Drug-Based Therapy News
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ProQR Therapeutics announces positive findings from a planned three-month interim analysis of its Phase I/II Stellar trial of QR-421a to treat retinitis pigmentosa (RP) in adults who have Usher syndrome type 2 or non-syndromic RP due to mutations in a specific part of the USH2A gene, called exon 13. QR-421a, ProQR’s experimental RNA therapy is designed to skip exon 13 in the RNA with the aim to stop or reverse vision loss. QR-421a given as a single intravitreal injection was safe and well-tolerated. It also showed early and encouraging evidence of activity, with 25% of patients showing a benefit across multiple outcome measures.
What this means for Usher syndrome: While this particular experimental drug is only applicable to those with Usher syndrome due to mutation(s) in exon 13 of the USH2A gene, early positive findings mean that the trial will continue as designed and could lead to other RNA/drug therapies that will benefit people with Usher syndrome caused by other mutations.
Patients from the same family and carriers of the same genetic mutation, develop a disease differently. This disparity may be due to the existence of mutations in other secondary genes that influences the onset and progression of the disease caused by the primary mutation. Two researchers from Dr. Cerón’s group, Dmytro Kukhtar and Karina Rubio-Peña, from Bellvitge Biomedical Research Institute (IDIBELL), have worked on this topic in the last few years. Utilizing CRISPR gene-editing technology, they introduced in C. elegans worms, mutations that cause RP in humans. Next, these mutations were classified into two groups: those that caused an obvious problem to worms and those that did not. Worms that were not affected by human mutations were used to search for other genes whose inactivation caused alterations in the mutant worms, but not in the control worms. Three genes were identified as candidate disease modifiers that may interact with the primary mutation to affect disease progression. The researchers then identified drugs that were harmful to worms harboring patient mutations, but not control worms.
What this means for Usher syndrome: Although it is important to find drugs that cure, it is also important to identify those drugs that could be harmful to patients with known genetic mutations.
Researchers at the University of New Hampshire have reported the first structural model for a key enzyme, PDE6, and its activating protein that play a role in some genetically inherited eye diseases, such as retinitis pigmentosa and night blindness. Creating atomic-level models is important for locating PDE6 mutations because we can learn to understand why they cause disease and develop new therapeutic interventions to manage retinal diseases. Michael Irwin, doctoral student in biochemistry stated, “Having detailed structural information about how PDE6 is activated by transduction will help us understand the molecular causes of visual disorders and blinding diseases resulting from mutations in these proteins.” Current treatments for genetically inherited retinal diseases may include gene therapy or drugs meant to inhibit the disease process. However, the drugs are not always successful in restoring the balance of PDE6 and preventing blindness.
What this means for Usher syndrome: By knowing the molecular structure of these visual signaling proteins and how they interact with each other can offer clues for the development of new drugs to restore vision and prevent blindness.
Excitotoxicity is a process in which neurons are damaged and killed due to excessive amounts of a specific amino acid, glutamate (Glu). This process appears to play a critical role in ocular neurodegeneration by causing retinal ganglion cell death and cell loss. Uncontrolled glutamate in the synapsis has significant implications in the pathogenesis of neurogenerative disorders. Approaches to control the level of glutamate include targeting neural tissue to protect from degradation, and microparticles are often used as a vehicle for targeted drug delivery due to their ability to maintain stable drug concentration for prolonged periods. They can even help increase efficacy by improving drug bioavailability (the ability of a drug to be absorbed and utilized by the body). Based on promising results, possible new investigations will focus heavily on microparticulate formulations and can be expected to open the field of ocular research to new alternatives.
What this means for Usher syndrome: Retinitis pigmentosa is an eye-disease that is characterized by progressive retinal degeneration. The promising utility of microparticulates may one day be used to deliver therapeutic drugs as a potential treatment for Usher syndrome.
Eloxx Pharmaceuticals is developing small molecules that permit read-through of point mutations that cause Usher syndrome 1F and 2A. Eloxx has entered into a partnership with the Foundation Fighting Blindness and is developing molecules that “read through” nonsense mutations. Scientists believe that approximately 10% of all the gene mutations across all known inherited retinal diseases are nonsense. Therefore, the “read through” molecules have the potential to help many people.
What this means for Usher syndrome: A subset of Usher syndrome patients, those with nonsense mutations, might be helped by this therapy.
Ganglion cells in the eye generate noise as the light-sensitive photoreceptors die in diseases such as retinitis pigmentosa (RP). Now, neurobiologists have found a drug and gene therapy that can tamp down the noise, improving sight in mice with RP. These therapies could potentially extend the period of useful vision in those with degenerative eye diseases, including, perhaps, age-related macular degeneration.
What this means for Usher syndrome: This type of therapy may also extend the period of useful vision in Usher syndrome.
ProQR Therapeutics N.V., a company dedicated to changing lives through the creation of transformative RNA medicines for the treatment of severe genetic rare diseases, today announced the first patient treated in the Phase 1/2 STELLAR clinical trial for QR-421a in patients with Usher syndrome type 2 or non-syndromic retinitis pigmentosa (RP). Interim data from the trial are expected to be announced by mid-2019. According to David G. Birch, Ph.D., Principal Investigator of STELLAR and Scientific Director of the Retina Foundation of the Southwest in Dallas, Texas, “The STELLAR study is one of the first studies of its kind exploring the impact of ProQR’s RNA therapies on patients with Usher syndrome type 2 due to an Exon 13 mutation. The STELLAR trial will explore whether QR-421a (ProQR’s RNA therapy) can slow disease progression or even reverse it.”
What this means for Usher syndrome: There may be a potential drug available to reverse blindness caused by Usher syndrome.
The United States Patent & Trademark Office (USPTO) has approved the usage of mesencephalic-astrocyte-derived neurotrophic factor (MANF) or cerebral dopamine neurotropic factor (CDNF) as a treatment for various retinal disorders including retinitis pigmentosa, macular degeneration, or glaucoma. Both factors can be administered as an eye drop or by intravitreal injection. MANF is believed to have potential because it is a naturally-occurring protein produced by the body to reduce or prevent cell death in response to injury or disease through unfolded protein response.
What this means for Usher syndrome: Since MANF reduces or prevents cell death, in the case of Usher syndrome, it could prevent photoreceptor cells from dying, and thus preserve vision.
ProQR Therapeutics announced that the FDA has cleared the Investigational New Drug (IND) application for QR-421a. QR-421a is a first-in-class investigational RNA-based oligonucleotide designed to address the underlying cause of the vision loss associated with Usher syndrome type 2 and non-syndromic retinitis pigmentosa due to mutations in exon 13 of the USH2A gene. ProQR plans to start enrolling patients in a Phase 1/2 trial named STELLAR in the coming months with preliminary data expected in mid-2019.
Sparing Vision, a French biotech, plans to use a naturally occurring protein called rod-derived cone-viability factor, which binds to a peptide on cone photoreceptor cells in the retina and allows more glucose to enter the cell. By allowing more glucose in, it will slow down or prevent cell death; thus stopping vision loss. This could be beneficial for patients with retinitis pigmentosa.
The nonprofit biomedical institute is seeking to acquire samples of every drug ever developed to see if they can be used to treat diseases besides those for which they were intended. That means collecting roughly 10,000 to 11,000 compounds discovered since the end of the 19th century. Most never made it to market, often because they weren’t effective or had unexpected side effects.
ProQR Therapeutics N.V. announced the results for their clinical trial of QR-110 LCA 10 is on track, and eight out of twelve patients have been enrolled in a Phase 1/2 trial. The results for safety and efficacy for the trial are expected to be announced in the second half of 2018. Currently, they planing to announce data from a QR-421 study for Usher Syndrome. The organization has received $7.5 million in funding from the Foundation Fighting Blindness (FFB) and hopes to use QR-421a for Usher Syndrome Type 2A to target mutations in exon 13.
ReNeuron, a developer of cell-based therapeutics, received a $1.5 million grant award from the UK Innovations agency. The project will allow further development of cell banks of ReNeuron’s hRPC candidate and as well as the development of product release assays for late-stage clinical development. The hRPC therapy is currently being tested in a Phase III clinical trial in the US for patients suffering retinitis pigmentosa.
Caroline C. W. Klaver, MD, PhD; Alberta A. H. J. Thiadens, MD, PhD
Children with retinitis pigmentosa who received vitamin A supplementation were associated with slower rate of cone electroretinogram amplitude compared to children who did not, a small study found.
Rajiv Gandhi Govindaraj, Misagh Naderi, Manali Singha, Jeffrey Lemoine, Michal Brylinski
Researchers at the LSU Computational Systems Biology group have developed a sophisticated and systematic way to identify existing drugs that can be repositioned to treat a rare disease or condition. They have fine-tuned a computer-assisted drug repositioning process that can save time and money in helping these patients receive effective treatment.
Nikolas L. Jorstad, Matthew S. Wilken, William N. Grimes, Stefanie G. Wohl, Leah S. VandenBosch, Takeshi Yoshimatsu, Rachel O. Wong, Fred Rieke, & Thomas A. Reh
NEI-funded researchers use a clue from zebrafish to discover the cues that reprogram Müller glia into retinal neurons.
Sarath Vijayakumar Frederic F. Depreux Francine M. Jodelka Jennifer J. Lentz Frank Rigo Timothy A. Jones Michelle L. Hastings.
These findings provide the first direct evidence of an effective treatment of peripheral vestibular function in a mouse model of USH1C and reveal the potential for using antisense technology to treat vestibular dysfunction.
Harvard Stem Cell Institute (HSCI) researchers at Brigham and Women’s Hospital (BWH) and Massachusetts Eye and Ear Infirmary and colleagues from Massachusetts Institute of Technology (MIT) have developed an approach to replace damaged sound-sensing hair cells, which eventually may lead to therapies for people who live with disabling hearing loss.
Researchers are working to find how fish can regenerate their eyes after they have been injured and if there is a way to make this happen the same way in a human eye.
Scientists from Brigham and Women’s Hospital (BWH), MIT, and Massachusetts Eye and Ear believe they may have found a way to treat hearing loss by regenerating hair cells in the inner ear and hope to begin clinical trials in 18 months.
The Foundation Fighting Blindness Clinical Research Institute (FFB-CRI) has announced an investment of up to $7.5 million to advance the potential therapy into and through a Phase II clinical trial for the usage of N-acetylcysteine-amide (NACA). NACA has recently emerged as a promising drug for Retinitis Pigmentosa because in several FFB-funded lab studies at Johns Hopkins University, it has slowed down retinal degeneration.
Frederic F. Depreux, Lingyan Wang, Han Jiang, Francine M. Jodelka, Robert F. Rosencrans, Frank Rigo, Jennifer J. Lentz, John V. Brigande and Michelle L. Hastings.
ASO delivery to the intra-amniotic cavity modulates neonatal gene expression and may serve as a therapeutic intervention in itself or when paired with a suitable postnatal therapeutic strategy. Further optimization of the method will broaden the potential impact and applicability of this approach.
Kumar N Alagramam, Suhasini R Gopal, Ruishuang Geng, Daniel H-C Chen, Ina Nemet, Richard Lee, Guilian Tian, Masaru Miyagi, Karine F Malagu, Christopher J Lock, William R K Esmieu, Andrew P Owens, Nicola A Lindsay, Krista Ouwehand, Faywell Albertus, David F Fischer, Roland W Bürli, Angus M MacLeod, William E Harte, Krzysztof Palczewski & Yoshikazu Imanishi.
A new study published in Nature Chemical Biology reports the first small molecule targeted therapy for progressive hearing loss in a mouse model of USH3, an USH classified by progressive loss of hearing and vision starting in the first few decades of life along with variable balance disorder.
Rajarshi Ghosh, Wang Likun, Eric S. Wang, B. Gayani K. Perera, Aeid Igbaria, Shuhei Morita, Kris Prado, Maike Thamsen, Deborah Caswell, Hector Macias, Kurt F. Weiberth, Micah J. Gliedt, Marcel V. Alavi, Sanjay B. Hari, Arinjay K. Mitra, Barun Bhhatarai, Stephan C. Schürer, Erik L. Snapp, Douglas B. Gould, Michael S. German, Bradley J. Backes, Dustin J. Maly, Scott A. Oakes, and Feroz R. Papa.
Allosteric inhibition of the IRE1α RNase preserves cell viability and function during endoplasmic reticulum stress.
New research shows that modifying a particular protein, IRE1, can put off cell death.
Jennifer J Lentz, Francine M Jodelka, Anthony J Hinrich, Kate E McCaffrey, Hamilton E Farris, Matthew J Spalitta, Nicolas G Bazan, Dominik M Duelli, Frank Rigo & Michelle L Hastings
New research shows that hearing and vestibular function can be rescued in a mouse model of Usher 1c using an antisense oligonucleotide.
"Ray of hope for human Usher syndrome patients": Uwe Wolfrum and his colleagues at Johannes Gutenberg University Mainz are increasing our understanding of Usher syndrome.
BioDiem has strengthened the preclinical case for its BDM-E eye disease drug with further positive results from formal studies that will help progress out-licensing opportunities for the drug. BDM-E has received Orphan Drug designation from the United States Food and Drug Administration for the treatment of the inherited degenerative eye disorder, retinitis pigmentosa.
This study, conducted in mice modelling the human disease retinitis pigmentosa, showed that the drug norgestrel could "rescue" light-detecting retinal cells. The synthetic progestin hormone, an active component of the contraceptive "mini-Pill," allowed mice which should have gone blind to retain their sight. A new study is now planned for next year to see if humans experience the same protective effects.
New treatment for nonsense mutations may soon be ready for use in Usher syndrome patients. A molecule known as PTC124 appears to cause the stop signal in a mutated USH1C to be ignored, allowing the protein to be formed normally in cell cultures.
Neurotech announced in Investigative Ophthalmology and Visual Science that their NT-501 implant slowed the loss of photoreceptors in three patients, including one with Usher syndrome type 2.
Jennifer Phillips, Ph.D., reviewed and put together a 'FAQ' on a small observational study of the effects of Valproic Acid, which was published in the summer of 2010 online in the British Journal of Ophthalmology.
QLT091001 is an orally administered synthetic retinoid replacement for 11-cis-retinal, which is a key biochemical component of the visual retinoid cycle, and is under investigation for the treatment of LCA and RP.
Some unexpected effects of lead exposure that may one day help prevent and reverse blindness have been uncovered.
Researchers at Trinity College Dublin have reported the development of a new drug delivery system which has the potential to treat degenerative diseases of the retina, including retinitis pigmentosa.
Neurotech Pharmaceuticals, Inc., today announced that the Company's product candidate, NT-501 demonstrated a strong biologic effect in two Phase 2 clinical trials for retinitis pigmentosa (RP)
Aminoglycocides have shown promising effects in cell cultures and may someday be used to suppress mutations involved in Usher syndrome.