Targeting microRNA with next-gen AMO to treat Diabetic Foot Ulcers

Efforts to advance wound healing treatments with microRNA technology are being led by Dr. Prabha Sampath from A*STAR Skin Research Labs in Singapore and Celligenics, a Singapore-based spin-off specializing in stem cell-derived regenerative technology.

The partners signed a S$2.1M research agreement in February 2022 to validate the use of miR-198 anti-miRNA oligonucleotides (AMO) for treating diabetic foot ulcers (DFUs) and developing cost-effective wound healing therapies. The idea is to accelerate wound healing and reduce the instance of complications such as amputations.

What are Diabetic Foot Ulcers, and why are they a challenge?

Diabetic Foot Ulcers are chronic wounds that develops in patients with diabetes. The primary reason is that people with diabetes have poor blood circulation, lose sensation in their extremities (feet and lower legs), and eventually wear a ‘hole’ in their foot.

Diabetic patient with non-healing foot ulcer.

Diabetes-related complications are on the rise

By 2045, it is expected that10.2% of the world’s adult population will develop diabetes, and 20% of these patients will develop diabetic foot ulcers. Within 3-5 years, 65% of patients with diabetic foot ulcers return to clinics, and about 20% of these patients eventually require amputation (see cartoon below).

Apart from Diabetic Foot Ulcers, other types of chronic wounds include pressure injuries and venous leg ulcers. Roughly 150,000 Singaporeans are affected annually with chronic wounds, causing a healthcare burden of about S$350M.

Infographic depicting trends in diabetes growth projection and clinical burden.

Our interest in miR-198 anti-miRNA oligonucleotides (AMO) is attributed to its ability to regulate healing in chronic wounds, which are generally difficult and slow to heal, by correcting their pathophysiology into that of normal wounds. Combining this breakthrough technology with our platform technology, with the latter greatly accelerating wound healing, provides us with the potential to develop a formidable combination protocol that will address global chronic wound diseases

Mr. Winston Lumenta, Head of Corporate Development at Celligenics

Current Treatment of DFU

A typical journey for DFU patients begins with a clinical evaluation for diabetic neuropathy (loss of sensation in lower limbs). Patients are further assessed for wound extent, depth, and presence of infection. Standard wound care treatment is provided, including dressing, systemic antibiotics, or therapy with expensive biologics encompassing growth factors to encourage wound closure.

However, clinical statistics paint a grim picture – Within 3-5 years, 65% of patients return to clinics with non-healing wound ulcers at the same or different sites.

Micro RNA and Chronic Wounds – The Science

miRNAs are small non-coding RNAs (~22 nucleotides in length) that bind to messenger RNAs (mRNAs) and regulate gene expression by altering protein synthesis. In other words, they play an important role in our bodies, enabling some activities to go ahead and others to stop. Importantly, aberrant miRNAs are linked to many diseases such as cancer, cardiovascular disease, and immune disorders. Since the discovery of the first functional human miRNA, let-7, in 2000, the race to develop functional and effective miRNA-based therapeutics for various diseases has increased exponentially.

In 2013, Dr. Sampath and her team discovered miR-198, a miRNA that acts as an “On/Off switch” regulating wound healing (Nature Publications).

In healthy, undamaged skin, miR-198 is abundant throughout the epidermis (the outermost skin layer). This miRNA restricts the movement of the epidermal skin cells (keratinocytes) and keeps the skin in its steady-state condition. Upon wounding, miR-198 is rapidly cleared from the epidermis, this event allows new keratinocytes to move across the wound bed and repair the skin. This on/off state can be compared to a seesaw.

In diabetic ulcers, the switch mechanism or “seesaw effect” is impaired, consequently retaining miR-198 in high numbers at the wound edge. This stops the keratinocytes from moving into the wound bed to repair the damaged wound leading to inadequate wound closure and delayed wound healing. (see cartoon below).

Image showing the biology of non-healing wounds (left) in diabetic patients and healing process achieved post-treatment with Anti-miR-198 oligonucleotide (right).

AMOs-198 derived biologics with Celligenics

Dr. Sampath and Celligenics intend to address the unmet demand for a new therapy that efficiently accelerates wound healing using cost-effective formulations. Currently, apart from antibiotics treatments and advanced dressings, few pharmaceutical drugs can be used as these compounds have serious side effects and can even trigger cancer .

Dr. Sampath and her group has developed anti-miR-198 (AMOs-198) that block the action of miR-198 with high specificity, leading to effective keratinocyte migration and wound closure, making it suitable for developing biologics to support wound healing.

AMos mode of action-processed-new-cropped

Biological action of AMOs-198 when applied to non-healing wounds.

How far are we with developing the biologics?

Dr. Sampath and her team have successfully developed the antisense AMOs-198 complex. The efficacy and non-toxicity of this complex have been tested on cell-based models and skin explants from donors. They are currently validating the AMOs-198 on patient skin samples sourced from a local hospital. Upon validation, the team will work with clinicians to conduct clinical trials with AMOs-198 to gather strong evidence for the clinical use of this molecule.

With her domain expertise in the field, Dr. Sampath will drive the collaborative research effort and anticipate the future commercialization of AMOs-198 as a potential innovative wound healing solution that significantly improves the quality-of-life of patients with diabetic foot ulcers.

A*SRL collaborates with public sector, the medical community and industry, and contributes actively to the Skin Research Institute of Singapore (SRIS) - a collaboration between A*STAR, Nanyang Technological University, Singapore, and the National Healthcare Group. SRIS brings together biologists, engineers, and clinicians to tackle clinically important questions in skin research.