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Reprogramming Skin Cells in situ as an Approach to Delivery of Cell Therapy

Researchers recently presented an interesting and novel approach to cell therapy based on reprogramming patient cells. The normal methodology involves taking a cell sample, then reprogramming and culturing the desired cells, and returning them to the body. In this case the process is inverted: a device capable of delivering reprogramming factors into cells via electroporation is touched to the skin, and triggered. Some of the reprogrammed cells then migrate to enhance regeneration in nearby tissues. This is probably not applicable to all or even a sizable fraction of the potential uses of cell therapy, but the researchers have found a few applications that seem to work well enough to justify further development of this approach.

Researchers have developed a new technology, tissue nanotransfection (TNT), that can generate any cell type of interest for treatment within the patient's own body. This technology may be used to repair injured tissue or restore function of aging tissue, including organs, blood vessels and nerve cells. "By using our novel nanochip technology, injured or compromised organs can be replaced. We have shown that skin is a fertile land where we can grow the elements of any organ that is declining."

Researchers studied mice and pigs in these experiments. In the study, researchers were able to reprogram skin cells to become vascular cells in badly injured legs that lacked blood flow. Within one week, active blood vessels appeared in the injured leg, and by the second week, the leg was saved. In lab tests, this technology was also shown to reprogram skin cells in the live body into nerve cells that were injected into brain-injured mice to help them recover from stroke. "This is difficult to imagine, but it is achievable, successfully working about 98 percent of the time. With this technology, we can convert skin cells into elements of any organ with just one touch. This process only takes less than a second and is non-invasive, and then you're off. The chip does not stay with you after the reprogramming of the cell starts. Our technology keeps the cells in the body under immune surveillance, so immune suppression is not necessary."

TNT technology has two major components: First is a nanotechnology-based chip designed to deliver cargo to adult cells in the live body. Second is the design of specific biological cargo for cell conversion. This cargo, when delivered using the chip, converts an adult cell from one type to another. TNT doesn't require any laboratory-based procedures and may be implemented at the point of care. The procedure is also non-invasive. The cargo is delivered by zapping the device with a small electrical charge that's barely felt by the patient. "The concept is very simple. As a matter of fact, we were even surprised that it worked so well. In my lab, we have ongoing research trying to understand the mechanism and do even better. So, this is the beginning, more to come."

Link: https://wexnermedical.osu.edu/mediaroom/pressreleaselisting/researchers-develop-regenerative-medicine-breakthrough

Comments

Looks like the real advance here is an improvement in electroporation:

"Bulk electroporation renders the entire cell membrane permeable and impacts on the cytoskeleton, which subdues the plasticity of the cell. In contrast, TNT creates a series of tiny channels, which affects just 2% of the cell membrane surface area and doesn't inhibit cell plasticity. Using [Topical Tissue Nano-Transfection], we have achieved greater than 98% transfection efficiency and cell transformation."

This does answer the question of why up till gene therapies designed to produce a cell secreted protein or signalling molecule haven't been performed via electroportation of the skin. On the other hand, couldn't they just have done more treatments with less effective past electroporation technology?

Posted by: Jim at August 8th, 2017 7:30 AM

Any in vivo reprogramming is to be welcomed, given the problems doing this in vitro and then returning the cells to the body. Will be interesting to see if Nano-Transfection can be done elsewhere in the body and not just rely on newly reprogrammed cells making there own way to where they need to be from the skin.

I think you answered your own question Jim, unless it's done on the nanoscale, electroporation disrupts the cell membrane too much to allow de-differentiation.

Posted by: Mark at August 8th, 2017 9:31 AM

@mark - yeah I didn't word that very well. This new electroporation is superior to the old sort for transforming cells.

I meant to ask "How come electroporation hasn't been used to turn skin cells into drug factories?". For example Liz Parish of BioViva got follistatin gene therapy, but used a viral delivery system. Electroporation sounds cheaper and easier, so how come it is not in use? If it is lower efficiency, then just do it on a few more sites on the body until a therapeutic dose is reached.

Whatever the reason behind electroporation not being used in the past, will this new tech enable it?

As an aside, the guy behind Butterfly Biosciences performed electroportation on himself:

https://bf-sci.com/?page_id=341
https://www.technologyreview.com/s/603217/one-mans-quest-to-hack-his-own-genes/

Posted by: Jim at August 8th, 2017 10:03 AM

It would seem to me easier and and of much greater $ market value to convert skin cells into more youthful skin cells.

Posted by: JohnD at August 9th, 2017 6:04 PM

@Jim
Because people don't just do gene therapy on themselves in general.
Only the crazy few.

As for the efficiency, the paper was talking of numbers in the range of 98% which is multitudes better than any viral vector.

The viral vector can travel inside though, with this you would need to turn it into a capsule you inject or implant into the body if you want to affect an internal organ.

Posted by: Anonymoose at August 9th, 2017 10:47 PM

After doing a bit more googling I see that electroporation as a gene delivery method is under development by a few companies, it just hasn't finished clinical trials and reached the market yet:

http://www.inovio.com/technology/electroporation-delivery/
http://www.inovio.com/technology/dna-monoclonal-antibodies/

@JohnD - You're probably thinking of applying the Yamanaka factors to 'rejuvenate' the skin cells. I'd speculate that from a SENS damage perspective you could use this electroporation to deliver enzymes to clean up hardly lysosomal wastes in the skin cells. Sure this would only work for the skin, but the skin is the largest organ in the body.

Posted by: Jim at August 10th, 2017 5:17 AM

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