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There have been various research projects that experimented with shRNA/miRNA/siRNA to specifically silence/knockdown NaV1.7 voltage gated sodium channels in small animals like rats & guinea pigs. (Example; my previous question: Is HSV-vector-mediated miRNA expression in dorsal root ganglia stable?

But I can't find any that's been done for humans... So I think it means scientists have not gotten to that stage (if they are interested in doing so), and I was wondering,

  • technically, how difficult do you think it is to make a shRNA/miRNA/siRNA that can silence/knockdown NaV1.7 in humans, given that they already know how to make it for NaV1.7 in small animals?
  • financially, how much money is needed to invent such a thing (and how hard to get a grant for it?)
  • if technically not too difficult, and not very expensive to invent just a sample, is this something not necessarily a professional researcher, but a student could try making as their research project?
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  • $\begingroup$ Why should any ethics comittee approve such experiments in humans? $\endgroup$ – Chris Jan 20 '16 at 16:35
  • $\begingroup$ Because especially when it is a partial silencing/knockdown, people who are suffering from pain after failed pain therapies or people with pain disorders can benefit from it, I think $\endgroup$ – pewiwe Jan 20 '16 at 16:58
  • $\begingroup$ What about potential negative side effects? Life is usually more complex than people think. $\endgroup$ – Chris Jan 20 '16 at 17:12
  • $\begingroup$ That's true, there could be side effects, although no serious ones seem to have been reported so far (but only in animals...). $\endgroup$ – pewiwe Jan 20 '16 at 20:41
  • $\begingroup$ Knockdown experiments in humans are almost always carried out on cell lines. In fact, I am doing a few such experiments myself at the moment (using U6 promoter expressed shRNAs introduced by lentiviruses). Doing it on humans would be extremely problematic for ethics committees due to the host of possible side effects. $\endgroup$ – March Ho Jan 24 '16 at 23:39
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The major hurdle for novel treatments to make it into humans is the assessment of its merits and added value over existing, proven treatments. And more importantly, the safety for humans has to be validated to a sufficient extent. The notorious from bench to bedside (Goldblatt & Lee, 2010) bottle neck. To answer your questions:

  • Technically, going from animals to humans may be a small step. Just increase the dose according to body weight. However, ethically it is a giant step. In fundamental research, lab animals are typically investigated only for the positive effects (e.g., amelioration of symptoms). In preclinical research, the animals have to be tested on side effects. Systemic injections, and even localized administration of potentially harmful virus vectors carries considerable risk. What if it returns to an infectious state? What are the side effects? Further, while animals can be treated systemically via iv injections, humans don't like needles. The FDA will put every possible danger and every possible discomfort to the patient into the spotlight.
  • Getting grants is hard. Going from bench to bedside is even harder, as the FDA, institutional review boards and the scientific community at large will scrutinize the plans.
  • To undertake clinical trials with humans is a team effort involving medical professionals, review boards, patients or healthy volunteers, an independent monitoring committee and so forth. It's not something you'll be doing in a few months. It can take years or decades to bring novel treatments to patients. It doesn't take one grant - it takes many, and development costs easily run into the tens of millions.

Reference
- Goldblatt & Lee, Am J Transl Res (2010); 2(1): 1–18

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  • $\begingroup$ @pewiwe - If you appreciate the answer, an upvote can help to show others that it's a useful answer. Thank-you comments are great, but SE works with a voting system. Thanks! $\endgroup$ – AliceD Jan 21 '16 at 23:02
  • $\begingroup$ Aw sorry i can't seem to upvote it because I registered as a guest :( $\endgroup$ – pewiwe Jan 22 '16 at 20:28
  • $\begingroup$ @pewiwe - perhaps consider converting to a real account? $\endgroup$ – AliceD Jan 22 '16 at 23:41

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