Hacker News Reader

Comment by mediaman | Hacker News Reader

There are two companies that have demonstrated cures to the Ebola and Marburg viruses: Tekmira, based in Vancouver BC, and Sarepta, in Boston. Initial data shows that they have 85%-100% cure rates receiving the medicine up to 72hrs from initial exposure, as tested on monkeys.

Unfortunately a portion of this research was funded by the DoD, which decided to cut funding in 2012 at least for the Sarepta Marburg cure, which significantly slowed down progress and prevented any stockpiling of the medicine.

View on HN

Please use caution when interpreting preclinical drug results. Yes, Tekmira saw great efficacy in non-human primates, but that doesn't necessarily translate into human efficacy. Tekmira focuses on RNAi therapeutics (a field in which I spent time on the research side in industry). Many RNAi companies have fallen from grace in recent years due to liver toxicity associated with lipid nanoparticle (LNP) siRNA delivery vehicles. Tekmira was a pioneer in lipid delivery, and they use an LNP vehicle in their TKM-Ebola therapy. I'm sure the siRNA they use is wonderful, with great knockdown and durability, but in this space it is the delivery vehicle forming the bottleneck. Disclaimers aside, Tekmira initiated a PhI trial of Ebola-TKM this past January and it will be interesting to see how the toxicity plays out.

I know very little about LNP delivery -- what's the cause of the toxicity?

As I understand it, the toxicity is caused by the implementation of the LNP delivery system, rather than a factor inherent to LNP delivery in general. As there are LNP systems that have proven to effectively deliver to target.

Basically, this LNP delivery system is for encapsulating a desired portion of RNA within a 'shell'[+], so that it may be delivered to a biological target.

The shell is necessary because siRNA is anionic and hydrophilic (negatively charged and water loving/binding.) Which makes it difficult to deliver to targets. It is also unstable in serum (component of blood) and can have unintended side effects if delivered to the wrong target.

There have been attempts to engineer custom siRNA directly. These attempts have resulted in siRNA that cause fewer unintended side effects and have higher stability. However, this method still requires high dosage in vivo and the effects are limited to the liver.

The more promising approach involves wrapping the siRNA in a lipid 'shell'. The 'shell' is inserted into the biological system and travels through the bloodstream to the target area.

The two underlying causes of toxicity (in some LNP delivery implementations) seem to be: the charge of the LNP system and the 'dosage' of the LNP delivery system.

Recent research has shown that it is possible to engineer these 'shells' in such a fashion that they can carry the siRNA safely to target, mitigate the undesirable surface charge, and require relatively low dosage.

Specifically, they have developed ionizable cationic lipids with pKa below 7 to encapsulate the 'package' at a low pH, while maintaining a relatively neutral surface charge at physiological pH. Also, the delivery 'package' itself is made much smaller.

([+] Lipid Nanoparticle delivery is a means of biological/in-solution transport for small matter in general, in this case it is specifically a means of delivering small interface RNA, siRNA, within a biological system.)

Disclaimer: I'm not an expert, but I do have experience in a somewhat related field. This is a high level explanation and it's possible that my explanation handwaves or is mistaken in some aspect.

These papers do a better job of explaining it than I can:

http://www.ncbi.nlm.nih.gov/pubmed/21179008

http://www.liposomes.ca/publications/311%20Wan%20et%20al%202...

So if the US DoD doesn't fund medical research, not a single other organization or country does? If that is the case, then turning DoD funding back on does not seem like a sustainable plan.

What is the response from the EU's member states (who's medical systems are often touted as superior)? After all, they're much closer to this than we are.

I don't know the answer to your question of whether other countries fund development of Marburg or Ebola treatments.

I believe at the time the DoD funded it out of pure national self-interest: regardless of geographic proximity, just one infected person on the wrong flight could present a massive national security risk.

To be fair the DoD did continue funding Ebola cures with Tekmira, and Tekmira earlier this year began dosing of the first human patient. That patient is healthy and the dosing is to test the safety profile of the drug. Reportedly the WHO has not requested any emergency supplies of Tekmira's drug yet.

The DoD funded it because they're worried about weaponized Ebola and Marburg. Given that the DoD is in the middle of a budget crunch, it's believable that they'd cut funding for defense programs against less-likely military threats.

Superior medical systems != superior medical research

When you talk about sustainable plans here, it's all about relative stability. Sure the DOD might not be a completely sustainable way to fund this research, but I would certainly vote to turn it back on given the alternative being zero funding. You could make the argument that something like the Gates Foundation might be better, but I don't think it's obviously better in all areas than the DOD.

The DoD is by far the largest, wealthiest, and most powerful institution on the planet when it comes to the broad range of things it's involved in.

Saying DoD attention and funding for something is 'unsustainable' is sort of like saying the efforts of our planet to solve some problem are not sustainable.

The US is solely responsible for, to my understanding, most of the breakthrough pathology research in the past hundred years or so. No indication that is going to change. At least it's a hell of a legacy to leave.

Please do correct me if I am wrong. I am no expert in pathology.

We have a lot of other medical research entities in the US (NIH, CDC, a bunch of top universities, private pharma...), and I think the DOD is probably responsible for very few of the breakthroughs of the past 100 years.

I'm not sure about the record of foreign governments, universities, companies, and other researchers, but I suspect the US is by far the biggest, but not the only. Just in the commercial world there are a lot of really excellent pharma and biotech companies outside the US - GSK, Roche, Bayer, Novartis, ...

Reply on news.ycombinator.com