Turn Biotechnologies

Turn.Bio is seeking to harness partial cellular reprogramming to reverse age-related epigenetic alterations using transient mRNAs that encode six reprogramming factors. The approach delivers the classical OSKM reprogramming factors, plus two more to facilitate more accurate reprogramming. By using mRNA instead of gene therapy, the company aims to achieve widespread yet transient reprogramming, preserving cell identity while restoring more youthful function.

ERA (Epigenetic Reprogramming of Aging)
Epigenetic alterations — age-related changes to the structures that regulate our gene expression — are one of the proposed reasons we age. In December 2016, researchers from the Salk Institute discovered that the intermittent expression of the four classical reprogramming factors could reverse epigenetic alterations in old mice without fully reversing the developmental clock, thereby reducing the risk of cancer or tumor-like structures.

The Turn states that their proprietary ERA (Epigenetic Reprogramming of Aging) platform allows them to reprogram “specific cells in the body to fight disease or repair damaged tissue.” They are “researching its applicability across multiple therapeutic areas, including dermatologic conditions, immunology, osteoarthritis, and ophthalmology.”

eTurna Delivery System
To realize the potential of mRNA for transient reprogramming required Turn to develop a novel delivery system. The lipid nanoparticles (LNPs) used for mRNA vaccines have a limited dispersion that is suitable for that purpose; however, when delivered in large amounts intravenously, LNPs have a strong tendency to concentrate in the liver. Consequently, they are ill-suited for large-scale delivery elsewhere in the body. The standard solution to this problem is to stabilize the LNPs with polyethylene glycol (PEGylated) lipids, but those tend to provoke an immune reaction.

In January 2024, the company announced that it had overcome these hurdles with a novel LNP system that they call eTurna. In addition to being nontoxic and biodegradable and thus safer than many alternatives, eTurna’s proprietary ionizable lipid stabilizes the LNPs and — combined with their smaller particle size — enables higher transfection rates than previous systems.

In a previous press release, the company announced that eTurna could “precisely reach in vivo dermal fibroblasts with an mRNA formulation. The eTurna-delivered formulation remained localized in the injection site and did not distribute to other organs.”

In the January 2024 press release, Turn also claims that eTurna directs the release of LNPs to specific tissue environments “and can be optimized for other cargoes and various routes of administration to target specific organs, tissues, and cells,” but it is not clear how robustly supported this claim is. The press release gives data on delivery to skin cells and T-cells ex vivo, which is logical, as the company has indicated that their initial targets will be dermatological and immunological. However, there are no data presented for specificity for “fibroblasts, endothelial cells, and keratinocytes.” nor for other cell types beyond the skin and T-cells, nor for systemic delivery or a model of competition between a target and non-target cell type.

TRN-001
TRN-001 is Turn’s candidate reprogramming therapeutic to rejuvenate the skin, improving its integrity, reducing inflammation and cellular senescence, and transfecting hair follicles. Some initial data on targeting the skin wth eTurna and ERA was discussed above. Turn is developing TRN-001 to both address medical needs (such as wound healing) and for aesthetic medical applications (such as to treat wrinkles, rough and dry skin, hair loss, greying hair, scars, and sun damage).

In October 2023, Turn announced that they had received positive feedback from FDA on their progress and plans for TRN-001 during an Initial Targeted Engagement for Regulatory Advice on CBER producTs (INTERACT) meeting.

In addition to TRN-001 for “skin rejuvenation,” Turn’s pipeline page lists TRN-006 for skin wounds, TRN-007 for hair, and TRN-008 for eyelash growth.

TRN-010
TRN-010 is a reprogramming system to enhance the effects of CAR-T therapies. By reprogramming patients’ T-cells into a more youthful state, Turn proposes that TRN-010 will prevent T-cell exhaustion and enhance their cytotoxic effects while potentially reducing costs. They state that their preclinical data show that TRN-010 treatment can increase T-cell proliferation and cytotoxicity against cancer cells by up to fivefold.

TRN-002
TRN-002 is a reprogramming system designed to restore the protective cartilage in aging and injured joints, enabling people to resume full lives, free from pain from osteoarthritis and injury. In preclinical studies (it is unclear whether these are in vitro or in vivo models), Turn states that “TRN-002 reduces oxidative stress and inflammation and improves the cell division cycle.”

TRN-003
TRN-003 is a reprogramming combination intended to treat glaucoma; Turn does not appear to have made further details available.

TRN-004
TRN-004 “is a formulation to rejuvenate ocular tissues, including corneal, limbus, and conjunctival epithelial cells and corneal endothelial cells. Preclinical results show TRN-004 reduces inflammation and oxidative stress and reduces cell senescence.”

The relationship between TRN-003 and 004 and Turn’s licensing agreement with HanAll (below) is unclear.

TRN-005
TRN-005 is a reprogramming formulation intended to treat muscle injuries, muscle atrophy, frailty, and sarcopenia (age-related loss of muscle mass and strength). According to the company, “Preclinical results demonstrate improvement in stem cell growth and differentiation, acceleration of muscle recovery, increases in fiber thickness and force output. And, what is particularly promising, TRN-005-treated muscles appear to be more resistant to later injuries.”

Licensing Agreement for Eye and Ear Diseases with HanAll Biopharma
In May 2024, Turn announced that it had signed a licensing agreement with Korea’s HanAll Biopharma to utilize ERA technology for ophthalmic and otic diseases. HanAll is a Korean biopharmaceutical company with long experience in the endocrine, circulatory, and urologic spaces. This agreement built on a previous 2022 investment in Turn by HanAll Bio.