Category Archives: Gene therapy

For Immediate Release: December 18, 2017

Espaol

The U.S. Food and Drug Administration today approved Luxturna (voretigene neparvovec-rzyl), a new gene therapy, to treat children and adult patients with an inherited form of vision loss that may result in blindness. Luxturna is the first directly administered gene therapy approved in the U.S. that targets a disease caused by mutations in a specific gene.

Todays approval marks another first in the field of gene therapy both in how the therapy works and in expanding the use of gene therapy beyond the treatment of cancer to the treatment of vision loss and this milestone reinforces the potential of this breakthrough approach in treating a wide-range of challenging diseases. The culmination of decades of research has resulted in three gene therapy approvals this year for patients with serious and rare diseases. I believe gene therapy will become a mainstay in treating, and maybe curing, many of our most devastating and intractable illnesses, said FDA Commissioner Scott Gottlieb, M.D. Were at a turning point when it comes to this novel form of therapy and at the FDA, were focused on establishing the right policy framework to capitalize on this scientific opening. Next year, well begin issuing a suite of disease-specific guidance documents on the development of specific gene therapy products to lay out modern and more efficient parameters including new clinical measures for the evaluation and review of gene therapy for different high-priority diseases where the platform is being targeted.Luxturna is approved for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy that leads to vision loss and may cause complete blindness in certain patients.

Hereditary retinal dystrophies are a broad group of genetic retinal disorders that are associated with progressive visual dysfunction and are caused by mutations in any one of more than 220 different genes. Biallelic RPE65 mutation-associated retinal dystrophy affects approximately 1,000 to 2,000 patients in the U.S. Biallelic mutation carriers have a mutation (not necessarily the same mutation) in both copies of a particular gene (a paternal and a maternal mutation). The RPE65 gene provides instructions for making an enzyme (a protein that facilitates chemical reactions) that is essential for normal vision. Mutations in the RPE65 gene lead to reduced or absent levels of RPE65 activity, blocking the visual cycle and resulting in impaired vision. Individuals with biallelic RPE65 mutation-associated retinal dystrophy experience progressive deterioration of vision over time. This loss of vision, often during childhood or adolescence, ultimately progresses to complete blindness.

Luxturna works by delivering a normal copy of the RPE65 gene directly to retinal cells. These retinal cells then produce the normal protein that converts light to an electrical signal in the retina to restore patients vision loss. Luxturna uses a naturally occurring adeno-associated virus, which has been modified using recombinant DNA techniques, as a vehicle to deliver the normal human RPE65 gene to the retinal cells to restore vision.

The approval of Luxturna further opens the door to the potential of gene therapies, said Peter Marks, M.D., Ph.D., director of the FDAs Center for Biologics Evaluation and Research (CBER). Patients with biallelic RPE65 mutation-associated retinal dystrophy now have a chance for improved vision, where little hope previously existed.

Luxturna should be given only to patients who have viable retinal cells as determined by the treating physician(s). Treatment with Luxturna must be done separately in each eye on separate days, with at least six days between surgical procedures. It is administered via subretinal injection by a surgeon experienced in performing intraocular surgery. Patients should be treated with a short course of oral prednisone to limit the potential immune reaction to Luxturna.

The safety and efficacy of Luxturna were established in a clinical development program with a total of 41 patients between the ages of 4 and 44 years. All participants had confirmed biallelic RPE65 mutations. The primary evidence of efficacy of Luxturna was based on a Phase 3 study with 31 participants by measuring the change from baseline to one year in a subjects ability to navigate an obstacle course at various light levels. The group of patients that received Luxturna demonstrated significant improvements in their ability to complete the obstacle course at low light levels as compared to the control group.

The most common adverse reactions from treatment with Luxturna included eye redness (conjunctival hyperemia), cataract, increased intraocular pressure and retinal tear.

The FDA granted this application Priority Review and Breakthrough Therapy designations. Luxturna also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The sponsor is receiving a Rare Pediatric Disease Priority Review Voucher under a program intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. A voucher can be redeemed by a sponsor at a later date to receive Priority Review of a subsequent marketing application for a different product. This is the 13th rare pediatric disease priority review voucher issued by the FDA since the program began.

To further evaluate the long-term safety, the manufacturer plans to conduct a post-marketing observational study involving patients treated with Luxturna.

The FDA granted approval of Luxturna to Spark Therapeutics Inc. The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines, and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nations food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Luxturna is the first gene therapy approved in the U.S. to target a disease caused by mutations in a specific gene

Andrea Fischer301-796-0393

888-INFO-FDAOCOD@fda.hhs.gov

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FDA approves novel gene therapy to treat patients with a ...

...FLOOD WATCH REMAINS IN EFFECT UNTIL 6 AM EDT EARLY THIS MORNING...* WHAT...Flooding caused by excessive rainfall continues to bepossible.* WHERE...Portions of New Jersey...and Pennsylvania...including thefollowing areas...in New Jersey...Hunterdon, Mercer, Middlesex,Morris, Somerset, and Warren. In Pennsylvania...EasternMontgomery, Lehigh, Lower Bucks, Northampton, Philadelphia, UpperBucks, and Western Montgomery.* WHEN...Until 6 AM EDT early this morning.* IMPACTS...Excessive runoff may result in flooding of rivers,creeks, streams, and other low-lying and flood-prone locations.* ADDITIONAL DETAILS...- Rainfall amounts of one half to an inch and a half of rainhave already fallen across the watch area. Heavy rainfallrates of 1/4 to 1/2 inch per hour are possible throughdaybreak, which may result in additional rises of creeks andstreams.- http://www.weather.gov/safety/flood

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Genprex, Inc. is a clinical-stage gene therapy company focused on developing life-changing therapies for patients with cancer and diabetes. - 69News...

BERKELEY, Calif., April 18, 2022 /PRNewswire/ -- Bakar Labs, the incubator at UC Berkeley's Bakar BioEnginuity Hub (BBH), announced today a unique collaboration with the Cystic Fibrosis Foundation to accelerate the application of new technologies for the treatment of cystic fibrosis. The CF Foundation is sponsoring a "Golden Ticket" competition at the new incubator and is encouraging companies with emerging technology in gene editing, gene delivery, and gene therapy/gene insertion that may work in CF to apply. Applications open Monday, May 2.

Up to three potential winners will be provided lab space and facilities at Bakar Labs. In addition to lab and office space, companies will have access to the extensive resources of the CF Foundation, including scientific experts and advice, lab/research tools and techniques, an extensive patient registry, clinical trial design support, and a Therapeutics Development Network of over 90 clinical trial sites in the US.

"Working with the CF Foundation entirely fits with the spirit of entrepreneurship to benefit society," said Regis Kelly, PhD, OBE, director of Bakar Labs and executive director at QB3, the University of California entrepreneurship institute that partnered with Berkeley to launch BBH. "Our double bottom line at Bakar Labs emphasizes public good on an equal basis with the potential for profit."

"This collaboration is inspiring," said David Schaffer, PhD, executive director of BBH. "Students and professors will see the potential of entrepreneurship fused with the resources and mission of a major patient advocacy organization. It will be a tremendous example that could well spur partnerships in a broad range of areas." Schaffer is Hubbard Howe Distinguished Professor at UC Berkeley, with appointments in the departments of chemical and biomolecular engineering, bioengineering, and molecular and cell biology.

"Collaborating with the CF Foundation creates an extraordinary opportunity," said Gino Segr, PhD, managing director of Bakar Labs. "We will draw attention to a devastating condition and make available special resources that will inspire and support a community of researchers and entrepreneurs to apply their breakthrough ideas to the development of a cure. We're delighted that Bakar Labs is now a proving ground for major advances."

A focus on entrepreneurship for the public good is now widely seen by many philanthropies and investors as a valuable and effective complement to their support of academic scholarship. The CF Foundation has achieved global admiration for its support of disease-related research efforts, not only by scientists in academic labs but by entrepreneurs in startup companies.

For more information, visit the CF Foundation Golden Ticket page on the Bakar Labs website or contact [emailprotected].

About the Bakar BioEnginuity Hub

The Bakar BioEnginuity Hub empowers fearless founders and founders in the making to realize bold solutions to our world's most pressing problems. Focused on people working at the convergence of the life sciences with the physical, engineering, and data sciences, the Bakar BioEnginuity Hub provides the intellectual, entrepreneurial, and community resources needed to learn and then to launch their own ventures. The Bakar BioEnginuity Hub is located on the UC Berkeley campus in the stunning Woo Hon Fai Hall. Visit bioenginuityhub.berkeley.edu.

About Bakar Labs

Bakar Labs is the flagship life science-focused incubator at UC Berkeley's Bakar BioEnginuity Hub. Operated by QB3, Bakar Labs provides extensive equipment, lab and office facilities, and a community of like-minded entrepreneurs to helps startups grow. Bakar Labs can support as many as 50 early-stage companies from around the world focused on translating life science based innovations that promise to improve human health. No UC affiliation is required to join. For information about how to join or form a partnership, visit bakarlabs.berkeley.edu.

Contact:

Kaspar Mossman(415) 514-9790[emailprotected]

SOURCE Bakar Labs

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Bakar Labs and the Cystic Fibrosis Foundation Support Entrepreneurs to Develop New Genetic Therapies for CF - PR Newswire

Clinical Neurosciences

Location: Southampton General HospitalSalary: 31,406 to 37,467 Per annumFull Time Fixed Term until 30 June 2023Closing Date: Wednesday 11 May 2022Interview Date: To be confirmedReference: 1784522FC

HAVE YOU GOT THE VISION TO CHANGE THE FUTURE?

The University of Southampton is committed to excellence in all we do, applying our insights and inventiveness to solve the most complex societal and environmental challenges. As a world-leading, research-intensive university, with a strong and high-quality educational offering, we are renowned for our innovation and enterprise and are within the top 1% of universities worldwide.

The Vision Sciences Research Group, based in the School of Clinical and Experimental Sciences have an exciting opportunity for a Post-doctoral Research Fellow to support an industry funded project: a proof of concept study to assess the efficacy of a gene therapy product in a laser-induced choroidal neovascularisation (CNV) mouse model.

You will join an established interdisciplinary team of research staff, students and senior academics studying retinal disease therapies. You will have prior molecular and cell biology laboratory experience, preferably involving animal (mouse) tissue. Your direct responsibilities will involve the downstream processing and analysis of mouse tissue from gene therapy experiments specifically: ELISA, qPCR, immunohistochemistry and confocal microscopy.

Additionally, you will lead in the statistical analysis of experimental results, the preparation of figures for peer-reviewed publications and the presentation of results at appropriate events. You will have a strong background in the skills involved in the day-to-day running of a research laboratory, such as preparing/updating risk assessments and standard operating procedures, maintaining laboratory consumables and equipment as well as supervising technical & junior research staff, as required.

Practical laboratory and statistical analysis skills are essential for this role, as well as an attention to detail and an ability to work pro-actively with colleagues. Prior experience of working with animal tissue and a history of publication in scientific journals would be a distinct advantage.

This post-doctoral position is full-time and fixed term until 30 June 2023. Informal inquiries should be directed to Prof Andrew Lotery, Chair of Ophthalmology, (A.J.Lotery@soton.ac.uk) in the first instance.

Applications for Research Fellow positions will be considered from candidates who are working towards or nearing completion of a relevant PhD qualification. The title of Research Fellow will be applied upon successful completion of the PhD. Prior to the qualification being awarded the title of Senior Research Assistant will be given.

Application Procedure:

You should submit your completed online application form at https://jobs.soton.ac.uk. The application deadline will be midnight on the closing date stated above. If you need any assistance, please call Jane Sturgeon (HR Recruitment Team) on +44 (0) 23 8059 4043 or email recruitment@soton.ac.uk Please quote reference 1784522FC on all correspondence.

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Research Fellow in Retinal Gene Therapy job with UNIVERSITY OF SOUTHAMPTON | 290122 - Times Higher Education

IRVINE, Calif. & BASEL, Switzerland--(BUSINESS WIRE)--Urovant Sciences, a wholly-owned subsidiary of Sumitovant Biopharma Ltd., announced that data from a Phase 2a trial of the investigational, novel gene therapy, URO-902, will feature as a late-breaker at the 2022 annual meeting of the American Urological Association (AUA2022), May 13-16, in New Orleans, Louisiana. The plenary presentation will include interim efficacy and safety data on URO-902 from the ongoing Phase 2a trial.

In addition, two podium presentations at AUA2022 will feature new analyses of data from the EMPOWUR 40-week extension trial of GEMTESA (vibegron) 75 mg, a Phase 3, randomized, double blind, active-comparator controlled multicenter study to evaluate long-term safety and efficacy in patients with symptoms of OAB. GEMTESA is approved by the U.S. Food and Drug Administration (FDA) for the treatment of OAB in adults with symptoms of UUI, urgency, and urinary frequency.

Overactive bladder remains a condition in need of additional treatment options. We look forward to sharing new data related to the use of GEMTESA in the OAB patient population as well as providing an initial read-out on the progress of our investigational gene therapy, URO-902, said Sef Kurstjens, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Urovant Sciences. We believe that URO-902 could potentially offer a new treatment option for patients with overactive bladder who have been inadequately managed by oral pharmacologic therapy, if approved by the FDA. The two podium presentations on GEMTESA will also add to the scientific and medical communitys understanding of this important therapy.

Data on the potential novel gene therapy, URO-902, will be presented during Friday mornings plenary session:

Late-Breaking Abstract PLLBA-03, presented by Kenneth M. Peters, M.D., principal investigator, and Chief of the Department of Urology at Beaumont Hospital, Royal Oak; Medical Director of the Beaumont Womens Urology and Pelvic Health Center and professor and Chair of Urology of the Oakland University William Beaumont School of Medicine in Rochester, Michigan., titled, Efficacy and Safety of a Novel Gene Therapy (URO-902; pVAX/hSlo) in Female Patients with Overactive Bladder and Urge Urinary Incontinence: Results from a Phase 2a Trial. This presentation will take place on Friday, May 13, at 11:21 to 11:29 a.m. CDT during the plenary session in the Ernest N. Morial Convention Center, Great Hall A.

Data on GEMTESA will also be featured in two podium presentations at the conference on May 15, 2022:

Abstracts are available in the Journal of Urology at the following links:

URO-902: https://www.auajournals.org/doi/10.1097/JU.0000000000002671.03

EMPOWUR-EXT older adults: https://www.auajournals.org/doi/10.1097/JU.0000000000002596.11

EMPOWUR-EXT PRO: https://www.auajournals.org/doi/10.1097/JU.0000000000002596.12

About the Phase 2a Study of URO-902

This 48-week multicenter, randomized, double blind, placebo-controlled, dose-escalation study will evaluate the efficacy, safety, and tolerability of a single administration of URO-902, a novel gene therapy being developed for patients with OAB who have failed oral pharmacologic therapy. URO-902 is administered via direct intradetrusor injections via cystoscopy into the bladder wall under local anesthesia in patients who are experiencing OAB symptoms and UUI.

The Phase 2a trial includes 80 female patients in two cohorts. The first cohort received either a single administration of 24 mg of URO-902 or matching placebo into the bladder wall, and the second cohort received 48 mg of URO-902 or matching placebo into the bladder wall. Patients will be followed for up to 48 weeks after initial administration. Exploratory endpoints included change from baseline to week 12 in mean daily micturitions, urgency episodes, UUI episodes, and quality of life measures, as well as assessing the safety and tolerability of this investigational gene therapy for OAB.

About URO-902

URO-902 has the potential to be the first gene therapy for patients with OAB. If approved, this innovative treatment has the potential to address an unmet need for patients who have failed oral pharmacologic therapies.

About the EMPOWUR Trial

The EMPOWUR trial was an international, randomized, double-blind, placebo and active comparator-controlled Phase 3 clinical trial evaluating the safety and efficacy of investigational vibegron in men and women with symptoms of overactive bladder, including frequent micturition, urgency, and UUI. A total of 1,518 patients were randomized across 215 study sites into one of three groups for a 12-week treatment period with a four-week safety follow-up period: vibegron 75 mg administered orally once daily; placebo administered orally once daily; or tolterodine ER 4 mg administered orally once daily.

About the 40-Week EMPOWUR Extension

The EMPOWUR 40-week extension trial was a Phase 3, randomized, double blind, active-comparator controlled multicenter study to evaluate the long-term safety and efficacy of vibegron in patients with symptoms of overactive bladder. The extension study enrolled approximately 500 EMPOWUR completers. The primary endpoint was safety, measured by incidence of adverse events. Secondary endpoints were changes from EMPOWUR baseline at week 52 in average daily micturitions, UUI, urgency, and total urinary incontinence.

About Overactive Bladder

Overactive bladder (OAB) is a clinical condition that occurs when the bladder muscle contracts involuntarily. Symptoms may include urinary urgency (the sudden urge to urinate that is difficult to control), urgency incontinence (unintentional loss of urine immediately after an urgent need to urinate), frequent urination (usually eight or more times in 24 hours), and nocturia (waking up more than two times in the night to urinate).1

Approximately 30 million Americans suffer from bothersome symptoms of OAB, which can have a significant impairment on a patients day-to-day activities.1, 2

About GEMTESA

GEMTESA is a prescription medicine for adults used to treat the following symptoms due to a condition called overactive bladder:

It is not known if GEMTESA is safe and effective in children.

IMPORTANT SAFETY INFORMATION

Do not take GEMTESA if you are allergic to vibegron or any of the ingredients in GEMTESA.

Before you take GEMTESA, tell your doctor about all your medical conditions, including if you have liver problems; have kidney problems; have trouble emptying your bladder or you have a weak urine stream; take medicines that contain digoxin; are pregnant or plan to become pregnant (it is not known if GEMTESA will harm your unborn baby; talk to your doctor if you are pregnant or plan to become pregnant); are breastfeeding or plan to breastfeed (it is not known if GEMTESA passes into your breast milk; talk to your doctor about the best way to feed your baby if you take GEMTESA).

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

What are the possible side effects of GEMTESA?

GEMTESA may cause serious side effects including the inability to empty your bladder (urinary retention). GEMTESA may increase your chances of not being able to empty your bladder, especially if you have bladder outlet obstruction or take other medicines for treatment of overactive bladder. Tell your doctor right away if you are unable to empty your bladder.

The most common side effects of GEMTESA include headache, urinary tract infection, nasal congestion, sore throat or runny nose, diarrhea, nausea, and upper respiratory tract infection. These are not all the possible side effects of GEMTESA. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Please click here for full Product Information for GEMTESA.

About Urovant Sciences

Urovant Sciences is a biopharmaceutical company focused on developing and commercializing innovative therapies for areas of unmet need, with a dedicated focus in Urology. The Companys lead product, GEMTESA(vibegron), is an oral, once-daily (75 mg) small molecule beta-3 agonist for the treatment of adult patients with overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency. GEMTESA was approved by the U.S. FDA in December 2020 and launched in the U.S. in April 2021. GEMTESA is also being evaluated for the treatment of OAB in men with benign prostatic hyperplasia. The Companys second product candidate, URO-902, is a novel gene therapy being developed for patients with OAB who have failed oral pharmacologic therapy. Urovant Sciences, a wholly-owned subsidiary of Sumitovant Biopharma Ltd., intends to bring innovation to patients in need in urology and other areas of unmet need. Learn more about us at http://www.urovant.com or follow us on Twitter or LinkedIn.

About Sumitovant Biopharma

Sumitovant is a global biopharmaceutical company leveraging data-driven insights to rapidly accelerate development of new potential therapies for unmet patient conditions. Through our unique portfolio of wholly-owned Vant subsidiariesUrovant, Enzyvant, Spirovant, Altavantand use of embedded computational technology platforms to generate business and scientific insights, Sumitovant has supported the development of FDA-approved products and advanced a promising pipeline of early-through late-stage investigational assets for other serious conditions. Sumitovant, a wholly-owned subsidiary of Sumitomo Pharma, is also the majority-shareholder of Myovant (NYSE: MYOV). For more information, please visit our website at http://www.sumitovant.com

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Urovant Sciences to Present Interim Data from Phase 2a Study of Potential Novel Gene Therapy, URO-902, and New Analyses of Data from Phase 3 EMPOWUR...

BOSTON Hydrocephalus, or water on the brain, occurs when the cerebral ventriclesfour interconnected cavities of the brain that are filled with cerebrospinal fluidbecome enlarged, but its cause is unknown in many cases. A better understanding could lead to improved treatments for hydrocephalus, which is the leading reason for brain surgery in children and is associated with neurodevelopmental disability. To provide insights, a team led by investigators at Massachusetts General Hospital (MGH) and Yale University analyzed variations in genetic sequences and gene expression patterns in the brains of patients with congenital hydrocephalus. The research, which is published in Nature Neuroscience, indicates that hydrocephalus does not result from a defect of cerebrospinal fluid plumbing but rather arises because primitive cells in the brain do not behave properly during development.

In patients with hydrocephalus, continued accumulation of fluid dilates the cerebral ventricles, increases pressure in the skull, and compresses the surrounding brain structure. This compression can cause acute symptoms such as vomiting and headache, and even coma or even death. In the long-term, brain compression can lead to neurocognitive issues and neurodevelopmental disabilities in children, even when a medical device called a shunt is surgically placed in the brain.

Neurosurgical shunting of cerebrospinal fluid addresses some consequences of the disease but does not target the underlying mechanisms, says senior author Kristopher T. Kahle, MD, PhD, director of Pediatric Neurosurgery at MGH and director of the Harvard Center for Hydrocephalus and Neurodevelopmental. Knowing the molecular cause of disease could be very helpful towards clinical decision making.

To provide insights, Kahle and his colleagues genetically sequenced cells from 483 children with hydrocephalus and their unaffected parents, using a profiling technology that uncovers gene mutations in patients across the entire genome. By combining the genetic sequence data with gene expression data, the team found that many hydrocephalus-associated genes converge not in fluid circulation components but instead in neuroepithelial cells, which are the earliest stem cells of the brain that arise during the first several weeks of development. These cells go on to generate all of the neurons and support cells of the brain.

This began to hint to us that rather than affecting fluid circulation, hydrocephalus gene mutations may be disrupting the earliest processes of human brain development to cause hydrocephalus, says colead author Phan Q. Duy, an MD/PhD student at Yale University School of Medicine.

The most frequently mutated gene in the studys patientscalled TRIM71codes for a protein that is part of a pathway that regulates the timing of stem cell development. When the investigators bred mice to express TRIM71mutations, the mice developed fetal-onset hydrocephalus similar to human patients. Mechanistically, stem cells in the brains of the Trim71-mutated mice prematurely generated neurons, leading to a deficient pool of stem cells to support brain growth and development. This caused deficient expansion of brain tissue and underdevelopment of the cerebral cortex.

The scientists note that the resulting altered structure of the brain is not capable of holding the pressure exerted by cerebrospinal fluid, and thus the brain deforms and its ventricles passively expand. The site of pathology is therefore not happening in the fluid itself, but rather the vesselor the brain tissuethats holding the fluid, says Duy.

The findings suggest that treatment strategies for hydrocephalus should go beyond draining fluid in the brain. A more nuanced treatment approach may include not only cerebrospinal fluid diversion but also other approaches more tailored towards improving neurodevelopmental function, says Kahle. In the long-term, with continued gene discovery and better understanding of how other gene mutations disrupt brain development to cause hydrocephalus, we may be able to develop drug treatments or even gene therapy to correct the gene mutations months before the birth of patients.

Beyond providing a better understanding hydrocephalus, this work may offer additional insights into other pediatric brain disorders. In fact, ventricular dilation is a common feature in developmental neuropsychiatric diseases such as autism and schizophrenia, and many of the processes involved with hydrocephalus may also be relevant for other structural brain malformations.

This work was supported by the National Institutes of Health, Rudi Schulte Institute, and the Hydrocephalus Association.

About the Massachusetts General Hospital

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Instituteconducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In August 2021, Mass General was named #5 in theU.S. News & World Reportlist of "Americas Best Hospitals." MGH is a founding member of the Mass General Brigham health care system.

Nature Neuroscience

Impaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus

4-Apr-2022

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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Genetic analysis provides insights into the cause of hydrocephalus, or water on the brain - EurekAlert

The cessation of operations does not come as a complete surprise.The biotech, in an earnings call in November last year, had flagged that it would run out of cash at some point in the second quarter.

According to Fridays SEC filing, a strategic process to find a solution, with Kaleido having engaged professional advisors, did not result in the identification of any viable transactions.

The company had already shrunk its workforce, back in January this year, following its decision to halt a planned phase 2 trial in chronic obstructive pulmonary disease (COPD) and to end its agreement with the COPD Foundation.

Last year, Kaleido received a warning letter from the US Food and Drug Administration (FDA) over a program it was running with its COPD drug in COVID-19 studies. The FDA said the company failed to seek an Investigational New Drug (IND) application for the study using its COPD therapy, KB109. Kaleido argued that it investigated KB109 as a food rather than a drug and did not need to be authorized under an IND.

Kaleidos closure comes as several other biotechs are experiencing a cash crunch and as investor sentiment in the sector would seem to be waning, for now. Biogen, bluebird bio, and Taysha, among others, have announced layoffs of late.

Last Tuesday, gene therapy player, bluebird Bio, reported it was cutting staffing numbers by nearly 30%, with it targeting up to US$160m in cost savings over the next two years. The restructuring drive is expected to lower the companys 2022 cash burn to less than $340m, with a 35 to 40% reduction in operating costs anticipated by year-end 2022.

In March, the biotech had warned that its financial position raised substantial doubt about its ability to continue as a going concern.

Bluebird bio has faced a number of unexpected hurdles recently in its bid to get approval for its investigational therapies.

In December 2021, the FDA paused a trial of its gene therapy candidate - lovo-cel - for sickle cell disease patients under the age of 18, while, in January this year, the US regulatory body extended the review period for the biologics licensing applications (BLA) for bluebird's lentiviral vector gene therapies betibeglogene autotemcel (beti-cel) for beta-thalassemia and elivaldogene autotemcel (eli-cel) for cerebral adrenoleukodystrophy (CALD).

CEO Andrew Obenshain, on a call last week, noted the combination of those setbacks plus a tough biotech market has taken some traditional financing off the table in the near term. Were optimistic that these options may be viable sources of funding in the future, but we recognize the need for action today.

Bluebird said it now intends to sharpen its focus on near-term catalysts, including anticipated FDA approvals for both of its gene therapies and that it also expects to submit a BLA for lovo-cel in Q1 2023.

The company outlined how it is intending to maintain targeted research efforts focused on in vivo lentiviral vector (LVV) gene therapies and that it will deprioritize direct investments in reduced toxicity conditioning and cryopreserved apheresis.

Texas based Taysha, a biotech also focused on gene therapies, announced a 35% reduction in employees at the end of March. It has narrowed its R&D pipeline to two programs: giant axonal neuropathy (GAN) and Rett syndrome.

Activities for other ongoing clinical programs will be minimized and all additional research and development will be paused to increase operational focus and efficiency, it added.

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Kaleido Biosciences is winding up operations as bluebird bio and other biotech firms announce layoffs - BioPharma-Reporter.com

The spectrum of viral vectors is very broad including both delivery vehicles developed for transient short-term and permanent long-term expression. Moreover, the types of vectors are represented by both RNA and DNA viruses with either single-stranded (ss) or double-stranded (ds) genomes. The main groups of viral vectors applied for gene therapy are summarized below and in , followed by examples of both preclinical () and clinical findings (). Finally, the approval of viral vector-based drugs is discussed.

The most applied viral vectors are certainly based on adenoviruses [4]. Naked dsDNA adenoviruses possess a packaging capacity of 7.5 kb of foreign DNA providing short-term episomal expression of the gene of interest in a relatively broad range of host cells. The original adenovirus vectors generated strong immune responses, whereas the so-called gutted second and third generation vectors containing deletions have proven to elicit substantially reduced immunogenicity [5]. Much attention has been paid to engineering packaging cell lines for large scale production of recombinant particles of Good Manufacturing Practice (GMP)-grade to support clinical trials [6]. AAV vectors carry a small ssRNA genome, which allows packaging of only 4 kb inserts [7]. Generally, AAV is considered to generate low pathogenicity and toxicity and provides long-term transgene expression through chromosomal integration [8]. One limitation of using AAV relates to the immune response triggered by repeated administration [9]. This problem has been addressed by applying a different AAV serotype for each re-administration. Another issue relates to the limited packaging capacity of foreign DNA into recombinant AAV particles [10]. This shortcoming has been addressed by engineering dual AAV vectors [11].

Herpes simplex viruses (HSV) are large enveloped dsDNA viruses characteristic of their lytic and latent nature of infection, which result in life-long latent infection of neurons and allows for long-term transgene expression [12]. Deletion of HSV genes has generated expression vectors with low toxicity and an excellent packaging capacity of >30 kb foreign DNA [13]. In contrast to HSV, retroviruses possess a ssRNA genome with an envelope structure [14]. Typically, retroviruses are randomly integrated into the host genome, which has been problematic, as previously described, in the therapy of SCID patients [2,3]. However, this shortcoming has triggered the development of safer vectors showing targeted integration and also improved helper cell lines [15]. Retroviruses can accommodate up to 8 kb of foreign inserts and have represented the gold standard vectors for long-term gene therapy applications. One drawback of retroviruses is their incapability to infect nondividing cells, which has enhanced the interest in application of lentivirus vectors for gene therapy. Although lentiviruses belong to the family of retroviruses, they have the capability of infecting both dividing and nondividing cells providing low cytotoxicity [16,17]. Possessing the same packaging capacity and chromosomal integration as conventional retroviruses, lentiviruses have become attractive for therapeutic applications requiring long-term expression.

Self-amplifying ssRNA viruses comprise of alphaviruses (Semliki Forest virus, Sindbis virus, Venezuelan equine encephalitis virus, and M1) and flaviviruses (Kunjin virus, West Nile virus, and Dengue virus) possessing a genome of positive polarity [18]. In contrast, rhabdoviruses (rabies and vesicular stomatitis virus) and measles viruses carry negative strand genomes [18]. Most of the self-amplifying RNA viruses possess a packaging capacity of 68 kb, and generate high levels of short-term transient gene expression [19]. Additionally, the ssRNA paramyxovirus Newcastle disease virus (NDV) replicates specifically in tumor cells and has therefore been frequently applied for cancer gene therapy [20]. Moreover, oncolytic cancer cell targeting vectors have been engineered for many of the listed ssRNA viruses above [21]. Another family of nonenveloped ssRNA viruses, namely Coxsackieviruses belonging to Picornaviridae, have been applied as oncolytic vectors [22,23].

Also, poxviruses and especially vaccinia viruses have been applied as delivery vectors [24]. The characteristic feature of poxviruses is their dsDNA genome, which can generously accommodate more than 30 kb of foreign DNA. Tumor-selective replication-competent poxvirus vectors have been engineered causing necrosis in nonhuman primates [25]. Additionally, vaccinia vectors, which replicate in tumor cells without damaging normal cells, were engineered by deletions in the thymidine kinase (TK) and vaccinia growth factor (VGF) genes [26].

Due to the many gene therapy applications of a number of viral vectors evaluated in preclinical animal models, only some examples can be presented here (). In this context, oncolytic adenoviruses have shown great promise in cancer therapy [27]. For instance, an oncolytic adenovirus engineered with a pancreatic cancer-targeting ligand SYENFSA (SYE), specifically infected and replicated in cancer cells, but not normal cells, provided effective oncolysis of pancreatic ductal adenocarcinoma PDAC) [28]. The AdSur-SYE vector, regulated by the survivin promoter, also showed high transduction efficiency in pancreatic neuroendocrine tumors (PNETs) [29]. Intratumoral administration of AdSur-SYE resulted in complete regression of subcutaneous tumors in a mouse model. In another approach, chimeric Adenovirus type 5 and type 3 vectors, which can selectively replicate in cancer cells, have been engineered [30]. Providing simultaneous expression of the secreted melanoma differentiation associated gene-7 (MDA-7) and interleukin-12 (L-24) from the chimeric Ad5/3 vector generated selective tumor cell death after intratumoral injection in animal models. Moreover, therapeutic activity was also confined to noninfected distant tumors due to the so-called bystander anti-tumor activity. To further enhance the therapeutic efficacy, the chimeric Ad5/3 vector was encapsulated in microbubbles for stealth delivery. Ultrasound treatment released and allowed replication of the vector, which together with secretion of MDA-7/IL-24 enhanced therapeutic activity, including promotion of apoptosis and inhibition of tumor angiogenesis. Due to the generally limited duration of therapeutic activity of adenovirus-based gene therapy, hybrid adenovirus vectors utilizing the Sleeping Beauty transposase system or clustered regularly interspaced short palindromic repeats (CRISPR) associated protein-9 nuclease have been used for chromosomal integration and permanent gene editing, respectively [31]. Oncolytic adenovirus vectors have also been used in combination with the expression of immunomodulatory proteins [32]. This approach can change the tumor microenvironment from immune-suppressive to immune-vulnerable due to activation of cytotoxic T cells. In another approach, the oncolytic adenovirus Enadenotucirev, an Ad11p and Ad3 chimeric vector, has demonstrated selective propagation and killing of tumor cells [33]. Due to the inability of replication in animal cells, Enadenotucirev was evaluated in a panel of primary human cells, which demonstrated >100-fold higher viral genome levels in tumor cells than in normal cells [33]. Furthermore, intravenous tolerability was assessed in mice. The resistance to inactivation by human blood components will potentially enable intravenous vector administration.

The X chromosome-linked neurodevelopmental disorder named Rett Syndrome (RTT) has been targeted by AAV vectors in a mouse model for RTT [34]. AAV vectors expressing the transcription regulator methyl CpG-binding protein 2 (MeCP2) delivered directly to the cerebrospinal fluid (CSF), showed dose-dependent side effects, but also extended survival of RTT mice. Moreover, the fatal neurodegenerative Huntingtons disease (HD) has been evaluated for AAV-based therapy in a HD mouse model [35]. Transgenic HD sheep expressing the full-length human huntingtin (HTT) gene were injected with AAV9 miRNA targeting exon 48 of the human HTT mRNA. The outcome was reduced human HTT mRNA and 5080% HTT protein in the striatum, indicating safe and effective gene silencing. Cystic fibrosis has been targeted by AAV-based expression of the cystic fibrosis transmembrane conductance regulator (CFTR) in a number of animal models showing a good safety profile, although no clear clinical benefits [36]. Recently, the AAV1 and AAV5 serotypes were tested using a dual-luciferase reporter system based on firefly and Renilla luciferases, respectively [36]. Both AAV1 and AAV5 were delivered into lungs of Rhesus macaques by microspraying, which resulted in a 10-fold higher vector genome number of AAV1 than AAV5. However, the AAV1-based luciferase activity was not statistically higher in comparison to AAV5. Moreover, serum neutralizing antibodies showed a dramatic increase for both AAV serotypes. There were no adverse events, indicating safe administration of AAV, which supports additional clinical trials, especially with the more lung-tropic AAV1 serotype. In another approach, AAV vectors have been applied for the treatment of Duchenne and limb girdle muscular dystrophies [37]. Furthermore, dual AAV technology allowed the expression of a 7 kb canine H2-R15 mini-dystrophin gene using a pair of dual AAV vectors [38]. The AAV9 was administered to the extensor carpi ulnaris muscle in a canine model for Duchenne muscular dystrophy. The outcome was widespread mini-dystrophin expression, restoration of dystrophin-associated glycoprotein complex, reduced muscle degeneration, and improved myofiber size distribution. In the context of hemophilia A, liver-specific promoter and enhancer elements with a codon-optimized human coagulation factor VIII (hFVIII) gene have been engineered [39]. One promoter-enhancer construct with high hFVIII immunogenicity was evaluated in an FVIII knockout mouse model applying AAV8, AAV9, AAVhu37, and AAVrh64R1 vectors. Based on the generation of anti-hFVIII antibodies, the vectors were divided into one group, where less than 20% of mice (AAV8 and AAV9) and the other with more than 20% of mice (AAVrh10, AAVhu37 and AAVrh64R1) generated anti-hFVIII antibodies.

Due to the long-term effect, HSV vectors have found many applications in various disease areas. For instance, HSV-based expression of proinflammatory cytokines has proven useful in treatment of painful diabetic neuropathy [40]. In this context, continuous delivery of HSV-IL-10 into the nerve fibers of mice with type I diabetes blocked nociceptive and stress responses in transduction of the dorsal root ganglion (DRG) [40]. It was suggested that macrophage activation in the peripheral nervous system is involved in the pathogenesis of pain and that HSV-based cytokine expression inhibited the development of painful neuropathy. In another approach, administration of nonreplicating HSV vectors expressing growth factors in the skin of mice resulted in the transduction of DRGs and prevented the progression of sensory neuropathy without causing any side effects [41]. Related to cancer, oncolytic HSV vectors have been applied in several preclinical studies [42]. The genome of the HSV-1 HF10 vector includes nonengineered deletions and mutations and frame-shift mutations lacking the expression of UL43, UL48.5, UL55, UL56, and latency-associated transcripts, while demonstrating overexpression of UL53 and UL54. HSV-1 HF10 replicates efficiently in tumor cells causing extensive cytotoxic damage. Moreover, activated CD4+ and CD8+ T cells and natural tumor killer cells were induced in tumors resulting in significant tumor growth reduction and prolonged survival. Oncolytic HSV-2 vectors have also been evaluated in animal studies on colon cancer cells and cancer stem-like cells (CSLCs) and are known to be tumorigenic and responsible for cancer recurrence and metastasis [43]. Significant inhibition of tumor growth was observed after administration of oncolytic HSV-2 vectors.

Retroviruses present the classic approach for long-term gene therapy applications and the first human gene therapy trial involved implantation of autologous bone marrow cells transduced ex vivo with gamma retrovirus vectors [44]. More recently, attention has been paid to target dendritic cells (DCs) by engineering of vectors with DC-specific promoters or by retargeting vector tropism [45]. Also, transduction of hematopoietic stem cells has supported antigen-specific immune tolerance. In another immunotherapy approach, the low gene transduction efficiency of 50% of chimeric antigen receptor-expressing T (CAR-T) cells was improved to more than 90% by optimization of precultivation conditions and antibody stimulation [46]. The transduced CAR-T cells showed antigen-specific cytotoxic activity and secreted cytokines by antigen stimulation. Related to cancer therapy, the nonlytic amphotropid retroviral replicating vector (RRV) Toca 511 encoding yeast cytosine deaminase (CD) was delivered to tumors in orthotopic glioma models [47]. When combined with 5-fluorocytosine (5-FC), CD in infected tumor cells converts 5-FC to 5-fluorouracil (5-FU) leading to cell death. Intravenous or intracranial administration of Toca 511 provided long-term survival in immune-competent mice after combination treatment with 5-FC. Prolonged survival was also observed in animals with pre-existing immune response to the vector, which supports the potential of readministration. The self-inactivating gammaretroviral vector (SINfes.gp91s), containing the codon-optimized transgene (gp91(phax)) and the promoter for the X-linked form of the immunodeficiency named chronic granulomatous disease (CGD), was demonstrated to protect X-CGD mice from challenges with Aspergillus fumigatus [48].

In the case of lentivirus-based gene therapy, a lentiviral vector carrying the human pyruvate kinase deficiency (hPKD) promoter and the PKLR gene was employed for addressing the monogenic metabolic disease PKD caused by mutations in the pyruvate kinase isoenzymes L/R (PKLR) gene [49]. When mouse hematopoietic stem cells (HSCs) transduced with lentivirus were transplanted into myeoblated PKD mice, the erythroid compartment was normalized providing a corrected hematological phenotype and reversion of organ pathology. Furthermore, analysis of the genomic insertion sites for the lentivirus vector in transplanted hematopoietic cells indicated no presence of genotoxicity. Lentivirus vectors have also been subjected to gene therapy applications of RNA silencing in the CNS [50]. Related to Parkinsons disease (PD), the misregulation and overexpression of -synuclein leading to its accumulation in neurons was counteracted by lentivirus-based RNA interference (RNAi) in the human dopaminergic cell line SH-SY5Y and in neurons in rat striatum [51]. Moreover, in another approach, the PD-related transcriptional upregulation of the GABA-producing enzyme glutamate decaorboxylase 1 (GAD1) or GAD67 was successfully knocked down by lentivirus-mediated shRNA-miR expression in a rat model for PD, demonstrating normalized neuronal activity [52]. In the context of Alzheimers disease, lentivirus vectors have been applied for RNA silencing to knock down BACE1 attenuated amyloid precursor protein (APP) cleavage and -amyloid production, resulting in reduced neurodegeneration and behavioral deficits in an Alzheimers disease mouse model [53]. In another approach, lentivirus-based siRNA expression showed reduced tau phosphorylation and number of neurofibrillary tangles in an Alzheimers disease mouse model [54]. Furthermore, lentivirus vector-based delivery of shRNAs targeting the HIV-1 coreceptor CCR5 and the R-region of the HIV-1 long terminal repeat (LTR) has been evaluated in humanized bone marrow/thymus (hu-BLT) mice [55]. The outcome was efficient inhibition of HIV infection and might provide a potential therapy against HIV. In another approach, the Cal-1 anti-HIV lentiviral vector was evaluated in pigtailed macaques [56]. Cal-1 lentivirus demonstrated safe integration and preclinical safety.

Alphaviruses have been mainly applied in preclinical gene therapy studies for cancer treatment [57]. The particular feature is that alphavirus vectors can be delivered in the form of naked RNA, layered plasmid DNA vectors and recombinant replication-deficient or -proficient particles. In this context, local administration of a replication-proficient Semliki Forest virus (SFV) vector expressing EGFP, generated prolonged survival in mice with implanted A549 lung carcinoma xenografts [58]. In another study, SFV-IL-12-based therapy was evaluated in a syngeneic RG2 rat glioma model, which resulted in 87% reduction in tumor volume and significant extension of survival [59]. In attempts to target tumor cell replication, six micro-RNAs (miRNAs) were introduced into the SFV genome. Intraperitoneal administration of engineered SFV4-miRT124 particles in BALB/c mice resulted in glioma targeting, limited spread in the CNS and significantly prolonged survival rates [60]. Moreover, the naturally occurring oncolytic alphavirus M1 was demonstrated to selectively kill zinc-finger antiviral protein (ZAP)-deficient cancer cells and also showed high tumor tropism and potent oncolytic activity in a liver tumor model [61].

In the context of flaviviruses, the granulocyte macrophage colony-stimulating factor (GM-CSF) expressed from a Kunjin virus vector was subjected to intratumoral administration in mice with subcutaneous CT26 colon carcinoma [62]. The treatment resulted in a cure of more than 50% of injected mice; tumors were undetectable 18 days after Kunjin-GM-CSF administration. Likewise, treatment of B16-OVA melanoma tumors led to significant tumor regression after 5 days and the cure rate in mice reached 67% [62]. Moreover, subcutaneous injection of Kunjin-GM-CSF resulted in regression of CT26 lung metastasis in BALB/c mice.

Among rhabdoviruses, recombinant vesicular stomatitis virus (VSV) has been applied for preclinical gene therapy studies. The low seroprevalence in humans and robust heterologous expression profile have supported a number of vaccine approaches against human pathogens [63]. For instance, VSV vectors expressing HIV-1 Gag and Env elicited robust HIV-1 specific cellular and humoral immune responses in nonhuman primates [63]. Furthermore, vaccinated animals were protected against challenges with a pathogenic SIV/HIV recombinant. However, the neurovirulence of VSV vectors has remained an issue of concern leading to strategies of developing attenuated vectors [60]. In another approach, a chimeric VSV vector, where the VSV G envelope was replaced by a lymphocytic choriomeningitis virus glycoprotein (LCMV-GP), the chimeric vector presented no harm to normal brain cells, but efficiently eliminated brain tumor cells in several tumor models in vivo [64]. Moreover, safe systemic administration was confirmed in mice and no humoral activity against VSV was detected, which provided the basis for repeated systemic injections. In preparation for future clinical trials, the oncolytic VSV-IFN-NIS vector expressing interferon- (IFN) and sodium iodide transporter (NIS) was evaluated in preclinical rodent models [65]. For instance, dose-dependent tumor regression was demonstrated in C57BL1/KaLwRij mice implanted with syngeneic 5TGM1 plasmacytoma tumors. However, KAS6/1 xenografts regressed at all VSV doses tested in SCID mice. Moreover, purpose-bred dogs with naturally occurring tumors were subjected to a dose-escalation study with VSV-IFN-NIS [66]. The intravenous maximum tolerated dose (MTD) was determined to 1010 TCID50 with mild to moderate adverse events. The VSV genome disappeared rapidly and anti-VSV antibodies were detected 5 days after administration in the blood. However, no infectious virus was detected in the plasma, urine or buccal swabs. In another study, VSV-based expression of human mucin 1 (MUC1) provided significant reduction of tumor growth in mice with established pancreatic ductal adenocarcinoma xenografts [67]. Furthermore, combination of VSV-MUC1 and gemcitabine resulted in superior therapeutic efficacy.

Measles viruses have found a number of gene therapy applications, which have been evaluated in preclinical animal models. In this context, the oncolytic MV-Edm was engineered to express NIS, which is depleted in aggressive and radioiodine resistant anaplastic thyroid cancer (ATC) [68]. Treatment with MV-NIS confirmed NIS expression and enhanced tumor killing. In another approach, measles virus was engineered to express a yeast-based bifunctional suicide gene encoding cytosine deaminase and uracil phosphoribosyltransfrerase named super-cytosine deaminase (SCD) [69]. The chimeric protein is capable of converting the nontoxic prodrug 5-fluorocytosine (5-FC) into highly cytotoxic 5-fluorouracil (5-FU). Furthermore, 5-FU is directly converted into 5-fluorouridine monophosphate (5-FUMP), which addresses the issue of chemoresistance to 5-FU in cancer treatment. Transduction with MV-SCD showed replication and efficient lysis of human ovarian cancer cell lines and primary tumor cells. Moreover, precision-cut tumor slices from human ovarian cancer patients demonstrated efficient infection by MV-SCD. The MV-SCD also showed strong oncolytic activity in a mouse xenograft model of human hepatocellular carcinoma (HCC) [70]. Furthermore, MV-SCD generated long-term virus replication in tumor tissue and induced apoptosis-like cell death independent of intact apoptosis pathways. In another study, MV-SCD was administered intratumorally in combination with systemic 5-FU in a TFK-1 xenograft mouse model, which resulted in significant tumor reduction [71]. Moreover, tumor reduction and significant survival benefits were observed in a HuCCT1 xenograft model [71].

Newcastle disease virus (NDV) vectors have been frequently used in preclinical cancer therapy studies due to their oncolytic activity [72]. Although NDV vectors expressing IL-2 showed promise, comparative studies with the less toxic IL-15 have been conducted. Intratumoral injection of NDV-IL15 and NDV-IL2 in melanoma-bearing mice showed efficient suppression of tumor growth [72]. However, the 120 day survival rate was 12.5% higher after NDV-IL15 treatment than that of NDV-IL2. Likewise, the survival rate was 26.6% higher for NDV-IL15 treatment in a tumor rechallenge experiment. In another study, reverse genetics were employed on the oncolytic NDV D90 strain to generate recombinant NDVs carrying the GFP gene [73]. The rescued virus showed tumor-selective replication and induced apoptosis in tumor cells in athymic mice with implanted lung tumors. It has also been demonstrated that expression of IL-2 and tumor necrosis factor-related apoptosis inducing ligand (TRAIL) enhanced inherent antineoplasticity by inducing apoptosis [74]. The NDV-TRAIL and the bifunctional NDV-IL2-TRAIL showed superior apoptotic function in comparison to NDV-IL2. Moreover, CD4+ and CD8+ proliferation was induced and expression of TFN- and IFN- antitumor cytokine expression was elicited. The NDV-IL2-TRAIL also exhibited prolonged survival in mice implanted with HCC and melanoma xenografts. In another study, the NDV Anhinga strain was applied for the expression of soluble TRAIL (NDV/Anh-TRAIL), which resulted in efficient suppression of HCC without significant cytotoxicity [75].

Coxsackieviruses have been used for several gene therapy applications [23]. For instance, the coxsackievirus B3 (CVB3) expressing the human fibroblast growth factor 2 (FGF2) was injected into ischemic hindlimbs of mice showing protection from ischemic necrosis [76]. The treatment improved the blood flow in ischemic limbs for more than 3 weeks. Moreover, the recombinant CVB3 showed a drastic decrease in virulence compared to wild type CVB3. Related to cancer, Coxsackievirus A21 (CAV21) expressing intercellular adhesion molecule-1 (ICAM-1) and decay-accelerating factor (DAF) reduced tumor burden in nonobese SCID mice implanted with melanoma xenografts [77]. A single administration of CAV21 was sufficient to provide efficient oncolysis and the systemic spread of CAV21 showed efficient regression in tumors distantly located from the site of viral injection. Furthermore, the same CAV21 vector was evaluated in SCID mice implanted with T47D and MDA-MB-231-luc breast tumor xenografts [78]. A single intravenous injection generated significant regression of pre-established tumors and also targeting and elimination of metastases. Furthermore, intravenous injection of CVA21 expressing ICAM-1 and DAF in combination with intraperitoneal injection of doxorubicin hydrochloride provided significantly enhanced tumor regression in comparison to either virus or drug alone in mice with implanted MDA-MB-231 tumors [79]. Related to prostate cancer, the low pathogenic enteroviruses, CVA21, CVA21-DAFv, and Echovirus 1 (EV1), were tested in SCID mice [80]. Systemic delivery induced regression of tumor xenografts and a therapeutic dose-response was obtained for escalating doses of EV1 in the LNCaP mouse model.

Finally, poxviruses have found several applications as gene therapy vectors. For instance, vaccinia virus vectors have demonstrated potential for treatment of pancreatic cancer [81]. In this context, the PANVAC system comprising of recombinant vaccinia and fowlpox viruses, carrying the tumor-associated antigens epithelial MUC-1 and carcinomebryonic antigen (CEA) as well as T cell stimulatory molecules, have been applied [82]. Sequential subcutaneous administration of the vectors has provided induced CEA and MUC-1 CTL responses in preclinical animal models. In the case of HCC, the light-emitting recombinant GLV-2b372 vaccinia virus was injected into HCC xenografts in the flank of athymic nude mice for assessment of tumor growth and inhibition of viral biodistribution [83]. It was demonstrated that flank tumor volumes decreased by 50% 25 days after injection, while tumor volumes increased by 400% in control mice. Related to prostate cancer, NIS expression from the GLV-1h153 vaccinia virus in combination with radiotherapy was evaluated in CD1 nude mice implanted with PC3 xenografts [84]. Combination therapy was superior to individual treatments both in xenograft and immunocompetent transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse models, demonstrating restricted tumor growth and improved survival rates. A vaccinia virus was engineered by mutating the F4L gene, the viral homologue of the cell-cycle-regulated small subunit of ribonucleotide reductase 2 (RRM2), which provided tumor-selective replication and cell killing [85]. It was confirmed that the F4L-mutated vector selectively replicated in immune-competent rat AY-27 and xenografted human RT122-luc orthotopic bladder cancer models, resulting in substantial tumor regression or complete ablation without causing any cytotoxicity. Moreover, antitumor immunity was established in rats cured of AY-27 tumors. Recently, a novel cowpox virus (CPXV) vector was engineered with a deletion of the thymidine kinase (TK) gene and insertion of the suicide gene FCU1, which is responsible for conversion of 5-FC into 5-FU and 5-FUMP [86]. Systemic administration of the modified CPXV vector showed accumulation in tumor cells and low infection and toxicity of normal cells. Moreover, intratumoral administration in U-87-MG glioblastoma and LoVo colon cancer models, induced relevant tumor growth inhibition.

A substantial number of clinical trials have been conducted or are currently in progress applying viral vectors (). For instance, the tumor-selective chimeric Enadenotucirev adenovirus vector was subjected to intravenous delivery in 17 patients with resectable colorectal cancer, non-small-cell lung cancer, urothelial cancer and renal cancer [87]. Tumor-specific delivery was observed in most tumor samples with no treatment-related serious adverse events.

Related to hemophilia, gene therapy has been employed already for three decades, mainly focusing on AAV-based vectors [88]. In addition to discovery of pre-existing neutralizing antibodies in animal models, clinical trials have revealed that liver transaminase levels are elevated and immune-related loss of transgene expression. The mechanism of the decrease in expression levels is not fully understood, but the use of different serotypes for consecutive administration of AAV has provided improved transgene expression [9], which has resulted in long-term expression of factors VIII (FVIII) and IX (FIX) and furthermore allows a cure of severe bleedings and joint damage associated with hemophilia. In this context, 11 hemophilia gene therapy clinical trials have been conducted and six ongoing phase I/II clinical trials have applied liver-directed AAV expressing either FVIII or FIX with some success [89]. Furthermore, stem cell-based lentiviral vector delivery has proven successful in establishing sustained high level FIX expression after differentiation of adipogenic, chondrogenic, and osteoblastic cells [90], which potentially can be applied for treatment of hemophilia B. Likewise, stem cell-based lentiviral gene therapy can provide life-long production of FVIII and the potential cure of hemophilia A [89].

The oncolytic HSV HF10 vector has been subjected to clinical trials in recurrent breast cancer, head and neck cancer, unresectable pancreatic cancer, refractory superficial cancer, and melanoma [42]. The studies demonstrated high safety and a low frequency of adverse effects in treated patients. Moreover, HF10 antigens were detected 300 days after immunization in pancreatic cancer patients. Combination therapy with HF10 and ipilimumab (anti-CTLA-4) showed a good safety profile and good antitumor efficacy in a phase II trial [42]. Related to retroviruses, a clinical trial in patients with recurrent high-grade glioma (HGG) is currently in progress with the Toca 511 retrovirus [47]. Moreover, Toca 511 was subjected to an open-label, ascending dose, multicenter phase I trial in patients with recurrent or progressive HGG [91]. The overall survival was 13.6 months and statistically better, relative to an external control group. Moreover, tumor samples from patients surviving more than a year demonstrated survival-related RNA expression in correlation with treatment-related survival. Currently, a phase II/III trial with Toca 511 is in progress [92]. In another approach, a gammaretroviral vector was employed for the treatment of chronic granulomatous disease (CGD), which relates to primary immunodeficiency, resulting in an impaired antimicrobial activity in phagocytic cells [48]. The phase I/II trial revealed that although bacterial and fungal infections were transiently resolved, clonal dominance and malignant transformations compromised the therapeutic effect, suggesting that alternative vectors should be considered for delivery [48]. In another cancer-related approach MV-NIS has been approved by the FDA for human clinical trials in myeloma patients, which could provide a potential strategy for targeting iodine-resistant ATC [66]. Oncolytic vaccinia viruses have also been subjected in a phase I clinical trial in 11 patients with refractory advanced colorectal or other solid cancers [93]. The study showed neither dose-related toxicity nor any treatment-related severe adverse events. However, a strong induction of inflammatory and Th1 cytokines indicated a potent mediation of potential immunity against cancer, which supports further trials with intravenously administered vaccinia virus in combination with expression of therapeutic genes, immune checkpoint blockade, or complement inhibitors. In another study applying poxviruses, the PANVAC-VF vaccine regimen composed of a priming dose of recombinant vaccinia virus and booster doses of recombinant fowlpox virus expressing CEA, MUC-1, and a triad of costimulatory molecules (TRICOM) was subjected to subcutaneous administration in patients with advanced pancreatic cancer [94]. The safety and ability of PANVAC-VF to induce antigen-specific T cells was demonstrated [80]. However, a phase III trial targeting patients with metastatic pancreatic cancer failed to meet the therapeutic targets and was terminated [95]. In another approach, a phase I trial for direct intratumoral injection of PANVAC-VF has generated some encouraging results [96].

In the context of HSV-based clinical trials, the oncolytic HSV M032 vector expressing IL-12 has been subjected to a phase I dose-escalating study in patients with recurrent or progressive malignant glioma [97]. Moreover, the HSV strain G207 lacking genes essential for replication in normal cells were evaluated in patients with recurrent glioblastoma multiforme [98]. After two doses of HSV G207 (totaling 1.15 109 pfu) no patients developed HSV encephalitis, but significant antitumor activity was observed. Furthermore, the study demonstrated safe multiple dose delivery including direct injections into the brain. In a phase I study in patients with recurrent/progressive HGG six of nine patients had stable disease of partial response and the median survival time was 7.5 months after a single-dose oncolytic HSV injection, indicating the potential for clinical response [99]. Furthermore, preclinical studies with HSV G207 have generated highly sensitive tumor killing, which support the initiation of the first-in-children study of intratumoral administration in children with recurrent or progressive supratentorial malignant tumors [100]. Alphaviruses have so far been subjected to only a limited amount of clinical trials. In this context, recombinant VEE replicon particles expressing the prostate specific membrane antigen (PSMA) were administered to patients with castration resistant metastatic prostate cancer in a phase I dose-escalation study [101]. The immunization showed no toxicity, but no PSMA-specific cellular immune response was detected with only weak signals detected by ELISA with a dose of 9 106 IU.

Similar results occurred when immunizations were performed with 3.6 107 IU. Despite the lack of clinical benefit and robust immune responses, immunizations elicited neutralizing antibodies, which encourages further dose optimization studies. In another approach, liposome-enveloped SFV vectors expressing IL-12 were subjected to systemic administration in a phase I study in melanoma and kidney carcinoma patients [102]. Intravenous injections provided a transient 5-fold increase of IL-12 in the plasma. Due to the encapsulation procedure, tumor targeting and protection against recognition by the host immune system was obtained, which also allowed repeated vector administration.

NDV has been used in a number of clinical trials [103]. For instance, NDV expressing multiple tumor-associated antigens (TAAs) has been demonstrated to provide long-term survival in phase II trials in patients with ovarian, stomach, and pancreatic cancer [104]. Furthermore, melanoma patients were immunized with NDV in a randomized double-blind phase II/III trial [105]. However, the study results suggested that there were no remarkable differences between the vaccinated individuals and those in the placebo group. In a phase II study 79 patients with solid tumors were subjected to intravenous administration of the NDV PV101 strain [106]. A lower dose of 12 109 pfu/m2 and an MTD of 12 1010 pfu/mL were applied, which resulted in objective response to the higher dose and progression-free survival ranging from 4 to 31 months. In another phase III trial, 335 patients with colorectal cancer were subjected to NDV immunotherapy [107]. It was demonstrated that vaccination with NDV provided prolonged survival and short-term improved quality of life.

Approaches on HIV gene therapy lentivirus vectors have been employed for targeting CCR5 by shRNA delivery [108]. The shRNAs were demonstrated to effectively inhibit CCR5 expression providing protection against HIV-1 infection in cell cultures [109]. Moreover, a self-activating lentiviral vector has been engineered to express a combination of the sh5 anti-HIV gene and the C46 antiviral fusion inhibitor peptide, which provided a synergistic effect on HIV-1 inhibition [108]. The promising results of preclinical studies triggered the first phase I clinical trial applying RNA interference to down-regulate CCR5 expression in HIV therapy [110].

Related to Coxsackieviruses, a phase I/II trial in melanoma patients with the CVA21 showed good tolerance, viral replication in tumors and increased antitumor activity [111]. The latter could be further enhanced by combination therapy with immune checkpoint blockade. In another phase II trial, CVA21 demonstrated induced immune cell infiltration in the tumor microenvironment of patients with melanoma [112]. Moreover, combination therapy of CVA21 and systemic pembrolizumab in a phase 1b study in melanoma patients showed a best overall response rate of 60% and stable disease in 27% of the patients [113]. Neither dose-limiting toxicity nor grade 3 or higher treatment-related adverse events were observed.

In the context of cystic fibrosis, a pseudotyped lentivirus vector with a fusion protein (F)/hemagglutinin-neuraminidase (HN) was optimized for promoter/enhancer sequences and evaluated in mice, and human airliquid interface (ALI) cultures in preparation for a first-in-man CF clinical trial [114]. The lentivirus vector carrying a hybrid cytosine guanine dinucleotide (CpG)-free CMV enhancer/elongation factor 1 alpha promoter (hCEF) expressed functional CFTR, retained 90100% transduction efficiency in clinically relevant delivery devices and showed acceptable toxicity and integration site profiles to support the initiation of a clinical trial in CF patients.

The first viral-based gene therapy drugs were approved some time ago in China [115]. In this context, oncolytic adenoviruses expressing the p53 gene (GendicineTM) [115] and AdH101 containing the E1b-55K deletion [116] are used for treatment of cancers with mutated p53 and head and neck cancer, respectively. GendicineTM has been used for 12 years in more than 30,000 patients with an exemplary safety record and has provided significantly better responses compared to standard therapies when combined with chemotherapy and radiotherapy [117]. Moreover, the progression-free survival times were significantly extended.

Furthermore, a second-generation oncolytic HSV vector expressing GM-CSF has been approved in the US and Europe for melanoma treatment [118,119]. Unfortunately, although the AAV-based Glybera drug was approved for treatment of the rare inherited disorder lipoprotein lipase deficiency, the high costs and limited demand forced the withdrawal from the market [120].

Additionally, several other viral-based drugs will most likely be on the market in the near future. For instance, oncolytic VV JX-594 (pexastimogene devacirepvec) for hepatocellular carcinoma treatment [121], Ad CG0070 expressing GM-CSF for bladder cancer [122], and the wild type retrovirus-based pelareorep (Reolysin) [123] for head and neck cancer are at late-stage development. Moreover, the third generation oncolytic HSV-1 G47, which was subjected to a phase II glioblastoma study [124], has been further designated as a Sakigake breakthrough therapy, which will provide priority reviewing and fast-track approval [118].

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Viral Vectors in Gene Therapy - PMC

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Gene therapy holds great promise, with the potential to effectively cure an array of diseases. Already, the Food and Drug Administration has approved two of these medicines, Roche's Luxturna and Novartis' Zolgensma, the latter of which was developed at AveXis. Yet, as with most cutting-edge technologies, there have been challenges, among them that gene therapies can be costly to develop and are difficult to manufacture.

For young companies like Taysha, these challenges were eased by easy access to money. The last few years had seen the biotechnology sector flushed with record amounts of capital from venture firms and the public markets. Taysha, notably, priced shares at the top end of the company's estimated range when it went public in September 2020, raising $157 million in the process.

But investor sentiment toward biotechnology companies, which reached new heights in the early stages of the coronavirus pandemic, has worsened substantially in recent months. While the downtown has affected drugmakers in all areas of research, it's been hard on those developing gene therapies. In addition to Taysha, at least ten other gene therapy developers have announced layoffs, cost cuts or restructured programs since December.

Taysha's current priorities are to advance one program targeting Rett syndrome, which is in preclinical testing, and another focused on giant axonal neuropathy, which is currently in an early-stage study that should produce results later this year. The company noted, too, that it expects to hit milestones this year in programs for two types of Batten disease and a rare form of infantile epilepsy.

But elsewhere, Taysha is cutting back. A small trial testing one of its therapies against Tay-Sachs disease will stop enrollment, for example, though patients who were previously dosed will continue to be followed.

"To increase operational efficiency, activities for other ongoing clinical programs will be minimized and all additional research and development will be paused," Session said in a statement Thursday.

Taysha announced the layoffs and strategic changes alongside fourth quarter and full-year earnings. The company spent $132 million on research and development last year, and ultimately tallied a $173 million loss from operations. Session said that, with existing cash, debt financing and the newly implemented strategy, Taysha should have enough money to operate into the fourth quarter of 2023.

Taysha shares were up as much as about 3% Friday morning, before dipping down to near $6.50 apiece.

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Yet another gene therapy developer turns to layoffs - BioPharma Dive

Dive Brief:

Orchard recently secured an important agreement on reimbursement in the U.K. for Libmeldy, a gene therapy approved in Europe in December 2020 for children with early-onset metachromatic leukodystrophy. The company is working to expand newborn screening for the ultra-rare disease in other European countries, where two patients were recently treated under early access schemes.

The restructuring announced Wednesday puts Orchard's focus on Libmeldy, which the company hopes to submit for approval in the U.S. later this year or early next, as well as on two earlier gene therapies also for inherited neurometabolic diseases.

"In light of our experiences and knowledge gained in this current and rapidly evolving market environment for gene therapy, our plan is to concentrate resources on programs that have the potential to make a remarkable difference to patients while also providing sustainable value to the business to enable the achievement our long-term vision," said Bobby Gaspar, Orchard's CEO, in a statement.

While Orchard will keep active other research programs for future partnerships, the company will discontinue investment in gene therapies it was developing for rare primary immune deficiencies, including two currently in clinical testing. The path to an approval application in the U.S. for one of those gene therapies is now longer, Orchard said, citing feedback the company recently received from the Food and Drug Administration.

Orchard will also discontinue investment in Strimvelis, a gene therapy originally developed by GlaxoSmithKline that was approved in Europe six years ago. Since then, only 16 patients have received the therapy, which treats a rare immune condition known as ADA-SCID.

The cutbacks aren't the first time Orchard has laid off staff and discontinued research. The company announced layoffs soon after the COVID-19 pandemic began and, in June of last year, stopped developinganother treatment for ADA-SCID.

This time, Orchard has company. At least nine other cell and gene therapy developers have announced layoffs, cost cuts or altered their research plans since December. Bluebird bio, long a leading company in the field, warned investors earlier this month that there was "substantial doubt" about its ability to remain solvent over the next year.

With the expected cost savings, Orchard now anticipates being able to fund operations into 2024 and said it will seek "strategic alternatives" for its discontinued programs.

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Orchard turns to layoffs in cutting gene therapy research - BioPharma Dive