Gene Therapy News
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Wake Forest Institute for Regenerative Medicine (WFIRM) scientists have fine-tuned their delivery system to send a DNA editing tool to alter DNA sequences and modify gene function. With this new method, researchers can package together the Cas9 protein and guide RNA for the CRISPR mediated gene editing. Previously, the two components—Cas9 protein and guide RNA—had to be delivered separately which was not as efficient. The new system offers the delivery efficiency of conventional lentiviral vectors that enable transient Cas9 expression. Transient Cas9 expression means a decrease chance of having unwanted effects when using this therapy.
What this means for Usher syndrome: For Usher patients, improving the efficacy of CRISPR technology means that they will be able to receive a more efficient treatment with very low side-effects.
Case Western Reserve University (CWRU) and Boston-based genetic medicine company Akouos have entered into an exclusive licensing agreement to develop a patented gene therapy that could potentially treat hearing loss associated with a type of Usher syndrome. It may be able to stop the progression of hearing loss and prevent deafness in people with USH3A. The hearing loss is “sensorineural,” meaning it is caused by abnormalities of the inner ear, while the vision is due to the degeneration of the retina at the back of the eye. The technology has allowed researchers to develop a more precise animal model of the hearing loss associated with Usher syndrome type 3A, and the potential for the technology to deliver the preservation of hearing and quality of life for children and adults diagnosed with the genetic disorder.
What this means for Usher syndrome: The development of a more precise animal model for USH3A will exponentially expedite the identification of novel and more efficient therapies to slow or complete stop the progression of this disease.
CRISPR (clustered regularly interspaced palindromic repeats) is a cutting-edge genetic editing technique that enables the targeting and editing of specific sequences in the human DNA. CRISPR is known to result in unwanted gene edits that can occur when working with embryos. However, if the edits are done on adult humans and children, no transference occurs, and any potential damage remains to one individual. Allergan and Editas Medicine EDIT, a pharmaceutical company in Cambridge, Massachusetts, has announced in July they are ready to enroll subjects into its first of its kind CRISPR-based therapy trials, a development that would involve gene editing inside the human body. A propriety EDIT-101 injection is administrated into the eye to deliver “gene-altering machinery” directly to the photoreceptor cells. Once injected, EDIT-101 cuts out the mutated DNA, including CEP290 gene responsible for progressive photoreceptor-cell loss, which leads to an inherited type of blindness, Leber congenital amaurosis 10. The goal is for this cut to be repair by the DNA-repairing process that will lead to the expression of the normal protein.
What this means for Usher syndrome: potential treatments for vision loss are being discovered every day. In this case, the use of CRISPR technology will help to replace and repair mutations present in the Usher proteins and thus, help to restore vision as well as hearing.
The identification of the causes and understandings of the functions of many inherited retinal diseases (IRDs) has led to the development of exciting new gene/disease specific treatment opportunities. There are numerous treatments available that are aimed at a level of not just targeting specific genes but also certain mutations. Therefore, gene/disease specific treatments rely on persistent target cells and sufficient visual function to work effectively. However, many patients are outside of this window of opportunity and must rely on other approaches.
What this means for Usher syndrome: there are many different treatment and therapy options that are in development for retinitis pigmentosa.
Researchers developed a mouse model with genetically defective rods that mimics developmental blindness disorders in humans. A team examined the structure of the defective retina, as well as its response to light with or without gene therapy. The rods that received gene therapy not only regained normal light response, but also recovered normal connections to other retinal neurons.
What this means for Usher syndrome: If future treatments for Usher syndrome can save photoreceptors from dying, the saved cells may be able to reconnect and become functional.
GenSight Biologics, a biopharma company focused on discovering and developing gene therapies for retinal neurodegenerative diseases and central nervous system disorders, announced that the independent Data Safety Monitoring Board (DSMB) has completed its first safety review of the ongoing PIONEER Phase I/II clinical trial of GS030 combining gene therapy and optogenetics for the treatment of Retinitis Pigmentosa (RP). No safety issues have been found for the first cohort of subjects who received a single intravitreal injection of 5e10 vg combined with a wearable optronic visual stimulation device. Therefore, the DSMB has recommended moving forward with the plan without any modification to the protocol and recruiting the second cohort of subjects to receive an escalated dose of 1.5e11 vg.
What this means for Usher syndrome: This clinical trial could lead to a treatment for RP and may be applicable to Usher syndrome.
Karen Andersen, Samira Kiani and their colleagues at Arizona State University described a method of rendering the CRISPR-Case9 gene-editing tool “immunosilent,” potentially allowing the editing and repair of genes to be accomplished reliably and without activating an immune response. Their study is the first to predict accurately the dominant binding sites or epitopes responsible for immune recognition of the Cas9 protein and experimentally target them for modification. These findings bring CRISPR a step closer to a safer clinical application.
What this means for Usher syndrome: This discovery could help pave the way toward FDA approval of CRISPR/Cas9 gene editing therapies to treat Usher syndrome.
Ophthotech has licensed exclusive rights to develop novel adeno-associated virus (AAV) gene therapy candidates for Best disease and other bestrophinopathies from University of Pennsylvania (Penn) and the University of Florida Research Foundation (UFRF). The agreement allowed Ophthotech to enter talks with Penn and UFRF to acquire a license for novel AAV serotype 2 based gene therapy product candidates for Best disease, an orphan inherited degenerative retinal disease caused by mutations in the BESTI gene. Additionally, Ophthotech says it expects to initiate a Phase I/II clinical trial for the Best disease candidate in the first half of 2021.
What this means for Usher syndrome: If the first clinical trials for Best disease using this novel AVV gene therapy are successful, this means Ophthotech will probably look for other eye-related diseases like Usher syndrome.
Adeno-associated viruses (AAV) engineered to target specific cells into the retina can be injected directly into the vitreous of the eye to deliver genes more precisely than with wild type AAVs, which must be injected directly under the retina. Researchers at the University of California, Berkeley inserted a gene for a green-light receptor into the eyes of blind mice, and a month later the mice could maneuver obstacles as easily as mice without visual impairments. The mice could use motion, brightness changes over time, and fine detail on an iPad.
What this means for Usher syndrome: Retinal delivery of AAV can always have the adverse effects of tissue inflammation and/or retinal detachment. This new strategy, delivering the modified virus into the vitreous, will prevent those side effects. For Usher patients, this means that, if successful, this therapy will increase the probability of success in restoring vision.
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.
Scientists at the Francis Crick Institute have discovered a set of simple rules that can determine the precision of CRISPR/Cas9 genome editing in human cells. These rules could help to improve the efficiency and safety of genome editing in both the lab and the clinic. By examining the effect of CRISPR genome editing at 1491 target sites across 450 genes in human cells, the team have discovered that the outcomes can be predicted based on simple rules. In this study, researchers have found that the outcome of a particular gene edit depends on the fourth letter from the end of the RNA guide, synthetic molecules made up of about 20 genetic letters (A, T, C, G). “The team discovered that if this letter is an A or a T, there will be a very precise genetic insertion; a C will lead to a relatively precise deletion and a G will lead to many imprecise deletions. Thus, simply avoiding sites containing a G makes genome editing much more predictable.”
What this means for Usher syndrome: Scientists will theoretically be able to repair the mutation present in an Usher gene by selecting the correct genetic letter from the end of the RNA guide.
The light scalpel has the potential of preventing the “ripple effect” that occurs following a trigger that leads to glaucoma or macular degeneration. By utilizing the femtosecond laser, small holes appear in the cells of the eye’s retina, making it possible to effectively inject drugs or genes in specific areas of the eye. The key feature of this technology is extreme precision because through the usage of gold nanoparticles, the light scalpel makes it possible to precisely locate the family of cells where the doctor will have to intervene.
What this means for Usher syndrome: In CRISPR/Cas9 editing or drug delivery, the utilization of the femtosecond laser will improve the delivery of the specific compound to the affected area with minimum side effects.
A US clinician has received a five-year £6.1 million grant to investigate the potential of advancing a gene therapy currently used in dogs to help retinitis pigmentosa (RP) patients. The treatment restored the night vision and stopped the progression of the daytime vision-loss in dogs with progressive retinal atrophy (PRA). PRA is an inherited condition in dogs and is caused by the same genes that are responsible for RP. This new grant will allow clinicians to build on primary studies in preparation for a possible clinical trial in human patients with RP.
For the last couple years, Ophthalmologist Dr. Kang Zhang and UC San Diego researchers have been working with CRISPR by injecting it into the eyes of mice with Retinitis Pigmentosa. According to Dr. Zhang, they have been able to bring back 30 percent of vision and sometimes 50 percent of vision. Zhang’s lab has recently received the green light to start clinical trials this fall and if the trial goes well then CRISPR can be applied to all human genetic diseases or conditions.
Researchers at Duke University believe they have developed an approach to treat retinal conditions such as Retinitis Pigmentosa, which include misfolded proteins in the cell that the eye cannot process. Scientists have shown by boosting the cells’ ability to process misfolded proteins could keep them from clustering inside the cell. They created and tested the strategy in mice, significantly delaying the onset of blindness. This technique would not be used to prevent cell death retinal diseases but also neurodegenerative diseases such as Huntington’s, Parkinson’s, and Alzheimer’s.
Ekaterina S. Lobanova, Stella Finkelstein, Jing Li, Amanda M. Travis, Ying Hao, Mikael Klingeborn, Nikolai P. Skiba, Raymond J. Deshaies, Vadim Y. Arshavsky
New research outlines a strategy that in mouse models significantly delayed the onset of blindness from inherited retinal degeneration such as retinitis pigmentosa.
Bill Whitaker of CBS’s 60 minutes interviewed Feng Zeng to learn more about Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR). Whitaker’s interview with Zhang provides basic facts that are accessible to anyone on CRISPR and its possibility of not only curing genetic diseases but preventing them altogether.
A retinal implant allowed a 69 year old woman with macular degeneration to see more than double the usual number of letters on the vision chart. Luxturna, the gene therapy was approved by the FDA in 2017, corrects a mutation found in Leber congential amaurosis (LCA).
Odylia Therapeutics aims to advance gene therapies that are getting left behind. Odylia’s focus is gene therapies with scientific promise but limited commercial opportunity that maybe gathering dust on the selves of labs or companies.
GenSight will start a clinical trial in the UK testing a combination of gene therapy and a wearable device to restore sight in patients with retinitis pigmentosa. The Phase I and II trial, PIONEER, will study the safety and tolerability of GenSight’s therapy called GS030, in patients with end-stage retinitis pigmentosa with vision not better than “counting fingers.” The first patient will be tested in the first quarter of 2018 and outcomes will be measured after a year.
What this means for Usher syndrome: If GenSight’s therapy succeeds, it will very likely be tested in other diseases such as Usher syndrome.
GenSight Biologics, a biopharma company focused on discovering and developing innovative gene therapies for retinal neurodegenerative diseases and central nervous system disorders, announced UK Medicines and Healthcare Regulatory Agency (MHRA) acceptance of the Company’s Clinical Trial Application (CTA) to initiate the PIONEER Phase I/II study of GS030 in patients with Retinitis Pigmentosa (RP).
Raghavi Sudharsan, Daniel P. Beiting, Gustavo D. Aguirre, William A. Beltran
In studying the late stages of disease in two different canine models of retinitis pigmentosa, a group of progressive and inherited blinding diseases, researchers found commonalities, specifically involving the innate immune system. The findings point to potential new treatment options for the conditions.
Geng R, Omar A., Gopal SR, Chen DH, Stepanyan R, Basch ML, Dinculescu A, Furness DN, Saperstein D, Hauswirth W, Lustig LR, Alagramam KN
Researchers developed a new USH3 mouse model that displays delayed-onset progressive hearing loss, then tested a viral therapy to preserve hearing in the mouse models. Their results show that gene therapy is a promising approach to preserve hearing in USH3 patients.
Samantha R. De Silva, Alun R. Barnard, Steven Hughes, Shu K. E. Tam, Chris Martin, Mandeep S. Singh, Alona O. Barnea-Cramer, Michelle E. McClements, Matthew J. During, Stuart N. Peirson, Mark W. Hankins and Robert E. MacLaren
Oxford researchers have shown that gene therapy might help reverse blindness caused by retinitis pigmentosa by reprogramming cells at the back of the eye to become light sensitive.
View the journal publication of this study: http://www.pnas.org/content/early/2017/09/26/1701589114
Alice Emptoz, Vincent Michel, Andrea Lelli, Omar Akil, Jacques Boutet de Monvel, Ghizlene Lahlou, Anaïs Meyer, Typhaine Dupont, Sylvie Nouaille, Elody Ey, Filipa Franca de Barros, Mathieu Beraneck, Didier Dulon, Jean-Pierre Hardelin, Lawrence Lustig, Paul Avan, Christine Petit, Saaid Safieddine
Scientists have recently restored hearing and balance in a mouse model of Usher syndrome type 1G characterized by profound congenital deafness and vestibular disorders caused by severe dysmorphogenesis of the mechanoelectrical transduction apparatus of the inner ear's sensory cells. These findings open up new possibilities for the development of gene therapy treatments for hereditary forms of deafness.
Scientists at the Boston Children’s Hospital, Massachusetts Eye and Ear and Harvard Medical School have spent several years refining a technique to repair one of the common genetic disorders that cause deafness, offering hope to millions. The genetic disorder they repaired is Usher syndrome.
Jie Zhu, Chang Ming, Xin Fu, Yaou Duan, Duc Anh Hoang, Jeffrey Rutgard, Runze Zhang, Wenqiu Wang, Rui Hou, Daniel Zhang, Edward Zhang, Charlotte Zhang, Xiaoke Hao, Wenjun Xiong, Kang Zhang.
Using the gene-editing tool CRISPR/Cas9, researchers have reprogrammed mutated rod photoreceptors to become functioning cone photoreceptors, reversing cellular degeneration and restoring visual function in two mouse models of retinitis pigmentosa.
For more information on this study: https://www.nature.com/cr/journal/vaop/ncurrent/full/cr201757a.html
Researchers from the National Institute on Deafness and Other Communication Disorders (NIDCD) and Johns Hopkins University School of Medicine showed that gene therapy was able to restore balance and hearing in genetically modified mice that mimic Usher Syndrome.
Kevin Isgrig, Jack W. Shteamer, Inna A. Belyantseva, Meghan C. Drummond, Tracy S. Fitzgerald, Sarath Vijayakumar, Sherri M. Jones, Andrew J. Griffith, Thomas B. Friedman, Lisa L. Cunningham, Wade W. Chien
For more information on this study: http://www.cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1525-0016(17)30013-8
Allergan and Editas Medicine have made an alliance to work with the gene-editing CRISPR to help prevent vision deterioration.
In this study, researchers introduced CRISPR into retinal cells, tested this genome tool to remove the Nrl gene in mice and three different mouse models of retinal degeneration. By measuring gene expression and examining the retinal cells, the researchers confirmed that rods became more cone-like, as predicted which allowed for rod degeneration to be prevented or slowed.
Yu W, Mookherjee S, Chaitankar V, Hiriyanna S, Kim JW, Brooks M, Ataeijiannati Y, Sun X, Dong L, Li T, Swaroop A, Wu Z
For more information on this study: http://www.nature.com/articles/ncomms14716
Lukas D Landegger, Bifeng Pan, Charles Askew, Sarah J Wassmer, Sarah D Gluck, Alice Galvin, Ruth Taylor, Andrew Forge, Konstantina M Stankovic, Jeffrey R Holt & Luk H Vandenberghe.
Two back-to-back papers in Nature Biotechnology describe how a team at Boston Children's Hospital and Harvard Medical School developed a new vector for gene delivery and restored hearing and balance in a mouse model with the Ush1c mutation.
Bifeng Pan, Charles Askew, Alice Galvin, Selena Heman-Ackah, Yukako Asai, Artur A Indzhykulian, Francine M Jodelka, Michelle L Hastings, Jennifer J Lentz, Luk H Vandenberghe, Jeffrey R Holt& Gwenaëlle S Géléoc.
Working with a mouse model of a human mutation, Dr. Gwen Géléoc and colleagues delivered a normal copy of the USH1C gene to the inner ear soon after the mice were born, which led to robust improvements enabling profoundly deaf and dizzy mice to hear sounds at the level of whispers and recover proper balance function.
Researchers have discovered a holy grail of gene editing -- the ability to, for the first time, insert DNA at a target location into the non-dividing cells that make up the majority of adult organs and tissues. The technique, which the team showed was able to partially restore visual responses in blind rodents, will open new avenues for basic research and a variety of treatments, such as for retinal, heart and neurological diseases.
In the next month, scientists from RetroSense Therapeutics will inject a virus deep into the retina of legally blind human volunteers. If this works, it means that optogenetics — a revolutionary neuroscience technique using channelrhodopsin-2 and other light-activated proteins — is feasible in humans as therapy.
Astra Dinculescu, Rachel M. Stupay , Wen-Tao Deng, Frank M. Dyka, Seok-Hong Min, Sanford L. Boye, Vince A. Chiodo, Carolina E. Abrahan, Ping Zhu, Qiuhong Li, Enrica Strettoi, Elena Novelli, Kerstin Nagel-Wolfrum, Uwe Wolfrum, W. Clay Smith, William W. Hauswirth.
The ongoing challenge to develop an animal model mimicking the effects of Usher III (in particular, the loss of vision) makes it impossible for researchers to test therapies in development using conventional means. This study has important implications for designing gene therapy studies in a rational manner, to produce Clarin-1 in the correct cell type and at levels that mimic its natural production.
Massachusetts researchers have made a significant advancement toward a gene therapy treatment that would reverse deafness.
A new study questions whether gene therapy to treat Leber congenital amaurosis type 2 (LCA2) actually saves the rods and cones, the photoreceptor cells that provide vision.
According to scientists at Washington University School of Medicine in St. Louis, "Doctors may one day treat some forms of blindness by altering the genetic program of the light-sensing cells of the eye."
Three patients have been treated so far with no serious adverse events after six months. They have been allowed to proceed to delivering a larger dose to the next group of patients.
"Gene therapy 'gave me sight back'" An article from the BBC about the impact of gene therapy on patients with LCA. Similar gene therapies are planned for people with Usher.
The US Food and Drug Administration (FDA) has approved Oxford BioMedica's Investigational New Drug (IND) application for the Phase I/IIa clinical development of UshStat to treat Usher syndrome type 1B. Oxford Biometica will enroll 18 patients with Usher type 1b at the Casey Eye Institute in Portland, Oregon. The study will be lead by Dr. Richard Weleber.
University of California, Berkeley professor of neurobiology, John Flannery, is developing ways to cure genetic diseases of the retina.
Researchers at Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences at Tufts have developed a new tool for gene therapy that significantly increases gene delivery to cells in the retina.
Oxford BioMedica, a U.K. partner of the Foundation Fighting Blindness, has received orphan drug designation from the European Medicines Agency (EMEA) for their emerging Usher syndrome gene therapy known as UshStat. The company is planning to launch a clinical trial for UshStat in 2011. The EMEA is the European Union’s regulatory agency for medicinal products. It functions similarly to the FDA in the U.S.
EU-funded scientists have succeeded in awakening dormant vision cones, an achievement that may lead to saving millions of people from going blind. The dormant cones, which normally remain in the eye even after blindness has occurred, were successfully reactivated by an international team of scientists led by the Friedrich Miescher Institute in Switzerland and the Institut de la vision in France.
Gene delivery to mitotic and postmitotic photoreceptors via compacted DNA nanoparticles results in improved phenotype in a mouse model of retinitis pigmentosa.
Unrelated to Usher syndrome, but the successful treatment of two children with ALD, a rare genetic disease, could impact gene therapy as an RP treatment. From NPR: "This marks a high point for the field of gene therapy."
A 9-year-old boy who received gene therapy for Leber congenital amaurosis (LCA) is interviewed on CBS Morning News with his parents and Dr. Stephen Rose of the Foundation Fighting Blindness. The segment includes a before and after video of him navigating a maze.
Pennsylvania researchers using gene therapy have made significant improvements in vision in 12 patients with Leber congenital amaurosis (LCA). The findings may offer hope for those with macular degeneration and retinitis pigmentosa.