Journal Club, Next Meeting October 26th

Journal Club this semester will be interesting. We will explore a Nature Proceedings paper about aptamer diagnostics that hasn't been peer reviewed and ask why, a review article about aptamer therapeutics that details many of the current and future problems associated with utilizing aptamers as drugs, and a Nature Biotechnology Letter about the selection of antibodies that is short but has a punch. Each of these are wildly different published presentation mediums so I would like to discuss how they are similar and different. Each paper discusses an important aspect of aptamer utility so I hope that we can also use these papers to spring board a discussion of how others are using aptamers. We will explore one main paper each month with some supporting documents.

For the first week, I would like to start off with a review of using aptamers as therapeutics since most of your projects deal with this in some way. The review includes a comparison of aptamers to antibodies. There are two main Aptamer companies that hold much of the intellectual property involved with nucleic acid aptamer technologies:
  • SomaLogic, lead by Larry Gold, formerly CEO of NeXstar, is headquartered in Boulder, Colorado and is the main aptamer diagnostics company. Dr. Gold also co-authored the "other" original aptamer paper with Craig Tuerk and is the lead author on one of the papers we will read this semester.
  • Archemix, currently lead by Ken Bate, started around the turn of the century (2000-ish) by Marty Stanton, David Epstein, Andy and Ron Breaker. Anthony Keefe is currently the senior director at X-chem, but was a senior PI at Archemix prior to this and is the first author of the review we will read this month.
Here is the reference for the paper for Journal Club September 28th:

Keefe et al. Aptamers as therapeutics. Nature Reviews Drug Discovery (2010) vol. 9 (7) pp. 537-50. You can find the PDF here.

When reading reviews, I first read the title/abstract and then make an outline of the review with the main headings, subheadings and figure/descriptions. Please start by doing this and then work your way through the review. Skip over the "Aptamers in the Clinic" section during your first read through. I will try to get one of the authors, Supriya Pai, to join us during lecture so think up some good questions for her also.

Some initial questions:
  1. Name some advantages/limitations of aptamers and antibodies. Do you feel one is superior than the other for therapeutics or are they each suited for particular tasks? Explain.
  2. What is a Spiegelmer and how can it prevent nuclease degradation? What other aptamer modifications can prevent degradation? Is this more important for therapeutics than diagnostics? Explain
  3. What is meant by pharmacokinetics and why should drug designers be concerned with therapeutic potency in vivo? You may need to look this word up elsewhere and see how it applies in the review.

Here is the reference for the paper for Journal Club October 26th:

Reddy et al. Monoclonal antibodies isolated without screening by analyzing the variable-gene repertoire of plasma cells. Nature Biotechnology (2010) vol. 28 pp. 965-969. You can find the PDF here.

Nature Biotechnology is probably my favorite journal and one of the reasons I'm having you read an article published therein. When reading a letter, appreciate that the authors published fast with only some preliminary ground breaking data. The work was done in 2009/early 2010 and the manuscript was received June 11. It is now in publication (less than a year). This is a short paper with only 2 figures and a table. Since it is short, I also want you to look over the Supplemental Data as the authors discuss this data. Again, it is another one partially out of the Ellington Lab. Due to this, I hope to have one of the authors come (in addition to Dr. Supriya Pai from last month).

When reading this article I want you to delve into more than just the data, focus on these questions:
  1. How is this article different from the review?
  2. What is the scope of this Journal or why did the authors choose this journal to publish in? Can you think of any other journals that may be appropriate (based on other journals referenced in the bibliography).
  3. How do you think the authors chose to put certain information in the supplemental? Why do you think they did this? (hint, check out the author guidelines for letters - found on page 3).
  4. Is there supplemental data that should have been included in the main article or vise versa? WhFind the limitations for
  5. What does it mean for the future of aptamers?
  6. How can these methods be easier or harder than selecting aptamers?
  7. Are the figures visually appealing?


Gwen Stovall said...

More questions ...
1. What properties do we want in a therapeutic aptamer?

2. What's IC50 or EC90? Does that relate to the Kd (dissociation constant)?

3. NOX-A12 drug was developed by selecting regular D-RNA against mirror-image target (D-amino acids). Then, the aptamers were resynthesized as L-RNA in order to bind the wildtype target (L-amino acid). How do you synthesize a protein with D-amino acids? Is this feasible for us?

4. What is meant by "avidity effects" (2nd to last paragraph on page 546)?

Nia_Fernandez said...

is journal club during class times? if so, can i give you my questions before hand, I know the students will have their own but just in case?

Brad Hall said...

Just post your questions to this comment list. I will compile them all. Journal club isn't till later this month though.

Mayank Aranke said...

I no longer have access to the article. I skimmed over it about a week ago, but it's requiring me to pay $32 to read it. Any way around this?

Brad Hall said...

Were you off campus when trying to access it? I think I posted the PDF on blackboard. But I cannot repose the article here on the APS due to copywrite restrictions. Just get it when on campus (when it opens back up).

Mayank Aranke said...

Ah, that would explain it! I'll get it tomorrow morning then. Thanks!

Mayank Aranke said...

Some questions:

1. What are the benefits/limitations of using a DNA oligonucleotide versus a RNA one, and vice versa?

2. What are some examples of an agonist aptamer? From my understanding, most of the ones we work with/develop are antagonists for a certain protein/pathway?

3. Is the benefit associated with Spiegelmers, decreased nuclease activity, worth the limitation of having a very limited protein domain?

4. Does modifying aptamers lead to increased reactivity as well as decreased nuclease activity?