Development of recombinant surfactant protein D therapy to prevent neonatal chronic lung disease

Premature infants have immature lungs which lack lung surfactant which is normally produced by the lungs and is essential for normal breathing. Premature infants therefore frequently require additional help to breathe after birth and are reliant on artificial respiratory support with ventilators and positive pressure devices in neonatal intensive care to keep their lungs from collapsing. Currently, babies born early receive surfactant replacement therapy which is derived from the lungs of animals. This has been very successful in saving their lives by stabilising their lungs and improving their ability to breathe. However current surfactant therapies in clinical use do not contain all of the components of normal human surfactant and more than half of babies now surviving after birth at less than 28 weeks gestation go on to develop chronic lung inflammation and neonatal chronic lung disease (nCLD), which leaves infants oxygen dependent and highly susceptible to life threatening reactions to common childhood viral infections, asthma and other chronic lung problems in later life. A component of the natural surfactant that is missing in current surfactant therapy is surfactant protein D (SP-D), a natural lung defence protein which plays an important role in keeping the lungs healthy and free from infection and inflammation. In fact, SP-D is so important in controlling lung inflammation that mice lacking the gene for SP-D spontaneously develop chronic lung inflammation causing emphysema, a destruction of the lung tissue that is common in smokers and in preterm babies whose lungs are immature and damaged by the need for positive pressure ventilation. SP-D has been shown to reduce inflammation in the lungs of preterm lambs. We have been able to produce a functional fragment of SP-D (rfhSP-D), have fully characterised its structure and shown that it works to reduce inflammation in animal models of human disease. Not only does treatment with rfhSP-D correct the emphysema in mice lacking SP-D, but the rfhSP-D is also effective in reducing inflammation in models of infection with bacteria, viruses, fungi and parasites as well as lung inflammation triggered by common fungal and house dust mite allergens. We aim to develop this fragment of the natural human surfactant protein as a new therapy to supplement surfactant treatments currently given to preterm babies, to see if this can help reduce the high incidence of chronic lung disease after preterm birth. To do this, we must first scale up production of the rfhSP-D to the required safety standards for human treatment and then carry out a clinical trial to see if babies can be treated safely with this additional missing surfactant protein. If this natural protein is shown to be safe and deliverable to the lungs of premature babies like current surfactant therapy, this will help determine the appropriate dosing regime for the next stage of clinical testing to see if supplementing current surfactant treatment with this extra protein will help reduce the incidence of chronic lung problems in babies born too early.

Surfactant protein D (SP-D) is one of a family of collagenous lectins that play an important part in pulmonary innate immunity. They contain a collagen-like region and a C-type lectin domain, and bind carbohydrates in a calcium-dependent manner. The technology to be used in this application is based on the human protein, Surfactant Protein D (SP-D). A recombinant fragment of the molecule, rhfSPD, has been developed that maintains the relevant anti inflammatory properties of the native SP-D. This fragment consists of a carbohydrate binding domain, a trimerising neck region and a short segment of the collagen domain. The fragment has been crystallised and its structure solved. IP rights in rfhSP-D and its uses reside in the University of Southampton

SP-D and rfhSP-D have well documented immunomodulatory and anti-inflammatory properties in the lung. Pre-clinical data show efficacy of rhSPD treatment in chronic inflammatory lung disease. Knock-out mice, lacking SP-D develop symptoms of COPD and emphysema relevant to chronic lung disease of infants which are correctable by treatment with recombinant SP-D. Efficacy of rfhSP-D has been demonstrated in multiple murine models of infectious (bacteria, viruses, fungi and parasites) and allergic lung inflammation triggered by fungal and house dust mite allergens.

Pre-clinical data in large animal models (neonatal lamb) show that intervention with rhSPD reduces inflammatory biomarkers of neonatal chronic lung disease.

The protein can be manufactured straightforwardly and we are currently in industrial process development to generate a robust GMP-capable manufacturing procedure. This will enable manufacture of the clinical batch to GMP for use in clinical trial.

The route to market will be as Prescription Only Medicine (POM). This will require that preclinical toxicology and safety be completed and an initial phase I clinical safety dose escalation study performed in pre-term infants at risk of nCLD

Human surfactant protein D (SP-D) is normally naturally produced in the lungs to combat infection and inflammation but it is deficient in lungs of preterm babies and in adults with asthma and chronic obstructive airways disease( COPD). This project aims to develop an artificial form of SP-D (rfhSP-D) to help treat preterm babies to help prevent them developing chronic lung problems or neonatal Chronic Lung Disease (nCLD)
15 million babies are born prematurely every year and over 50% of premature infants born at less than 28 weeks gestation develop nCLD which can require long-term home oxygen therapy for up to 4-5 years. This is a significant public health burden and health economic arguments are compelling. Lower respiratory morbidity primarily or exclusively affecting children, and perinatal conditions, account for 12.6% of the leading causes of Disability Adjusted Life Years (DALYs: an indicator of the number of years lived with a disability and years lost due to premature mortality); by way of contrast, adult ischaemic heart disease and cerebrovascular disease account for 6.8% (World Health Organisation 2002). Neonatal intensive care days cost up to £1800 per day for high dependency. In addition to this there is the cost of multiple readmissions, adverse consequences including poor neurodevelopmental outcome (i.e. cerebral palsy), education of healthcare and societal costs. The annual societal economic burden associated with preterm birth in the United States was estimated to be at least $26.2 billion in 2005 (National Institute of Health, 2007: Preterm Birth Causes, Consequences, and Prevention).

Current surfactant therapy has been very successful in reducing mortality after preterm birth but has led to a concomitant rise in survivors with nCLD. Treatment with rfhSP-D would be additional to current surfactant therapies all of which lack this critical anti-inflammatory surfactant protein component. We see development of rfhSP-D as an additional treatment for all premature neonates born prior to 28 weeks for the prevention of nCLD. The incidence of preterm birth is increasing and with increased survival at lower gestational ages, this has led to much higher rates of nCLD, making it a high priority for the development of new treatments. The immediate health care costs and poor associated long term respiratory and neurodevelopmental outcomes are a major public health burden.

However rfhSP-D is a natural anti inflammatory agent in the lung which is also lacking in other lung diseases such as asthma and chronic obstructive airways diseases (COPD). If we show safety and efficacy as a treatment for neonatal lung disease, the risk in developing rfhSP-D as an anti inflammatory for these complex diseases in which SP-D has also been shown to be lacking is less. Over 65 million people have Chronic Obstructive Pulmonary Disease (COPD) (WHO report). Currently the treatment for COPD and asthma is largely restricted to therapies that alleviate symptoms. "Successful development of a therapy that halts or significantly alters the course of the disease would revolutionize its treatment and marketplace..'" (May 2005 press release, Decision Resources). rfhSP-D acts to reduce inflammation by promoting removal of dead and dying cells from the airways; these are present at higher levels in the lungs of patients with COPD and asthma, causing chronic inflammation.Low levels of SP-D
As a novel, non-steroidal, natural, anti-inflammatory, disease modifying treatment for COPD and asthma, we see rfhSP-D being used as a treatment for moderate and severe patients for the prevention of exacerbations and worsening of disease. This projected costs of treatments for these diseases which are also rising in incidence is estimated to increase to $41.23 billion by 2017 (Visiongain report).

Thus if rfhSP-D is effective as a new natural anti inflammatory agent it could potentially improve the lives of millions of people with lung problems.