Nanotechnology breakthrough will lead to a better bionic eye for the blind

(c) American Chemical Society

 
Scientists from Hebrew University of Jerusalem researchers, in collaboration with colleagues from Tel Aviv University and Newcastle University, have developed a new light-sensitive film that could one day form the basis of a bionic eye (or an artificial retina) that could help people suffering from retinal damage or degeneration.

Sildenafil (Viagra) may not be safe in Retinitis Pigmentosa

Sildenafil (Viagra) is a PDE5 inhibitor in wide use for the treatment of erectile dysfunction. It is known to increase the level of cGMP, and ultimately increases penile response to sexual stimulation. Sildenafil preferentially inhibits PDE5 more than PDE6, both of which are expressed in the retina. Therefore, there is a potential for this drug to alter retinal function, not only in normal subjects, but also in patients with PDE6 gene mutations such as in some forms of RP. 

Stem cells close to cornea may help treat Macular Degeneration or Retinitis Pigmentosa

Scientists at the Southampton General Hospital and the University of Southampton have found a pool of stem cells around the corneal limbus that can be induced to become retinal cells. Such cells can then potentially be transplanted into the eye of the patient of macular degeneration or retinitis pigmentosa to stop the disease or even cure it.  

New genetic mutations in Bardet Biedl Syndrome identified

UK researchers have identified genetic mutations responsible for Bardet-Biedl Syndrome (BBS), a rare condition that causes blindness, opening the door for personalized treatment and tailored gene therapies.

What is Bardet-Biedl syndrome?
Bardet-Biedl syndrome is a disorder that affects many parts of the body. The signs and symptoms of this condition vary among affected individuals, even among members of the same family.

Increased risk of acute angle closure observed in patients with retinitis pigmentosa

Clinician scientists from Taiwan, in a large observational study of over 380 patients over a 15-year period, have observed increased risk of acute angle closure in patients with retinitis pigmentosa (RP). In addition, they also noticed that angle closure attack occurred earlier in life, with the risk higher in males, in patients with RP, compared to the general population where such an attack is more commonly seen in elderly females.

The association between RP and glaucoma was first proposed in 1862. Since then, it has been considered a difficult diagnosis to make in patients with RP due to coexistent changes such as retinal nerve fiber layer defect and visual field defect in RP, which are also seen in patients with glaucoma.

As is known, RP is a major cause of blindness in adults. Intraocular pressure (IOP) elevation may aggravate the visual impairment in RP patients with preexisting retinal and optic nerve dysfunction. Acute angle closure, the major risk factor for blindness among angle closure eyes, may cause particularly devastating damage to RP patients. Angle closure related IOP elevation is preventable by timely intervention to widen the drainage angle in susceptible eyes.




Advice: If you are a patient with RP, It is a good idea to get a check done by your retina specialist if you ever feel your vision has reduced suddenly from the previous state, or you have significant pain in or around the eye/s.

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QLT announces clinical & regulatory update for oral retinoid program for inherited retinal disease

QLT announced that, following meetings with the U.S. Food and Drug Administration and the European Medicines Agency, the Company believes that it is close to finalizing a pivotal trial protocol for QLT091001 for the treatment of inherited retinal disease such as Leber Congenital Amaurosis (LCA) and Retinitis Pigmentosa (RP) due to mutations in the LRAT and RPE65 genes, both orphan indications.

The Company expects to provide final guidance on its development plans in these indications before the end of the first quarter of 2014 after final feedback from the European regulatory agency.

Additionally, QLT has initiated recruitment of subjects for a Phase IIa proof-of-concept trial of its drug candidate, QLT091001, in adult subjects with Impaired Dark Adaptation (IDA), a condition that results in decreased ability to recover visual sensitivity in the dark after exposure to bright lights.

The Company also announced the launch of a compassionate use program for QLT091001 in LCA and RP, as well as plans for a patient registry and an update on its retreatment study in these indications.

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New animal model may help develop new treatments for RP

Developing new treatments for diseases such as RP have been difficult for many reasons. Apart from the fact that it was difficult to pinpoint the genetic defect in the disease, lack of an adequate animal model that could be used to test any new treatment to study its effect and follow the effect for a few months has been an underlying problem for many years now.   

Hence the recent publication in IOVS of success in creating a genetically modified mini-pig may help in the development of newer and improved treatment paradigms, and may eventually help lead us to a cure diseases such as retinitis pigmentosa (RP), which is the most common inherited retinal disease in India. The researchers used miniature pigs, weighing about 150 pounds at full growth, instead of the larger pig, since managing the smaller pigs was much more easier. 

This model has been developed by researchers in the Department of Ophthalmology & Visual Sciences at the University of Louisville, along with researchers from the National Swine Resource and Research Center, University of Missouri.

For those from the scientific background, here's the abstract from IOVS. " ... describes the creation of an inbred, transgenic mini-pig that carries a mutant human rhodopsin gene which is expressed in the retina and is associated with progressive loss of light-evoked ERG responses. This is a significant achievement of considerable practical value in an era in which translational activity for retinal diseases is burgeoning. The rationale for generating this pig is laid out well, and the design appears to have multiple advantages over the existing retinal dystrophic pig. There are many rodent models of retinitis pigmentosa (RP) and conditions resembling RP, but what has been lacking is a large animal model that more accurately mimics the situations encountered when treating human patients. One potential animal model is the pig. There is an existing pig model of retinal degeneration (RD); however, a number of factors have made this model difficult to use, including the large size of the animals at the time of degeneration as well as molecular genetic considerations. The article describes the successful development of a genetically accurate RP-like condition in a mini-pig.

This model should prove quite valuable to people working on treatment of RD, including traditional pharmacologic approaches and regenerative strategies, such as stem cell transplantation. The authors evaluated six transgenic founders whose retinal function was studied with full-field electroretinography from three months through two years. Progeny from one founder were generated and genotyped to determine the transgene inheritance pattern. Retinal mRNA was isolated and the ratio of P23H to wild-type pig RHO measured. The result is a powerful new tool for retinal degeneration research that should be of interest to a wide range of workers in that field."

The Pro23His (P23H) rhodopsin (RHO) mutation is the cause for the most common form of human autosomal dominant retinitis pigmentosa (adRP), with a high propensity for disease characteristics to pass to the next generation. This study was focused on establishing a transgenic miniature swine model of RP using this human P23H RHO gene. 

Animal models are used to screen for safety and efficacy of new treatment paradigms for diseases such as RP, which includes newer treatment modalities such as medications, stem cell therapies, gene therapy, and the artificial retinal prosthesis.

The prevalence of RP in India is considered to be significantly higher compared to other nations. With some small sample studies indicating that RP may affect about 1 in 1000 in some areas, to almost 1 in 500 in some rural areas in India, we potentially have a population of about a million RP patients. 

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POSITIVE PRELIMINARY RESULTS FROM PHASE 1b TRIAL OF QLT091001 IN SUBJECTS WITH RETINITIS PIGMENTOSA DUE TO RPE65 AND LRAT MUTATIONS

QLT Inc. has announced positive preliminary results from its international multi-center Phase 1b proof-of-concept clinical trial of QLT091001 for the treatment of Retinitis Pigmentosa (RP) due to inherited genetic mutations in retinal pigment epithelium protein 65 (RPE65) or lecithin:retinol acyltransferase (LRAT) (also known as early-onset RP). 

The Phase 1b study showed rapid, statistically significant and clinically meaningful changes in visual fields (VF) from baseline values, as well as improvements in visual acuity (VA), in the study of 17 RP subjects. In addition, small subsets of RP subjects were investigated for secondary effects on other key vision parameters impacted by RP, such as decreased retinal sensitivity, and the data available in these subsets showed notable and promising increases in average sensitivity levels. The single-course treatment data with QLT091001 represents the first stage of dose regimen testing as the basis for a longer term multiple course regimen in RP due to mutations in RPE65 and LRAT. 

RP is a disabling group of genetic eye diseases associated with progressive loss of vision including night blindness, constricted peripheral vision resulting in difficulties with daily activities, and in later life, reduced central vision, inability to read, and in many cases progression to severe blindness. RP can be caused by many different gene defects and symptoms can start at varying ages; patients with mutations in the RPE65 and LRAT genes tend to show vision loss very early in life (this type of RP is also known as early-onset RP).

In the open-label, multi-center Phase 1b clinical study, 17 subjects (ranging in age from 6 to 55 years, mean 29 years) with either RPE65 (12 subjects) or LRAT (5 subjects) mutations received a 40 mg/m2/day dose of QLT091001 once daily for seven days with post-treatment follow-up at 7, 14, and 30 days. Visual fields and visual acuity are key measures of clinically relevant visual function. VF was assessed using Goldmann Visual Fields (GVF) and VA was assessed using best-corrected visual acuity (BCVA, ETDRS letters); GVF maps were converted to assess the remaining functional retinal area for analysis. After a single 7-day course of treatment with QLT091001, the average retinal areas from baseline showed statistically significant improvements of 34% at day 7 (p=0.005), 29% at day 14 (p=0.02) and trended towards a statistically significant improvement of 23% at day 30 (p=0.07) in the evaluable subjects meeting GVF test criteria (n=14 subset). In the intent-to-treat (ITT; all subjects enrolled) analysis (n=17), the average retinal area from baseline improved by 22% at day 7 (p=0.03, statistically significant), 16% at day 14 (p=0.13) and 18% at day 30 (p=0.096). The evaluable subset of 14 subjects excludes three patients in the VF analysis because they did not meet criteria as determined by a third-party reader. Nine of 17 subjects (53%) showed an improvement in VA over baseline in at least one eye by greater than or equal to five ETDRS letters. 

Measurement of Goldmann Visual Field Improvement from Baseline
GVF analysis – retinal area	Day 7	Day 14	Day 30
Avg. increase from baseline – evaluable subjects (n=14) Avg. increase from baseline – ITT (n=17)	34% (p=0.005)* 22% (p=0.03)*	29% (p=0.02)* 16% (p=0.13)	23% (p=0.07) 18% (p=0.096)

(*statistically significant)

Following single-course treatment with QLT091001, the Retinitis Pigmentosa patients in the clinical trial experienced a rapid and significant improvement in certain visual function parameters, as per Dr. Hendrik Scholl of the Wilmer Eye Institute at Johns Hopkins University. He also added that the discovery of the genetic cause of retinal degeneration has revolutionized insight into disease processes at a molecular level and has given the physicians encouragement for potential therapeutic approaches.  

Baseline values in subjects showed a broad range of moderately to severely reduced visual acuities and visual fields. All subjects reported early onset of night blindness as one of the hallmarks of disease.

Additional tests included spectral-domain optical coherence tomography (OCT), full-field electroretinography (ERG), and quality of life assessments. Also, in small subsets of subjects, the effects of QLT091001 on several parameters of light sensitivity in dim light (night vision), pupillary reflexes, and responses of the visual cortex to potential changes in visual stimuli (functional magnetic resonance imaging, fMRI) were measured.

The fMRI substudy (n=2) showed activation of several previously quiet areas of the visual and parietal cerebral cortex after treatment. In addition, the substudy in dark adapted visual fields (n=2) showed a 16- fold average increase in sensitivity at 10%-50% of locations tested in each eye within days of the first dose. With longer dark adaptation, light sensitivity increases averaged 40-80-fold greater than baseline at 40%- 83% of the locations tested. Full-field sensitivity (FST) and pupillometry results supported the large increases in sensitivity in both eyes.

The additional secondary endpoints evaluated to date in this study support and are consistent with the changes in VF and VA observed following single course treatment with QLT091001.

Ongoing analysis of the safety profile of QLT091001 demonstrates a safety profile consistent with the Company’s Phase 1b study in patients with Leber Congenital Amaurosis (LCA). A retreatment study for the RP cohort has been initiated to assess the effects of repeat QLT091001 therapy in these patients. The database on this study remains open and further analyses of additional anatomic tests (OCT) and retinal sensitivity tests (ERG) are also ongoing to further explore the optimal baseline characteristics of responders for clinical development purposes.

The RP (early-onset RP) Phase 1b clinical study is being conducted at seven leading centers for the treatment of inherited retinal diseases in the U.S., Europe and Canada.

About Synthetic Retinoid Drugs
Genetic diseases in the eye such as Leber Congenital Amaurosis (LCA) and Retinitis Pigmentosa (RP) arise from gene mutations of enzymes or proteins required in the biochemistry of vision. QLT091001 is a replacement for 11-cis-retinal, which is an essential component of the retinoid-rhodopsin cycle and visual function, and is under investigation for the treatment of LCA and RP. QLT091001 has received orphan drug designations for the treatment of LCA and RP by the European Medicines Agency, and for the treatment of LCA and RP due to inherited mutations in the LRAT and RPE65 genes by the U.S. Food and Drug Administration (FDA). The drug has also been granted two Fast Track designations by the FDA for the treatment of the LRAT and RPE65 genetic mutations in both LCA and RP.

About Leber Congenital Amaurosis (LCA)
LCA is an inherited degenerative retinal disease characterized by abnormalities such as roving eye movements and sensitivity to light, and manifesting in severe vision loss from birth. Both rod and cone photoreceptors are affected in LCA. Eye examinations of infants with LCA reveal normal appearing retinas. However, a low level of retinal activity, measured by electroretinography, indicates very little visual function. According to current epidemiological estimates, LCA affects approximately one in 81,000 newborns worldwide, of which approximately 10% carry the inherited deficiencies of either RPE65 or LRAT.

About Retinitis Pigmentosa (RP) Due to RPE65 and LRAT Mutations
RP is a set of hereditary retinal diseases demonstrating clinical features similar to LCA. RP is also characterized by degeneration of rod and cone photoreceptors, but it presents with a more variable loss of vision in late childhood to adulthood. Deficits in dark adaptation and peripheral vision are particular hallmarks of RP. RP is currently estimated to affect at least 300,000 individuals worldwide, of which approximately 20%–30% are autosomal recessive (arRP). It is currently estimated that less than 3% of autosomal recessive RP patients carry the inherited deficiencies of either RPE65 or LRAT.

About QLT
QLT is a biotechnology company dedicated to the development and commercialization of innovative ocular products that address the unmet medical needs of patients and clinicians worldwide. We are focused on developing our synthetic retinoid program for the treatment of certain inherited retinal diseases, developing our proprietary punctal plug delivery system, as well as U.S. marketing of the commercial product Visudyne® for the treatment of wet age-related macular degeneration.

Derived from the press release from QLT Inc.