26-27 - A peptide approach to regenerative medicine

Regenerative medicine is a rapidly expanding field with the potential to provide innovative new treatments for hard-to-treat diseases. Many treatments rely on the use of stem cells or cell therapies, but these are both technically challenging and expensive to produce. To address this, a number of biotech companies are looking for alternative ways to enhance the efficacy of regenerative medicine treatments, while also improving their cost and accessibility.

Using novel therapies, such as peptides, offers a different approach that can stimulate the body’s own cells to repair and regenerate at the site of damage, while avoiding the uncertainties involved in in vitro cell culture. Developing regenerative peptides offers an exciting opportunity to help patients with unmet needs in an affordable, accessible and predictable way.

Stem cell therapies have been used in a wide range of biomedical applications, from treating burns victims with skin grafts, to improving osteoarthritis symptoms by injecting mesenchymal stem cells into the affected joints. However, to date, success stories have been sparse and anecdotal. Results are often inconsistent, with high variability between patients, partly due to the delicate nature of stem cells. Even though understanding of their characteristics and preferred culture conditions has improved over time, stem cells may still change their surface markers and lose their ability for self-renewal and differentiation during the cell growth and division process, rendering treatments less effective.

The source of stem cells has also faced ethical and political controversy. Today, induced pluripotent stem cells (adult cells that have been reprogrammed to regain the ability to differentiate) or hematopoietic stem cells (stem cells that are extracted and derived from umbilical cord blood) are most common, but these are difficult to produce. Moreover, only specialist medical centres or facilities can meet the highly specific conditions required for cell growth. This means the cost of generating and maintaining enough stem cells for one course of treatment tends to be high, in turn reducing accessibility for patients.

In response to the challenges involved in stem cell research, many biotech companies are investigating other agents or treatments that can induce the regeneration of tissues to repair injuries and revitalise body functions. One approach is to use stimulatory agents to activate the body’s own stem cells. For example, platelet-rich plasma (PRP) treatment is commonly used in orthopaedic surgery and sports medicine, and more recently in the treatment of ocular surface diseases. PRP therapy uses injections of a concentration of a patient’s own platelets to accelerate the healing process.

This treatment has several disadvantages, however, including unclear classification, as a result of different preparation methods, inconsistent naming conventions and numerous reporting requirements. PRP has not yet been approved by the US Food and Drug Administration, but it is widely used in various clinical settings.
In the case of ophthalmology applications, most PRP studies have had positive outcomes, with at least two-thirds of patients experiencing some improvement. It is hard to regulate the content of PRP treatments, however, as the level of relevant blood proteins can vary between patients. For example, patients who have higher levels of signalling molecules, called inflammatory cytokines, in their blood may also have higher levels in their PRP, which can cause negative effects and reduce the efficacy of the treatment.

Moreover, because of the way that PRP treatments are absorbed and used by the body, most of the repair is superficial, as most of the relevant proteins cannot reach the target site. This means that the recovery of sensitivity in the cornea is limited. To further develop PRP as a standardised, stable treatment option, more studies are needed to better understand the importance of controlling batch-to-batch differences in the levels of key blood components, such as growth factors, platelets, leukocytes and cytokines. Alternatively, preparing treatments from pooled blood from multiple donors could help to control and standardise the quality of PRP for more consistent results.

Another approach to regenerative medicine uses novel peptides to stimulate and regenerate patients’ own stem cells to speed up the healing process and repair damaged tissues. For example, pigment epithelium-derived factor (PEDF) is a multifunctional protein known to be both anti-inflammatory and anti-angiogenic, meaning it inhibits the growth of new blood vessels. In addition, one of its functional domains is known to have stem cell regenerative properties and to support the growth, survival and differentiation of neurons and various stem cells. Many studies have shown that a fragment of that functional domain, called a PEDF-derived short peptide (PDSP), can promote the growth and expansion of limbal epithelial stem cells, as well as meibomian gland stem cells. Therefore, it can be used to treat dry eye disease by speeding up the cornea repair process through stimulation of corneal stem cell proliferation and differentiation, anti-inflammation and meibomian gland recovery.

The PDSP has also been shown to promote the growth of mesenchymal stem cells that can differentiate into multiple tissue types, including bone, cartilage, muscle and fat cells, and connective tissue. Therefore, it has the potential to treat other conditions, such as osteoarthritis, by promoting cartilage regeneration, repairing damage and relieving joint pain.

Regenerative peptides are attractive drug development targets for several reasons. First, they are easy to manufacture, using a method called solid phase peptide synthesis (SPPS), which provides consistent quality and minimises batch-to-batch differences. Every impurity is closely monitored and prespecified during the manufacturing process to ensure the quality of the drug.

Second, with economy of scale, the cost of these drugs can be significantly reduced, and may even be cheaper than PRP treatments. Third, with proper storage conditions and formulations, peptides can be manufactured in large quantities and stored for several years. This long shelf-life greatly improves accessibility for patients, especially those living in rural regions.

Fourth, using a single, naturally occurring peptide minimises complications caused by immune responses, DNA toxicity or inconsistencies in the drug contents, resulting in a better and more predictable safety profile. Finally, with consistent quality and scalable quantities, it is possible to conduct large-scale clinical trials to assess the efficacy of regenerative peptide treatments across a wide range of patients and, therefore, to assess their potential for use in general populations.

PDSPs are already showing promising results. For example, the PDSP platform is being developed and further optimised to tackle a range of diseases, such as dry eye syndrome, neurotrophic keratitis, limbal stem cell deficiency, skin wound healing and osteoarthritis.

In an ophthalmology application for the treatment of dry eye disease, the peptide has been tested in two Phase II studies with over 300 patients and has shown an excellent safety profile and encouraging efficacy results. The drug is administered by topical eye drops and the unique mechanism of action works by encouraging the regeneration of limbal stem cells. This method can achieve efficacy much more quickly than traditional anti-inflammatory drugs, which usually take about three to six months to reach significant improvement. Patients may experience early onset benefits in signs (an objective measure of the level of corneal repair) and symptoms (a subjective measure of patients’ feelings assessed by questionnaire) within two weeks. The promising results from peptide studies demonstrate their potential as a more affordable, accessible and predictable approach to regenerative medicine.

As regenerative medicine technologies continue to advance rapidly, they bring renewed hope for patients with currently untreatable medical conditions. While each approach has its own advantages and disadvantages, by working together as a research community and utilising the strengths of each one, hopefully many more creative solutions will bring transformative treatments to patients soon. References available on request.