Bringing biologics to eye health: Regenerative medicine for inflammatory disorders

With all due respect to how quickly healthcare evolves, it was not all that long ago that regenerative medicine—an industry that is expected to grow to approximately $152 million annually by 2026 in the United States¹—was viewed as more science fiction than actual medical science. This was the prevailing sentiment as recently as the early 1990s.

Despite the significant medical breakthroughs we had already begun to achieve at that time, such as the Human Genome Project, cloning, radiosurgery and the SmartPill, the first known usage of the term ‘regenerative medicine’ in 1992² was simply applied to technologies that would be relevant to hospitals in the future. Today, that future has clearly become reality, as the science of regenerative medicine and its related products—stem cells, edited genes and other biomaterials—can be utilised to help the body heal itself in a variety of ways when administered appropriately.

As we have progressively learned more about the hundreds of different biological pathways in the human body, we have also gained a better understanding of how the body heals naturally through those pathways. From chronic skin wounds and traumatic brain injuries to diabetes and certain cancers, the use of regenerative medicine has grown exponentially.

From an ophthalmological standpoint, biologics have proven effective in treating one of the most chronic and debilitating conditions, affecting some 350 million people worldwide: dry eye disease (DED). DED is a condition that produces a myriad of symptoms due to a loss of homeostasis in the eye’s tear film. It can be managed with the introduction of biological eye drops, administered individually or in tandem with other modalities based on disease severity, to return tear film back to a state of homeostasis while preventing further disease progression and improving the corneal surface.

Basics of biologics and regeneration

Biologics include a range of products such as vaccines; blood and blood components; allergenics; somatic cells; gene therapy; tissues; and recombinant therapeutic proteins.³ They may be isolated from a variety of natural sources, typically proteins from humans, animals or microorganisms, and can also consist of sugars, nucleic acids or a combination of such substances.

Biologics are acellular and complex, however, since they are not a pharmaceutical product, they are less likely to produce adverse effects in patients. Their ability to promote healing without scarring is a significant benefit in the treatment of DED and other corneal disorders, such as meibomian gland dysfunction, which is the most common cause of DED.

Meibomian glands that do not function properly produce an incorrect amount of lipids to cover the tear film surface so there is evaporative loss of the aqueous layer and dryness/inflammation; evidence shows that the use of a biologic on the cornea can significantly help to keep the tear film healthy.

Ophthalmologists and optometrists are also becoming more aware that if we can keep the corneal surface in good overall health, we can also decrease complications and affect outcomes with cataracts (both before and after surgery), photorefractive keratectomy refractive surgery and LASIK surgery, all of which can also result in inflammation.

Impact of inflammation

Table 1. Biologics options for treating dry eye disease

Although the human body is designed to heal, a lack of healing can occur on the corneal surface if inflammation persists. Some investigators have described DED as “a vicious cycle of corneal epithelial damage and inflammation”.⁴

And when chronic inflammation is present, patients are at higher risk for cancer because their cells continually try to regenerate but cannot quite do so because of the nature of the inflammatory environment. However, when we can control the inflammation, the patient has more of a microenvironment in which regeneration can be better controlled.

So, what are the biologics options that are currently available for the treatment of DED? They include the following (see Table 1):

• Autologous serum, a blood-derived eye drop that mimics the biochemical properties of natural basal tears to heal the ocular surface epithelium;
• Autologous platelet-rich plasma, a preparation that concentrates platelets in a small volume of plasma to treat the ocular surface; and
• Preservative-free allogeneic drops that can be used to stimulate stem cell communication without cell contact.

In particular, allogeneic drops are becoming more commonly prescribed as a maintenance therapy for mild-to-moderate or severe DED, especially when there are corneal findings such as punctate epithelial keratitis. Other conditions that respond to this treatment include neurotrophic keratitis and exposure keratitis. These drops can also be used in patients with DED who have not responded to traditional therapies and patients who have had post-surgical ocular surface issues.

The use of biologics can decrease the inflammatory response associated with graft-versus-host issues that can arise after a corneal transplant or other currently common surgical procedures on the cornea. Other autoimmune diseases that result in chronic inflammation, such as Sjögren’s syndrome, Stevens-Johnson syndrome, diabetes and essentially any condition in which the immune system is turning on itself are also candidates for biological therapies.

Future perspectives and concerns

It is the ability to regenerate that is the novel element of biologics, which provides an opportunity that is not available with drugs, surgery or radiation. And as the science behind regenerative medicine continues to evolve and the field diversifies, we will see more iterations of treatments that will help us to care for patients across the healthcare spectrum. We will also see more regulation and safer care planning.

However, it is important to note that there are not yet many products on the market that fit the true biologic category, especially for the eye. Despite this, there continues to be broad marketing of unapproved products⁵ described as regenerative medicine therapies, such as natural growth hormones. The United States Food and Drug Administration (FDA) has received reports of blindness, tumour formation, infections and more because of the use of unapproved products, and has urged all physicians act ethically and legally when deciding to prescribe a biologic to any patient.

There also exists misinformation on the general use of stem cellsto improve various corneal surface problems. The problem with stem cells in this regard is that they require a delivery system that will typically involve injection; there are reports of stem cell injections into the eye causing many complications for patients.

In addition, the utilisation of stem cells is not ideal because they are difficult to grow, and if they are not treated correctly within the appropriate microenvironment and do not receive needed nutrients, they will die. Stem cells also act differently throughout different parts of the body because of the microenvironments they are in, and if they are not working properly, they never quite heal.

We can accomplish more without stem cells when working with products that are acellular, which tend to offer better delivery systems, such as drops, and for which adverse effects are not of particular concern. Medicine in the future will probably not need cells at all.

We also expect to see more progress in the aspect of preventative care through biologics. Depending on when we initiate treatments, outcomes can be significantly improved. For instance, if we incorporate a biologic at the point of mild or moderate DED, we could potentially prevent severe cases by allowing the body enough assistance to get to a healing phase and not to a phase of chronic inflammation and scarring.

It is clear that regenerative medicine holds a prominent place in our present healthcare space and provides future hope for the treatment of many different conditions.

C. Randall Harrell, MD

E: dr.harrell@regenerativeplant.org

Dr Harrell is the founder, chairman and CEO of Regenerative Processing Plant.

References

1. Regenerative medicine market size to hit USD 151,949.5 million by 2026. News release. Globe Newswire. 7 Mar 2022. Accessed online 20 Apr 2022. https://www.globenewswire.com/news-release/2022/03/07/2397751/0/en/Regenerative-Medicine-Market-Size-to-Hit-USD-151-949-5-Million-by-2026-Exhibit-a-CAGR-of-26-1.html

2. A very brief history of regenerative medicine. Genesis Biologics. 18 May 2018. Accessed online 20 Apr 2022. https://genesisbiologics.com/brief-history-regenerative-medicine/

3. What are “biologics” questions and answers. FDA. 6 Feb 2018. Accessed online 20 Apr 2022. https://www.fda.gov/about-fda/center-biologics-evaluation-and-research-cber/what-are-biologics-questions-and-answers

4. Promising novel treatment for dry eye disease revealed by new research. News release. University of Manchester. 13 Jan 2022. Accessed online 20 Apr 2022. https://www.manchester.ac.uk/discover/news/promising-novel-treatment-for-dry-eye-disease-revealed-by-new-research/

5. Important patient and consumer information about regenerative medicine therapies. US Food and Drug Administration (FDA). 9 Jul 2021. Accessed online 20 Apr 2022. https://www.fda.gov/vaccines-blood-biologics/consumers-biologics/important-patient-and-consumer-information-about-regenerative-medicine-therapies