SAN FRANCISCO—Amarantus BioScience Holdings Inc., a biotechnology company focused on the development of diagnostics and therapeutic products in the areas of neurology, psychiatry, ophthalmology and regenerative medicine, has announced positive effects of mesencephalic-astrocyte-derived neurotrophic factor (MANF) for the protection from vision loss in an animal model of retinitis pigmentosa (RP). MANF was discovered utilizing Amarantus’ proprietary PhenoGuard Protein Discovery Engine.
MANF, the company’s lead therapeutic program, is a targeted therapeutic to address the underlying programmed cell death (apoptosis) associated with a wide range of devastating human disorders with a priority to identify drugable orphan indications, including RP.
Amarantus President and CEO Gerald E. Commissiong led the Neurotrophic Factors Group at the U.S. National Institutes of Health in the 1990s, where he became keenly interested in astrocytes because they dramatically outnumber neurons in terms of number of cells and morphological complexity.
After years of research, his team demonstrated that astrocytes from one region of the brain (substantia nigra) secreted molecules that protected neurons from that region of the brain (dopaminergic neurons of the substantia nigra) better than astrocytes from any other brain region. Shortly after his group published its findings, another group published an almost identical set of results, giving Commissiong confidence that they were on the right track.
“From there, another important issue needed to be resolved,” Commissiong realized. “In order to use astrocytes as a tool for discovering the neurotrophic factors responsible for the protection we were seeing, we needed a stable source of astrocytes capable of being used in a systematic screening process over and over again. It was here that I reached into some of my early research experience to engineer some proprietary methods to immortalize the astrocytes we were using to generate the initial results in order to turn them into stable cell lines that could be used for neurotrophic factor discovery.”
In the current study, the aim was to evaluate the efficacy of protecting visual acuity by a single intravitreal injection of MANF in the rd10/rd10 genetic mouse model of RP. These animals carry a spontaneous missense point mutation in Pde6b (cGMP phosphodiesterase 6B, rod receptor, beta polypeptide). Mutations in this gene are found in human autosomal recessive RP. Visual acuity was determined by measuring the spatial frequency threshold by optokinetic tracking. This method allows for a non-invasive assessment of visual acuity in rodents and higher species, including humans.
A single intravitreal administration of MANF after the onset of retinal degeneration on day 31 resulted in a statistically significant protective effect on visual acuity on day 38 and day 45, as compared to vehicle-treated animals. This is the first observation of MANF providing a functional benefit on vision in a model of RP. These data complement previously announced effects of MANF on preserving retinal morphology in RP models. The experiments were conducted at a leading ophthalmology contract research laboratory.
“Our results are the first observation of protection of vision in an RP model by MANF, and add a seminal functional visual acuity readout to the initial morphological protection findings reported from the University of Miami’s Bascom Palmer Eye Institute,” said Dr. David A. Lowe, president and CEO of NeuroAssets and member of the Amarantus board of directors. “These data further support our focus on ophthalmic orphan indications, as exemplified by our recent application to the FDA for orphan designation in RP.” The company expects to receive a response in the near future.
“These promising data provide a compelling basis to continue the further development of MANF in RP towards first-in-man studies,” said Commissiong. “We will continue moving forward with a strategic development plan focused initially on orphan ocular diseases, where we see tremendous potential for MANF. We are hopeful to develop better treatments for patients suffering from diseases that lead to blindness due to an array of medical conditions. Ultimately, we believe proof of concept for MANF in human studies in ocular diseases will support MANF development in other therapeutic areas where significant compelling preclinical efficacy data has been published and confirmed by independent groups, as well as the company’s own datasets. We firmly believe MANF has blockbuster potential in ophthalmology, neurology, cardiology and metabolic disorders, including diabetes.”
RP is a group of inherited diseases involving retinal degeneration. The cell-rich retina lines the back inside wall of the eye and is responsible for capturing images from the visual field. People with RP experience a gradual decline in their vision because photoreceptor cells (rods and cones) die. Symptoms include a progressive degeneration of peripheral and night vision as well as the degeneration in color perception and central vision; night blindness is one of the earliest and most frequent symptoms of RP. RP is typically diagnosed in adolescents and young adults. The rate of progression and degree of visual loss varies from patient to patient, with most people with RP becoming legally blind by age 40. There are approximately 100,000 patients in the United States, 100,000 patients in Europe and 50,000 patients in Japan diagnosed with RP, qualifying it as an orphan indication. There are currently no approved treatments in the market. It is estimated that RP is a multibillion-dollar market opportunity.
