The Road to Regeneration
Could regenerative peptide therapy pave the way for new treatment methods for severe dry eye?
Maria Chen, Haishan Jang | | 5 min read | Review
Severe dry eye disease (DED) affects the productivity and quality of life of millions of people. Prompted by the prevalence of this chronic condition, many pharmaceutical companies have set out in search of more robust treatments. Solutions have thus far been elusive but, with new advances in regenerative peptide therapy, researchers are poised to provide more reliable and affordable treatment options. This new class of treatments may have the potential to offer patients full relief of all symptoms within the next decade.
DED is becoming increasingly prevalent. In 2020, there were an estimated 1.52 billion cases worldwide; after the COVID-19 pandemic, which led to more people spending prolonged time in front of screens (a risk factor for the disease), this number is even higher. Other risk factors include aging, eye surgeries, dry environments, long-term contact lens use, and autoimmune diseases.
The condition results from various defects affecting proper tear production and the composition of the tear film. These include decreases in both tear volume and mucin production, and the dysfunction of the meibomian glands. Without normal tear lubrication of the corneal surface, corneal damage can occur, leading to noninfectious inflammation and further damaging the corneal surface via lymphocyte infiltration and proinflammatory cytokines. This vicious cycle worsens DED and impairs a patient’s quality of life.
DED currently has no cure and requires continual disease management. Patients and their clinicians urgently need more effective therapies.
A bumpy road to speed up healing
Current DED treatments are effective in patients with milder symptoms. Artificial tears with demulcents can retain surface moisture and immune modulators can help control inflammation, allowing the body’s natural healing processes to repair damage. However, in moderate to severe cases, such treatments are often insufficient to control discomfort unless they can be combined with acceleration of the healing process.
The vast potential of regenerative medicines
There are several ways to apply regenerative medicine for DED. For some rare, severe cases with corneal ulcers or perforations, surgery may be needed to graft autologous or allogeneic limbal stem cells to the site or cover the cornea with amniotic membrane (1,2). In other cases that can’t be helped by artificial tears or anti-inflammatory agents, autologous serum eye drops and platelet-rich plasma are gaining popularity (3,4). Recent reports have also indicated that corneal epithelial stem cell-derived eye drops can be effective (5). But even though these treatments have shown some efficacy in small scale clinical studies, they are expensive and often lack consistency.
Instead of using stem cells or their derivatives directly as treatments, another approach is to stimulate the endogenous stem cells to promote regeneration and repair. However, trials using different growth factors to treat DED more often than not led to dead ends because of systemic side effects (including kidney disease) and concerns of oncogenic effects with long-term usage.
The need for a cost-effective and robust therapy for severe DED remains.
A new approach
Regenerative peptides hold great promise for stimulating local stem cells without undesirable safety concerns. Compared to full-size proteins, peptides better penetrate tissues to reach local stem cells, especially for topical applications. Peptides also limit systemic exposure, which reduces unwanted side effects. Additionally, because short peptides can usually be synthesized chemically, manufacturing costs are likely to be much lower than for therapies that rely on growth factors or stem cells. With better long-acting and slow-release formulation technologies, regenerative peptides have the potential to become an ideal new class of therapies in DED treatment.
At BRIM Biotechnology, we have developed BRM421, a regenerative peptide for moderate-to-severe DED treatment. The active pharmaceutical ingredient is a synthetic peptide composed of 29 amino acids derived from a multifunctional protein, pigment epithelium-derived factor (PEDF), with neurotrophic and anti-inflammatory properties. The functional domain of PEDF chosen to generate PEDF-derived short peptides (PDSP) also has a unique mechanism of action that promotes the “stemness” of certain types of cells, including mesenchymal stem cells (6). These properties enable the application of PDSPs to a broad range of diseases requiring rapid tissue repair.
In the eyes, this unique mechanism of action stimulates the proliferation and differentiation of corneal limbal stem cells, which accelerates corneal repair and heals ocular wounds in DED patients. BRM421 has shown promising clinical outcomes in two phase II studies (7); treatment with BRM421 ophthalmic solution was found to relieve most dry eye symptoms – including dryness, burning, stinging, and photophobia – in as few as seven days. Most patients reported they felt less burning and stinging in the morning and less dryness in the evening – times when DED sufferers usually feel most uncomfortable.
The safety of BRM421 has also been demonstrated. Of the more than 370 patients tested, none dropped out because of the treatment or reported serious adverse effects associated with the drugs. The only adverse events seen were caused by an excipient in the formulation, which can cause brief instillation pain. With these encouraging reports of efficacy and favorable safety profiles, BRM421 may enter a phase III study by the end of 2022.
- Q Le et al., “Outcomes of limbal stem cell transplant: a meta-analysis,” JAMA Ophthalmol, 138, 660 (2020). PMID: 32324211.
- OG Mead et al., “Amniotic membrane transplantation for managing dry eye and neurotrophic keratitis,” Taiwan J Ophthalmol, 10, 13 (2020). PMID: 32309119.
- JB Nadelmann et al., “Effect of autologous platelet-rich plasma eye drops in the treatment of dry eye disease (DED),” Invest Ophthalmol Vis Sci, 62, 1234 (2021).
- Review of Ophthalmology, “Will We Ever cure Dry Eye?” (2019). Available at: https://bit.ly/3KQvcw8.
- Ophthalmology Advisor, “Corneal Epithelial Stem Cell Treatment Improves Dry Eye Disease Symptoms” (2021). Available at: https://bit.ly/39OnQwj.
- N Brook et al., “Pigment epithelium-derived factor regulation of neuronal and stem cell fate,” Exp Cell Res, 389, 111891 (2020). PMID: 32035134.
- PY Huang et al., “Topical BRM421 ophthalmic solution improves signs and symptoms of moderate to severe dry eye patients in clinical trials,” Invest Ophthalmol Vis Sci, 62, 1335 (2021).