SNAs, Immunomodulatory spherical nucleic acids

[ThreeWs]

There are ever new approaches to treating diseases as well as cancers. Here are two items on a radically new "tool" in development that has great potential. Authors claim that by organizing immunomodulatory nucleic acids into SNAs (Spherical Nucleic acids) performance is enhanced by SNA "... rapid cellular uptake, endosomal delivery, and multivalent binding. ... Immunomodulatory nucleic acids act by agonizing or antagonizing endosomal toll-like receptors ... proteins involved in innate immune signaling."

Abstract PNAS pnas.org/content/early/2015...

Researchers at AuraSense Therapeutics have shown that SNAs are potent "drugs" to both dampen or boosting the immune response. Think about not just the cancer side of CLL but the autoimmune component that often accompanies the cancer cells. Other descriptions in this article are inspiring and hope filled.

Lay article with illustrations:

kurzweilai.net/spherical-nu...

WWW

[SeymourB]

Just when I was getting comfortable with the list of animals in the zoo that I know of, you bring up yet another, WWW! I know I can count on you for that!

They've apparently been around since 1997, and are already being used in testing for things like Staph Aureus:

en.wikipedia.org/wiki/Spher...

So this sounds like yet another huge field with great promise - but this one is already delivering a lot. I found this article while searching for their possible use with CLL:

bloodjournal.org/content/bl...

It talks about how specific these SNAs are in targeting particular cell types.

[ThreeWs in reply to SeymourB]

Nice find Seymour, though a very dense read or is it me?

In my own neck of the woods, being at OSU, too. I am headed there on the 5th of April for my 12 week monitoring so I will ask about this if possible.

I was first made aware of TLRs as targets at an LRF Conference in Brooklyn NY in 2009 but the re jiggering to a spherical delivery was not discussed at that time. I have always wondered about the side effects from nanoparticle based therapies. Hard to believe there would not be some.

You realize that all these advances are going to lead to a major epidemic of pre treatment patient decision failure, I've dubbed TAD-too-Complex or Treatment Anxiety Disorder Complex Put da lime in da coconut, drink it all up!

WWW

[SeymourB in reply to ThreeWs]

Yeah, it's dense. A lot of it is poor academic style, and some of it is my lack of education, I'm sure.

evacommentary.org/images_ra...

From what I'm reading from this small sample (N=1), the actual goal of nanoparticles it to reduce side effects. It would seem to be a targeted therapy. I can't imagine any therapy lacking a side effects, but compared to chemo or radiation, it sounds pretty good to me.

I think we all have "TAD" already! It's all part of the medical experience. It starts with a physician or nurse saying "try to relax" before every painful procedure. Does saying that help anyone? Doesn't it become a Pavlovian sort of chant that actual induces anxiety before the procedure begins?

Then, use techno-speak, and high APM (acronyms per minute) increases the anxiety further. A swarm of verbal gnats.

CLL is a classic anxiety disease. How many of us end up on psyche meds after dx? CLL is like an Alfred Hitchcock disease - it keeps you waiting, with occasional, building surprises, followed by long periods of lack of information. The only thing missing is the soundtrack.

I think the lime in the coconut was only effective for bellyaches, and never became mainline therapy for anything else. I think it failed all the phase I trials.

=seymour=

[Cllcanada Top Poster CURE Hero]

You want dense.. here is the patent...

google.ca/patents/WO2009120...

G3139... that tweaked for me...turns out to be Genasense...

fda.gov/ohrms/dockets/ac/06...

A BCL2 inhibitor from the dark ages...

An interesting exercise in not being able to meet FDA approval.

~chris

[SeymourB in reply to Cllcanada]

The patent combines all that is great about legal terminology with that of medical terminology, without actually being pure Latin, and then adds numeric references, and comma separated lists instead of tables, without being an actual computer language. It's truly a dark art to be this obscure in print.

That G3139 is the oligonucleotide, and it sounds like it's what has all the negative side effects when applied alone.

"In the present study, we describe a novel strategy to minimize

the adverse stimulatory side effects of G3139 in CLL B cells using

anti-CD20 Ab (rituximab)–conjugated immunoliposomal nanoparticles

(RIT-INPs)."

So they're binding an anti-CD20 antibody (rituximab) to an INP - Immunoliposomal NanoParticle. This is what makes it more targeted. The rituximab whacks the B-Cells that have CD20, and the INP also downregulates some other CDs that keep the B-Cells from proliferating quickly.

"Both G3139-NPs and G3139-RIT-INPs are spherical nanostructures

(Figure 2B)."

So this is not ye-olde G3139 oligonucleotide, this is the spherical "death star" nucleotide that amplifies its effect.

"The RIT-INPs carrying G3139 were much more effective in Bcl-2 down-regulation than free G3139 (Figure 5A). Accordingly, induction of apoptosis by RIT-INP–G3139 was more potent than free G3139 and HER-INP–G3139 (Figure 5B)."

So I think they're saying that combining ab targeting of CD20 with the death star is what makes this different from past attempts that had more side effects.

Kids, don't try this at home ... these are trained professionals, who really need to do this a few more times before it appears at a cancer center near you:

"Several factors, such as insufficient dosage and duration of Bcl-2 down-regulation, insufficient or variable surface CD20 expression, and the reduced CD20 internalization property, may contribute to limited therapeutic efficacy with RIT-INP–G3139. Detailed pharmacokinetic and

pharmacodynamic evaluation of the RIT-INP–G3139 formulations

is warranted to achieve a reproducible therapeutic outcome."

So this is NOT a magic bullet yet. But it's another test of the prototype Magic Gun - targeted therapy.

[PaulaS Volunteer]

After reading (or trying to read) all the above posts, I am definitely suffering from what WWW helpfully describes as

"pre treatment patient decision failure"

and "TAD-too-Complex" ("Treatment Anxiety Disorder Complex")

So I'll leave the nanoparticle discussions to the experts, and go find a lime to put in that coconut juice...

Paula