Possible Gene Therapy For Regrowing Human Limbs, This Salamander Gene Could Hold the Key

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A gene shared by salamanders, zebrafish and mice could point toward a new path for regenerative medicine: researchers have identified key genetic programs involved in regrowth and used them to partially restore digit regeneration in mice. The findings do not bring human limb regeneration within immediate reach, but they offer a promising proof of principle for future gene-based therapies.

Investigating a common gene in three very different species — axolotls, mice and zebrafish — scientists have discovered the potential for a novel gene therapy aimed at eventually regrowing limbs in humans, according to new research published this week.

“This significant research brought together three labs, working across three organisms to compare regeneration,” said Wake Forest Assistant Professor of Biology Josh Currie, whose lab studies the Mexican axolotl salamander. “It showed us that there are universal, unifying genetic programs that are driving regeneration in very different types of organisms, salamanders, zebrafish and mice.”

The research, with results appearing in the Proceedings of the National Academy of Sciences, included David A. Brown, a plastic surgeon who studies digit regeneration in mice at Duke University, and Kenneth D. Poss, who studies fin regeneration in zebrafish at the University of Wisconsin-Madison.

Each year, around the world, more than 1 million limb amputations occur because of vascular diseases such as diabetes, traumatic injuries, cancer or infections, according to annual Global Burden of Disease statistics. The number is expected to rise with the aging population and the increase in diabetes diagnoses.

That looming challenge has inspired Brown, Currie and Poss to search for a treatment beyond prosthetics, for something that could replace the complex senses and motor skills of an actual limb.

They might have found the start of a solution in something called SP genes, which the scientists discovered are vital for limb regeneration and shared by the mouse, zebrafish and axolotl.

Therapy Makes up for Missing Gene

The scientists chose to study these three animals for specific reasons:

The axolotl excels at regeneration, with the ability to regrow complete limbs; tails, including the spinal cord; parts of the heart, brain, liver, lungs and jaw.

Zebrafish offer one of the best models for appendage regeneration because their tail fins regrow rapidly and have unlimited capacity for regrowth. The zebrafish also can regenerate its heart, spinal cord, brain, retinas, kidneys and pancreas.

Mice represent mammals like humans, and they already can regenerate the tips of their digits. Humans, too, can regrow their fingertips when an injury preserves the nailbed. That allows regrowth of flesh, skin and bone.

Currie said that once the scientists determined the regenerating epidermis, or skin, of all three species expressed the SP genes SP6 and SP8, they set out to test what the genes do and how they work.

Biology Ph.D. student Tim Curtis Jr. contributed to the research in the Currie lab, with assistance from undergraduate Elena Singer-Freeman, a Goldwater Scholar and 2025 Wake Forest biochemistry and molecular biology graduate.

Emulating the Abilities of Salamander Genes

In salamanders, SP8 does the work in regenerating limbs. Using CRISPR gene-editing technology, Currie’s lab removed SP8 from the axolotl genome. Without SP8, the axolotl could not properly regenerate the limb bones; a similar result occurred with the mouse digits missing SP6 and SP8.

With that information in hand, Brown’s lab used a tissue regeneration enhancer found in zebrafish to develop a viral gene therapy.

That therapy delivered a secreted molecule called FGF8, a gene that is usually turned on by SP8, to encourage digit bone regrowth and partially restore the regenerative effects of the missing SP genes in mice.

Human limbs don’t have that kind of regenerative power — but might someday, with a therapy that emulates the abilities of SP genes.

“We can use this as a kind of proof of principle that we might be able to deliver therapies to substitute for this regenerative style of epidermis in regrowing tissue in humans,” Currie explained.

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Building the Foundation for Human Therapies

Although it will require much more research to take the findings from mouse digits to human limbs, Currie called this study foundational in the search for therapies to regrow limbs after injury or disease.

“Scientists are pursuing many solutions for replacing limbs, including bioengineered scaffolds and stem cell therapies,” Currie explained. “The gene-therapy approach in this study is a new avenue that can complement and potentially augment what will surely be a multi-disciplinary solution to one day regenerate human limbs.”

He said the decision to collaborate among scientists studying such different animals made all the difference in this research.

“Many times, scientists work in their silos: we're just working in axolotl, or we're just working in mouse, or just working in fish,” Currie said. “A real standout feature of this research is that we work across all these different organisms. That is really powerful, and it's something that I hope we'll see more of in the field.”

Original Article: Enhancer-directed gene delivery for digit regeneration based on conserved epidermal factors; Proceedings of the National Academy of Sciences; DOI:10.1073/pnas.2532804123

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