is in clinical trial for

treating transthyretin amyloidosis. EVs are nature’s own antigen delivery system, posing minimal

immunogenicity/toxicity risk and their surface integrins confer intrinsic tissue tropism. They have

been engineered to display targeting moieties, which are fused to EV anchor domains. Emphasis

here will be on the lactadherin C1-C2 anchor domain (which binds to the EV surface) and its fusion

to a high affinity anti-HER2 scFv, resulting in HER2 receptor targeting EVs. These were loaded

with mRNA that encodes the enzyme HChrR6, which can activate several prodrugs, including

CNOB and CB1954 (tretazicar). (The loaded and targeted EVs are called ‘EXODEPTs’.) Systemic

delivery of EXODEPTs along with either CNOB or tretazicar resulted in the killing of HER2+ breast

cancer xenografts in mice without any off-target effects, indicating gene delivery exclusively to

the cancer. Attaining specific tumor targeting and loading of the EVs with the HChrR6 mRNA were

greatly facilitated by the fact that the activated drug of CNOB, MCHB, is highly fluorescent and

can be visualized non-invasively in living mice. Tretazicar (whose activation could also be

visualized vicariously by MCHB) was effective at its safe dose; the EVs needed to be delivered

only twice; and there were no side effects. Thus, the results augment clinical transfer potential

of this regimen. Examples of EV targeting using other anchor proteins, e.g., Lamp2b and CD47,

will also be briefly discussed. As the EV anchor domains can be fused to other targeting moieties,

the approach is generic for specific gene delivery also in other diseases.