Retinopathy of Prematurity - Recent advances in treatment

This is a brief discussion of promising Newer therapies of treatment in Retinopathy of prematurity (ROP). The question is asked several times in theory exams in one or another form. Brief mention of new therapies can yield a good score for the long answer Question.

Introduction

Retinopathy of prematurity (ROP) is a developmental disorder that occurs in the incompletely vascularized retina of premature infants and is an important cause of blindness in children in both developed and developing countries.

Progress in neonatal intensive care in recent years has led to increased survival of extremely low birth weight (ELBW) infants weighing ≥1000 g at birth and, subsequently, to an increased incidence of ROP.

The incidence is increasing in developing countries like India in view of the rising numbers of preterm deliveries and improved neonatal care. Traditional modalities of treatment included cryotherapy and laser therapy, which were laborious and required special training. Hence, research is on way to find novel treatment modalities directed at various levels of pathogenesis for this blinding disease.

This post is based upon the article published in Indian Pediatrics. Let us review the newer modalities of treatment for ROP.

The first one is

Anti-Vascular Endothelial Growth factor Therapy

Vascular endothelial growth factor A (VEGF-A) is a known promoter of angiogenesis and is upregulated by hypoxia. the role of vascular endothelial growth factor (VEGF) in neovascularization and vascular permeability of ROP is established. 

Hence, therapy for ROP is directed at treating the underlying pathogenesis by decreasing VEGF levels, either by completely ablating the peripheral avascular retina that produces the VEGF (LASER therapy) or by inactivating VEGF by binding it after its production (anti-VEGF therapy).

Bevacizumab, a humanized recombinant antibody, that inhibits the biological activity of VEGF, has been widely used as an off-label treatment for ocular angiogenesis disorders, including age-related macular degeneration, proliferative diabetic retinopathy, and neovascular glaucoma. It is a complete antibody rather than an antibody fragment like ranibizumab.

Bevacizumab eliminates the angiogenic threat of ROP (The BEAT–ROP study), Bevacizumab, given to extremely immature infants by intravitreous injection as low dose monotherapy (0.625 mg in 0.025 mL of solution) or up to 0.75 mg, has not shown systemic or local toxicity.

Insulin-like growth factor-1

When IGF-I is persistently low, vessels cease to grow, maturing avascular retina becomes hypoxic, and vascular endothelial growth factor accumulates in the vitreous. 

Data indicate that serum IGF-I levels in premature infants can predict which infants will develop retinopathy of prematurity and further suggests that early restoration of IGF-I in premature infants to normal levels could prevent this disease. The drug is under study and no studies to prove its efficacy have been published yet.

Granulocyte Colony Stimulating Factor

Granulocyte colony-stimulating factor (GCSF), commonly used to increase leukocyte counts in neutropenic adults and children might also have a regulatory effect on vasculogenesis and thus prevent ROP. GCSF has been shown to increase levels of insulin-like growth factor-1(IGF-1), which supports the normal, measured, calm vascularisation of the retina.

Filgrastim is a human granulocyte colony-stimulating factor (G-CSF)‚ produced by recombinant DNA technology. Its potential role in the prevention of ROP is now being studied. As this drug is more easily available in India with costs ranging from 2500 – 3000 INR, this would be a beneficial adjunct to the treatment of ROP in a developing country like ours.

Jun Kinase (JNK) Inhibitors

The Jun kinases (JNK) belong to the mitogen-activated protein kinase (MAPK) family. JNK1 is a critical factor in hypoxia-induced retinal VEGF production and that promotes hypoxia-induced pathological angiogenesis.

Intravitreal injection of a specific JNK inhibitor decreases retinal VEGF expression and reduces pathological retinal neovascularization without obvious side effects. D-JNKi,  the specific JNK-1 inhibitor is the drug that is under study for the prevention of ROP.

Gene Therapy

A series of small studies have investigated the association of genes and severe ROP or failure of treatment. 

It is believed that through techniques in gene therapy, alternative splicing, and RNA interference, we may meet with greater success in restoring ocular ‘angiogenic privilege.'

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Image Source [1] - Häggström, Mikael (2014). "Medical gallery of Mikael Häggström 2014". DOI:10.15347/wjm/2014.008. ISSN 2002-4436. Public Domain.(with permission)

Author

Ajay Agade | DNB(Pediatrics), FNB(Pediatric Intensive Care), Fellowship in Pediatric pulmonology and LTV

Ajay is a Paediatric Intensivist, currently working in Pediatric Pulmonology & LTV at Great Ormond Street Hospital NHS, London