Category Archives: Gene therapy

SOUTH PLAINFIELD, N.J., Oct. 24, 2019 /PRNewswire/ --PTC Therapeutics, Inc., (NASDAQ: PTCT) today announced new results from its investigational gene therapy, PTC-AADC, in patients living with aromatic L-amino acid decarboxylase (AADC) deficiency. The datademonstrated clinically meaningful and sustained improvements in motor, cognitive and language milestones. These included the ability to sit, walk, and talk and represents up to five years of follow up post-treatment.1,2 PTC-AADC is a one-time gene therapy treatment of the human dopa decarboxylase (DDC) gene administered into the putamen, which supports production of key neurotransmitters. The data were presented at the Child Neurology Society 48th Annual Meeting.

"We are excited to see the transformational effects in AADC deficiency patients in this long-term study as patients with severe AADC deficiency never achieve the ability to sit, walk or talk," said Stuart Peltz, Ph.D., Chief Executive Officer of PTC Therapeutics. "We are on track to submit a BLA to the FDA by the end of the year and are proud to be on the verge of bringing the first commercial treatment for AADC deficiency patients which is in line with our mission of bringing clinically differentiated treatments to patients with rare disorders."

New analysis evaluated outcomes of 26 patients with AADC deficiency across three separate clinical trials,2 making it the most comprehensive analysis of patients treated with PTC-AADC to date. Specifically, these results showed that 12 months post-treatment with PTC-AADC, patients' mean body weight had increased from 12.0 kg to 15.2 kg, and the frequency of oculogyric crises (involuntary upward eye movement) was reduced.2 Dyskinesia (involuntary movements) was the most frequently recorded adverse event, however most events were mild or moderate and all cases resolved by 10 months post-treatment.2

"In addition to failing to reach key developmental milestones, such as walking and talking, children with AADC deficiency can experience severe symptoms that affect their everyday lives. These symptoms can include episodes of oculogyric crises, which can last for minutes or hours and involve sustained upward movement of the eyes, involuntary movements of the neck, tongue protrusions and jaw spasms, which can be very distressing for patients and their families," said Claudio Santos, M.D., Senior Vice President, Global Medical Affairs, PTC Therapeutics. "The post-treatment data presented at CNS confirm reductions in the number of patients experiencing oculogyric crises, suggesting that this gene therapy treatment has the potential to make a real difference in the lives of patients with AADC deficiency."

A separate analysis of a long-term study demonstrated the sustained efficacy of PTC-AADC up to five years.1 These are the longest data available for any investigational treatment for AADC deficiency. These results showed clinically meaningful and sustained improvements in motor, cognitive and language milestones up to five years post-treatment with PTC-AADC.1

An additional abstract building on the existing understanding of AADC deficiency was also presented, giving a disease state overview that highlights the potential importance of a gene therapy to treat this condition.3

About aromatic L-amino acid decarboxylase (AADC) deficiencyAromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic condition caused by a mutation in the dopa decarboxylase (DDC) gene, resulting in a lack of functioning AADC enzyme, which is responsible for the final step in the synthesis of key neurotransmitters dopamine and serotonin.4

AADC deficiency results in delays or failure to reach developmental milestones such as head control, sitting, standing, walking, or talking, low muscle tone (also known as muscular hypotonia), severe, seizure-like episodes involving involuntary eye movement (also known as oculogyric crises), autonomic abnormalities, and the need for life-long care.4 Given this neurologically devastating illness, patients with severe AADC deficiency have a high risk of death during childhood. There are currently no approved therapies that address the underlying cause.

About PTC Therapeutics, Inc.PTC is a science-driven, global biopharmaceutical company focused on the discovery, development and commercialization of clinically-differentiated medicines that provide benefits to patients with rare disorders. PTC's ability to globally commercialize products is the foundation that drives investment in a robust pipeline of transformative medicines and our mission to provide access to best-in-class treatments for patients who have an unmet medical need. To learn more about PTC, please visit us onwww.ptcbio.comand follow us onFacebook, on Twitter at @PTCBio, and on LinkedIn.

For More Information:

Investors:Emily Hill+ 1 (908) 912-9327ehill@ptcbio.com

Media: Jane Baj+1 (908) 912-9167jbaj@ptcbio.com

References:

Forward-LookingStatements:This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. All statements contained in this release, other than statements of historic fact, are forward-looking statements, including statements regarding: the future expectations, plans and prospects for PTC; expectations with respect to PTC's gene therapy platform, including any potential regulatory submissions; PTC's strategy, future operations, future financial position, future revenues, projected costs; and the objectives of management. Other forward-looking statements may be identified by the words "guidance", "plan," "anticipate," "believe," "estimate," "expect," "intend," "may," "target," "potential," "will," "would," "could," "should," "continue," and similar expressions.

PTC's actual results, performance or achievements could differ materially from those expressed or implied by forward-looking statements it makes as a result of a variety of risks and uncertainties, including those related to: expectations with respect to the potential financial impact or PTC's ability to realize the anticipated benefits of the acquisition of Agilis and its gene therapy platform, including with respect to the business of Agilis and expectations with respect to the potential achievement of development, regulatory and sales milestones and contingent payments to the former Agilis equityholders with respect thereto and PTC's ability to obtain marketing approval of PTC-AADC and other product candidates acquired from Agilis, will not be realized or will not be realized within the expected time period; significant transaction costs, unknown liabilities, the risk of litigation and/or regulatory actions related to the acquisition of its gene therapy pipeline, as well as other business effects, including the effects of industry, market, economic, political or regulatory conditions; the eligible patient base and commercial potential of PTC-AADC; and the factors discussed in the "Risk Factors" section of PTC's most recent Annual Report on Form 10-K, as well as any updates to these risk factors filed from time to time in PTC's other filings with the SEC. You are urged to carefully consider all such factors.

As with any pharmaceutical under development, there are significant risks in the development, regulatory approval and commercialization of new products. There are no guarantees that any product will receive or maintain regulatory approval in any territory, or prove to be commercially successful, including PTC-AADC.

The forward-looking statements contained herein represent PTC's views only as of the date of this press release and PTC does not undertake or plan to update or revise any such forward-looking statements to reflect actual results or changes in plans, prospects, assumptions, estimates or projections, or other circumstances occurring after the date of this press release except as required by law.

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SOURCE PTC Therapeutics, Inc.

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PTC Therapeutics Announces Results from Long-Term AADC Deficiency Gene Therapy Treatment Demonstrating Sustained Improvements - BioSpace

October 22 2019, 12:01am,The Times

Progress in gene editing has huge potential and should be welcomed

A leap forward in genetic science has the potential to improve the life of our species. It builds on the momentous 2012 discovery of the Crispr/Cas9 technique, which made it vastly easier to edit genes. This breakthrough revolutionised the study of heritable human diseases by allowing scientists to reproduce them more easily in laboratory animals, and opened up the tantalising possibility of one day curing them by editing embryos or even the genes of adult patients. The new advance, by scientists at Harvard and MITs Broad Institute, makes the technique far more effective, meaning that its use in treating diseases is becoming a real prospect. We should embrace it.

The new technique tackles a key weakness in Crispr/Cas9 gene editing. In 2012 scientists realised that

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The Times view on a breakthrough in treating heritable disease: Gene Therapy - The Times

MENLO PARK, Calif., Oct. 24, 2019 (GLOBE NEWSWIRE) -- Adverum Biotechnologies, Inc.,(Nasdaq: ADVM), a clinical-stage gene therapy company targeting unmet medical needs in ocular and rare diseases, today announced that the first patient was dosed in the third cohort (n=9) of the ongoing OPTIC phase 1 clinical trial for ADVM-022 for the treatment of neovascular or wet age-related macular degeneration (wet AMD). Patients in this cohort are receiving a single intravitreal injection of gene therapy candidate ADVM-022 at a dose of 2 x 10 ^11 vg/eye.

We are excited to report dosing the first patient in the third cohort of OPTIC. This expansion of OPTIC will generate important clinical data to support the further development of ADVM-022, said Aaron Osborne, MBBS, chief medical officer of Adverum. Based on the recently presented data from the first cohort of OPTIC, which demonstrated a sustained response to a single injection of ADVM-022 out to a median of 34 weeks, with no patient in the first cohort requiring anti-VEGF rescue therapy, we believe that ADVM-022 has the potential to be a transformative treatment option for patients with wet AMD.

Dante Pieramici, M.D., co-director of the California Retina Research Foundation, Managing Partner of The California Retina Consultants and investigator in the OPTIC trial, said, An intravitreal gene therapy that can significantly reduce the number of injections required to maintain vision would be welcomed by patients with wet AMD as well as their caregivers and physicians. Im encouraged by the recently presented clinical data from the first cohort of the OPTIC trial showing that the therapy was safe and well tolerated with no rescue injections required in patients who previously required frequent anti-VEGF injections to control their wet AMD.

About the OPTIC Phase 1 Trial of ADVM-022 in Wet AMDThe multi-center, open-label, phase 1 trial is designed to assess the safety and tolerability of a single intravitreal (IVT) administration of ADVM-022 in patients with wet AMD who are responsive to anti-vascular endothelial growth factor (VEGF) treatment. In the first cohort, patients (n=6) received ADVM-022 at a dose of 6 x 10^11 vg/eye and in the second cohort (n=6) patients received ADVM-022 at a dose of 2 x 10^11 vg/eye. In the third cohort (n=9), patients are receiving ADVM-022 at a dose of 2 x 10^11 vg/eye and in the fourth cohort (n=9), patients will receive ADVM-022 at a dose of 6 x 10^11 vg/eye. Patients in the first and second cohorts received prophylactic oral steroids, while patients in the third and fourth cohorts will receive prophylactic steroid eye drops. The primary endpoint of the trial is the safety and tolerability of ADVM-022 after a single IVT administration. Secondary endpoints include change in best-corrected visual acuity (BCVA), change in central subfield thickness (CST) and macular volume, as well as mean number of anti-VEGF rescue injections and percentage of patients needing anti-VEGF rescue injections. Each patient enrolled in the study will be followed for a total of two years.

Eight leading retinal centers acrossthe United Statesare participating in the OPTIC phase 1 trial for ADVM-022. For more information on the OPTIC phase 1 clinical trial of ADVM-022 in wet AMD, please visithttps://clinicaltrials.gov/ct2/show/NCT03748784.

About ADVM-022 Gene TherapyADVM-022 utilizes a propriety vector capsid, AAV.7m8, carrying an aflibercept coding sequence under the control of a proprietary expression cassette. ADVM-022 is administered as a one-time intravitreal injection, designed to deliver long-term efficacy, reduce the burden of frequent anti-VEGF injections, optimize patient compliance, and to improve vision outcomes for wet AMD and diabetic retinopathy patients.

In recognition of the need for new treatment options for wet AMD, the U.S. Food and Drug Administration granted Fast Track designation for ADVM-022 for the treatment of this disease.

Adverum is currently evaluating ADVM-022 in the OPTIC study, a phase 1 clinical trial in patients 50 years and older with wet AMD. Additionally, Adverum plans to submit an Investigational New Drug Application for ADVM-022 for the treatment of diabetic retinopathy to the U.S. Food and Drug Administration in the first half of 2020.

About Adverum Biotechnologies, Inc.Adverum Biotechnologies (Nasdaq: ADVM) is a clinical-stage gene therapy company targeting unmet medical needs for serious ocular and rare diseases. Adverum is evaluating its novel gene therapy candidate, ADVM-022, as a one-time, intravitreal injection for the treatment of its lead indication, wet age-related macular degeneration. For more information, please visit http://www.adverum.com

Forward-looking StatementsStatements contained in this press release regarding events or results that may occur in the future are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Such statements include, but are not limited to statements regarding: Adverums plans for advancing ADVM-022; the potential benefits of ADVM-022: the expected timing of submitting an IND for diabetic retinopathy, all of which are based on certain assumptions made by Adverum on current conditions, expected future developments and other factors Adverum believes are appropriate in the circumstances. Adverum may not achieve any of these in a timely manner, or at all, or otherwise carry out the intentions or meet the expectations disclosed in its forward-looking statements, and you should not place undue reliance on these forward-looking statements. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, which include risks inherent to, without limitation: Adverums novel technology, which makes it difficult to predict the time and cost of product candidate development and obtaining regulatory approval; the results of early clinical trials not always being predictive of future results; the potential for future complications or side effects in connection with use of ADVM-022; obtaining regulatory approval for gene therapy product candidates; enrolling patients in clinical trials; reliance on third parties for conducting the OPTIC trial and vector production; and ability to fund operations through completion of the OPTIC trial and thereafter. Risks and uncertainties facing Adverum are described more fully in Adverums Form 10-Q filed with the SEC on August 8, 2019 under the heading Risk Factors. All forward-looking statements contained in this press release speak only as of the date on which they were made. Adverum undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.

Investor and Media Inquiries:

Investors:Myesha LacyAdverum BiotechnologiesVice President, Investor Relations and Corporate Communicationsmlacy@adverum.com1-650-304-3892

Media:Cherilyn Cecchini, M.D.Account Supervisorccecchini@lifescipublicrelations.com1-646-876-5196

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Adverum Biotechnologies Doses First Patient in Third Cohort of OPTIC Phase 1 Clinical Trial of ADVM-022 Intravitreal Gene Therapy for Wet AMDPatients...

A more efficient approach to gene therapy that could lower costs and improve patient outcomes has recently been developed by a team from Scripps Research. This work, published on October 17 in the journal Blood, offers a potential alternative to the standard process of delivering gene therapy, which is expensive, time-consuming, and requires many steps to administer healthy genes to the patients stem cells.

If you can repair blood stem cells with a single gene delivery treatment, rather than multiple treatments over the course of many days, you can reduce the clinical time and expense, which removes some of the limitations of this type of approach, explained research leader Bruce Torbett, PhD, associate professor in the Department of Immunology and Microbiology.

The goal of gene therapy is to introduce a healthy version of a gene to a patients stem cells to replace a defective copy of this gene. This approach is designed to treat inherited conditions caused by genetic mutations, such as sickle cell anemia. Patients with sickle cell have a mutation in a gene that codes for a protein in blood cells, leading to misshaped cells that cause a myriad of clinical issues. The goal of gene therapy is to replace this mutated gene with a healthy copy to restore normal protein synthesis and eliminate the disease symptoms. This is often done by implanting the healthy gene into a modified virus, known as a viral vector, and having this virus use its innate ability to infiltrate host cells and inject this healthy gene into them.

Gene therapy treatments typically require the harvesting of a small population of hemopoietic stem cells, the cells that serve as precursors for all types of blood cells, from the patients blood. Viral vectors containing therapeutic genes are then introduced to these cells with the goal being for them to insert this genetic information into the stem cells.

The hemopoietic stem cells defend themselves from viral penetrance using interferon-induced transmembrane (IFITM) proteins that block the viral vectors. For this reason, many gene therapies require a large number of vectors and many attempts for success, which is an expensive process.

In their work, the Scripps team focused on caraphenol A, a molecular relative of resveratrol, a natural compound made by grapes and other plants present in wine. Resveratrol is known to have antioxidant and anti-inflammatory properties. Although caraphenol A shares these anti-inflammatory properties, it served a much different purpose in this work.

Observing the chemical properties of resveratrol and associated molecules such as caraphenol A, Torbett and colleagues wanted to investigate whether they could be used in gene therapy to improve the viral vectors ability to enter blood stem cells. Enhancing viral vector penetrance into host cells would be advantageous, being that the cells natural defense mechanisms against viral attacks present a challenge in gene therapy.

This is why gene therapy of hemopoietic stem cells has been hit-or-miss, explained Torbett. We saw a way to potentially make the treatment process significantly more efficient.

The researchers found that by adding caraphenol A to human hemopoietic stem cells with the viral vector present, the stem cells defense was weakened, and the viral penetrance increased. When these treated stem cells were implanted into mice in this study, they were observed to produce blood cells that contained the new genetic information.

In addition to saving costs, this approach also cuts down the time required for a patient to receive a gene therapy treatment. Reducing treatment time is not only convenient for the patient, but it lowers the chance that the stem cells lose their self-renewing properties as well. The more time the stem cells spend being outside of the body and being manipulated, the higher the likelihood of them losing their proliferative ability is.

Torbetts team is continuing to research how stem cells combat viral attacks, hoping to lower the cost of gene therapy while improving efficiency.

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New Gene Therapy Approach Reduces Cost and Improves Efficiency - DocWire News

Novartis raised its earnings forecast for the third time this year as its new gene therapy got off to a strong start in its first quarter of reported sales.

Earnings excluding some items are expected to increase by a mid- to high-teens percentage this year, the Basel, Switzerland-based company said. Novartis in July forecast a low double-digit to mid-teens percentage rise.

The focus is on gene therapy Zolgensma as the company discloses the first quarterly sales of the product that costs $2.1 million. The treatment exceeded analysts estimates despite concerns over coverage barriers.

Piqray, a breast cancer drug, is also in the spotlight with Novartis counting on the medicine to become one of its next growth drivers. The drug beat sales estimates.

Investors are looking for an update on an investigation into problematic data involving Zolgensma. The company has faced criticism that it should have told regulators about the data irregularities before the drugs approval in May.

Shares in the company have climbed about 15 per cent this year, in line with a gain of about 15 per cent for a Bloomberg index of European pharma companies. Bloomberg

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Novartis raises earnings forecast as new gene therapy gets off to strong start - The Irish Times

KENDALLVILLE Eighteen-month-old Omarion Jordan plays with his toys in his Kendallville home under the watchful eye of his mother, Kristin Simpson, and the family dog. Hes wiggly and active, with no hint of the rare genetic disease that could have taken his life before age 2.

Omarion has a rare genetic disorder called severe combined immunodeficiency syndrome, SCID for short and better known as the bubble boy disease made famous in a 1976 television movie starring John Travolta as well as an episode of the 1990s sitcom Seinfeld. The disease affecting 40 to 100 American newborns each year makes them extremely vulnerable to infections, which left untreated, kills most children before they turn two.

Simpson said SCID is caused by a random gene mutation on the maternal side. She said, she has no family history that would indicate the disease was ever present in other family members.

Omarion was born normally, but began to have skin infection symptoms before he was 3-months-old, she said. Doctors thought he had an extreme case of eczema or cradle cap.

Simpson said everything changed when Omarion got his 3-month vaccinations.

He had a bad reaction. He had no immune system to react with the vaccine, she said. He was covered in a green, pus-like substance.

Simpson took Omarion to the emergency room twice, but was sent home. She then made an appointment with her pediatrician, not knowing then that it would be months before she saw her apartment again.

The pediatrician sent us right to the hospital, Simpson said. It was 1 weeks to clear the infection. I had to drop everything. I never came back (to the apartment) after that morning.

Doctors sent Omarion and his mother on a four-hour ambulance ride to Cincinnati Childrens Hospital for tests. There, Simpson learned that the standard treatment for SCID was a bone marrow transplant. When a two-month search for a bone marrow match came up empty, doctors suggested another route.

There was a trial at St. Jude (Childrens Hospital) for gene therapy and we were given the option, Simpson said. We were flown to St. Judes on a private jet.

The experimental gene therapy used Omarions own bone marrow, altered to correct the missing gene. The altered bone marrow is transplanted back into Omarions body, carried by an HIV virus with all the harmful cells removed.

Its like a car, Simpson said. They take out the harmful elements and use the virus as a carrier for the altered gene.

Experimental gene therapy comes with both reward and risk. The treatment could be a breakthrough cure for Omarion and other children affected by the gene mutation.

The risks include developing leukemia, which has happened to some patients in the small trial group, other unknown side effects and the enormous financial cost. Treatment costs run into the millions of dollars.

Gene therapies, while breaking new ground in fighting tough-to-cure ailments, are a cutting edge field of medicine, but also an exceptionally expense one. For example, a gene therapy drug called Zolgensma is the most expensive drug ever approved in the United States, according to a Bloomberg Businessweek story about Omarion and the rise of gene therapies. A one-time infusion costs $2.1 million.

Omarions case has received national media attention, including the story from Bloomberg Businessweek, which published a story June 5 about the balance of rapidly progressing gene therapy and its high cost, and other outlets including NBC News, WebMD.com and CNN Health.

Simpson is grateful that St. Judes Children Hospital, the worlds leader in the treatment of childhood diseases, has picked up the entire tab for Omarions treatment.

Simpson said that at St. Jude, she and her mother were the only family members allowed inside Omarions isolation room. Everyone else was fully masked and gowned. They were in the isolation room for months.

Omarion received his bone marrow transplant Dec. 20, 2018, and finally left the hospital in April. Omarion will have checkups every three months for the foreseeable future and an annual checkup for the rest of his life.

Today hes healthy, thanks to a cutting-edge gene therapy treatment, and a walking miracle.

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Gene therapy gives "miracle boy" a second chance at life - KPCnews.com

Let's play a game of word association. I'll go first.

Cell Therapy

What words spring to mind? CRISPR? Medicine? Genetic disorders? Cancer? Gene therapy?

What about green tea? Unlikely, I imagine.

But in a new study published today in Science Advances, researchers from East China Normal University have created an elegant system for activating genetically edited cells using green tea.1Realizing the promise of cell therapiesEngineered cell therapies, deemed the "next frontier" in modern medicine, contain specific cellular material that triggers a desired effect in vitro or in vivo. Such therapies are in development in laboratories across the globe for an array of different conditions, including acute myocardial infarction (heart attack), brain cancer, breast cancer, diabetes and liver diseases. They offer a novel avenue of therapeutics for patients suffering from diseases for which treatment options are limited.For their efficacious and safe use in the clinic, scientists need to be able to regulate the activity of these cells in vivo. Essentially, they require a "remote control". This has proven a major barrier for the delivery of cell therapies to patients. Initial work in this field has adopted antibiotics such as doxycycline or tetracycline as remote-control triggers for gene expression in the cells. However, regular use of antibiotics may result in antibiotic resistance and other adverse side effects.So, what alternatives exist?Haifeng Ye, Professor at East China Normal University, says "Ideal trigger molecules for clinical biomedical applications would be natural, non-toxic, highly soluble, inexpensive, and perhaps even beneficial to health."Previous studies have reported that remote control switches can be activated through the use of food or cosmetic preservatives, vanillic acid, benzoate and phloretin for example. These molecules do not naturally occur in food however, and the safety implications of their long-term use is not well known.A green solution?Nothing beats a good cup of tea. It is the second most popular beverage on the planet (following water) and can be found in the household cupboards of 80% of Americans. Tea is available in a variety of forms, including but not limited to black tea, oolong tea, white tea and green tea. A plethora of research studies have documented the numerous health benefits of green tea consumption, including anticarcinogenic, anti-inflammatory, antimicrobial, and antioxidant effects.The components of green tea most heavily researched with regards to health are the polyphenols, of which the most pertinent are flavonoids, and the most pertinent flavonoids are the catechins.2Post green-tea consumption, the tea catechins and phenolic acids undergo metabolic processing to form the antioxidant protocatechuic acid (PCA). In their latest study, Ye and team have utilized this antioxidant as a "remote control" for activating gene switches in cells. "PCA is a major tea catechin compound produced by humans following green tea consumption that has powerful antioxidant activity. Therefore, in this study, we showed the use of protocatechuic acid (we call it PCA), a metabolite after tea drinking, as a trigger molecule," Ye told Technology Networks.PCA-inducible gene switchesIn the study, the scientists engineered PCA-inducible gene switches in mammalian cells. Initially, they explored the potential for using PCA to monitor cell-based long-term therapies in vivo by integrating the genetic switch into HEK-293 cells and found that the cell line demonstrated reversible and tunable induction kinetics, which the authors regard as "excellent switching performance". This was characterized by negligible basal expression and nonsaturating increases in the transgene output over the course of a 15-day trial.Next, they microencapsulated and implanted the HEK cells into mice. Ye tells us, "The alginate-poly (L-lysine)-alginate-based encapsulation technology was used in our study for cell therapy. This clinically validated implant technology enables the free diffusion of metabolites, nutrients and proteins of lower molecular weights (<72 kDa) across the biocompatible capsule membrane while shielding their cellular content from physical contact with the hosts immune system. The implant technology has been successfully validated in human clinical trials and the performance of the material is continuously improved for clinical applications."The researchers found that, regardless of delivery method (intraperitoneal, oral intake from water, or oral intake from concentrated green tea), PCA could control the secretion of a reporter protein, SEAP, in a dose-dependent manner.Making CRISPR more crisp?CRISPR gene-editing shows promise in revolutionizing personalized medicine. A notable key issue with CRISPR, however, is the "off target" effects that limit its specificity. In this study, the scientists used the PCA-responsive cells to perform more targeted CRISPR gene editing: "By applying newly-designed fusion-protein-based PCA-controlled gene switches to Pol III promoters, we created trigger-inducible expression systems for gRNAs to program PCA-mediated CRISPR/Cas9-activity," says Ye.Exploring diabetes treatment with PCA-induced cell therapyYe and colleagues next tested the potential of the PCA remote control system for treating experimental diabetes using a mouse model. Using the switch, they engineered two different cell lines: one that enabled PCA-inducible expression of the reporter protein SEAP and insulin, and the other producing a short variant of human glucagon-like peptide 1 and SEAP. Implantation of these cells into mouse models of type 1 diabetes and type 2 diabetes mellitus resulted in restored homeostatic fasting blood glucose concentrations and glucose tolerance upon PCA injection.Recognizing that the translation of research findings from mouse models to humans in the clinic can be problematic, the scientists then decided to explore the PCA remote control switch efficacy in non-human primate models of diabetes. In parallel to the treatment efficacy observed in the type 2 diabetic mice, daily oral administration of PCA rapidly increased the expression of glucagon-like peptide 1 and restored glucose homeostasis in diabetic monkeys.In terms of safety, blood biochemical analyses related to inflammatory responses found that white blood cell count, lymphocytes, monocytes, eosinophils, and basophils, did not increase at any point during the treatment when compared with pre-treatment.The study findings certainly excite the authors, "Although there have not yet been preclinical studies for the application of engineered cellbased therapies in humans, this first-in-monkey study demonstrates the feasibility of safely and successfully scaling up a treatment strategy by controlling microencapsulated engineered cells to release therapeutic outputs from animals such as mice to larger NHPs. Therefore, this study substantiates the medical utility of concepts developed in synthetic biology," they note in the discussion of the paper.How much tea is too much tea?Hypothetically, if this therapy was to reach the clinic, I ponder over the possibility of an individual consuming "too much" green tea, and how this might impact the therapy. Ye is quick to inform me that this would not be an issue, "Only custom prepared concentrated green tea can activated the implanted designer cells. The normal green tea drinks cannot activate the implanted cells because of low concentration," he says.The future looks greenThe study is comprehensive, assessing the PCA "switch" in a variety of cell lines and mammalian models with a variety of control measures in place.Thus, in which direction will this research go next? I ask Ye, who tells me, " We will next focus on solving the following limitations:(1) The PCAON-switch was stably integrated into [the] genome by a "Sleeping Beauty" transposon system. Due to a random integration, unwanted insertional mutagenesis might occur. We will next consider using gene editing tools, such as CRISPR, to enable facile and permanent integration of the switch into the targeted genomic sequences in human cells without insertional mutagenesis;(2) The chassis of the HEK-293 cells are easily handled, transfected, and compatible to the PCAON-switch. For translational applications, they must also be safe (no side effects) in humans. Hence, we will test the therapeutic efficiency of the PCAON-switch in autologous parental cells from patients own mesenchymal stem cells, which may provide immunocompatible and noncarcinogenic autologous or allogeneic cell sources;(3) The lifespan of the designer cells inside the alginate microcapsules is an imperative issue. To realize long-term cell therapy, we will further improve the encapsulation technology."Haifeng Ye, Professor at East China Normal University, was speaking with Molly Campbell, Science Writer, Technology Networks.References:1. A green teatriggered genetic control system for treating diabetes in mice and monkeys," by J. Yin; L. Yang; K. Dong; J. Jiang; S. Xue; Y. Xu; X. Wang; H. Ye at East China Normal University in Shanghai, China; L. Mou; Y. Lu at First Affiliated Hospital of Shenzhen University in Shenzhen, China.2. Reygaert. 2018. Green Tea Catechins: Their Use in Treating and Preventing Infectious Diseases. Biomed Research International. doi: 10.1155/2018/9105261.

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Green Tea Acts as a "Remote Control" To Switch on Cell Therapy - Technology Networks

The honeymoon period for gene therapy developers was short-lived. Shares of at least 26 are trading lower now than they were a year ago, amounting to roughly $18 billion in lost market value.

Relief may not come soon, either. Analysts suspect investors aren't just looking for promising safety and efficacy data anymore;they want to know how companies intend to make money off these treatments. Most don't have answers to that question yet.

"There's this phase, not just in gene therapy, but in most companies or technologies, where it's all exuberance and development," said Tyler Van Buren, an analyst at Piper Jaffray. "A lot of that can end once rubber hits the road and you have to launch a product."

Bluebird bio is having this problem. The Boston biotech's share price is down 41% from a year ago and 26% since mid-June, when executives said the European launch of its Zynteglo gene therapy would be pushed back from 2019 to 2020.

Mani Faroohar of investment bank SVB Leerink argues the delay has dimmed investor confidence in smaller biotechs working on "transplant" gene therapies like Zynteglo, which treats a blood disorder known as beta-thalassemia by harvesting a patient's stem cells, engineering them to produce a form of hemoglobin, and infusing them back into patients.

"If the bellwether can't launch a product that they've been spending billions of dollars on over the course of 10 years, how is a $400 million company somewhere going to do it?" Faroohar told BioPharma Dive.

Bluebird isn't the only gene therapy leader to get knocked recently.

Swiss pharma giant Novartis remains on damage control following a data scandal that, to some extent, tarnished the approval of its Zolgensma gene therapy. Roche's acquisition of Spark Therapeutics, meanwhile, is taking longer than expected because of antitrust concerns.

Delays to the Spark deal may be having a particularly outsized effect on gene therapy stocks. Signs that the Federal Trade Commission took issue with the pairing, which many analysts assumed would be a sort of "check-the-boxes" acquisition, started to show up in early April.

No gene therapy acquisitions have been announced since, and Faroohar doesn't expect that to change until buyers have more clarity on what's holding up Roche. With the deal's timeline already extended by months, shareholders of other companies might not be willing to wait around for a resolution.

"If you paralyze the acquirers, that makes it very difficult to make a compelling case for a lot of these companies that certainly wouldn't be able to commercialize their own products without raising a lot of diluted capital," Faroohar said.

Van Buren sees the Spark deal as a more minor issue, given that gene therapy continues to be one of the hottest areas in drug development. Even so, he acknowledged that it could discourage "natural bidders" from coming to the table, which lowers the probability of certain acquisitions.

The gene therapy field evolved rapidly over the last decade and, by 2025, the Food and Drug Administration expects to clear for market 10 to 20 cell or gene therapy products annually.

Investor sentiment is shifting with the times. As Bluebird, Novartis and Spark Therapeutics proved these treatments can move through the clinic and gain regulatory approval, investors became increasingly interested in marketing and manufacturing strategies even for drugs in early development.

"For so long, [gene therapy companies] didn't really trade on, 'What's my margin structure going to be? What's my distribution method? How do I realize attractive pricing in Europe versus Japan versus the U.S.?'" Faroohar said.

Now, investor awareness "about some of these very nuanced commercial questions is catching up."

One of their biggest commercial concerns revolves around insurance coverage, since the U.S. insurance system wasn't designed to handle incredibly expensive, potentially one-time treatments like Zolgensma, which Novartis offers at $2.1 million through a five-year installment plan.

Another commercial sticking point has been manufacturing. Bluebird, for example, pinned Zynteglo's slower launch on tweaks the company was making to the therapy's production process.

Ensuring consistent and quality manufacturing will likely be a challenge for others too. PwC proposes in a new report that the growing interest in gene therapy will lead to greater competition for the time and resources of contract manufacturers working in the space. The competition could, in turn, result in higher costs or supply constraints, and may force companies to invest more in their own manufacturing a development seen with projects begun by Novartis, Pfizer, Sarepta and Bluebird.

"The days of 100% outsourcing and letting somebody else deal with it I don't see that being the standard model," said Karen Young, U.S. Pharmaceutical and Life Sciences Leader at PwC.

The industry, however, is still getting acclimated to the small-scale, highly personalized, logistically daunting processes required for cell and gene therapy production. Building in-house capabilities and a team with the technical know-how to run them would likely be an expensive, time-consuming endeavor.

These challenges are, of course, predicated on a gene therapy having positive clinical data. On that measure, analysts have observed investors becoming harder to impress.

Van Buren noted to BioPharma Dive how shares of Adverum Technologies, which is working on gene therapies for eye and rare diseases, plummeted in mid-September because investor expectations about one of the company's trial readouts were "almost impossibly high."

"It got crushed as if a trial failed, when it was actually an objectively positive outcome," he said.

Adverum's therapy targets an eye disease known as wet AMD, which already has treatment options in Regeneron's Eylea and Roche's Lucentis. Both Van Buren and Faroohar expect that in markets where patients respond well to the standards of care, such as wet AMD and hemophilia, there will be even more pressure for gene therapy developers to show their treatments are safe and long-lasting.

Data and post-approval obstacles, combined with potentially diminished M&A prospects, set the stage for a tough road ahead for gene therapy stocks.

"It becomes harder to put together a compelling long-case for a lot of gene therapy stocks, even if they continue to produce a very attractive set of data and potentially transformative clinical products," Faroohar said.

Editor's Note:Paper losses for the group of gene therapy companies included in BioPharma Dive's analysis were calculated by using historical valuations compiled by Koyfin, measured against current market capitalizations. Stock change over 52 weeks was measured from Oct. 1, 2018 to Oct. 1, 2019.

Publicly traded biotechs were included based on whether gene therapy, or gene editing, made up the bulk of their pipeline, yielding a list that's representative of the field but not exhaustive. Large pharmas involved in gene therapy were not included, nor were companies dedicated to autologous or allogeneic cancer cell therapies.

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Gene therapy stocks have taken a beating. Their recovery may be slow - BioPharma Dive

Scientists have developed a fast, efficient and economical method to create viral delivery vectors used in gene therapy to deliver modified versions of genes to treat disorders caused by genetic defects, including spinal muscular atrophy (SMA).

The findings were reported in the study, Production of adeno-associated virus vectors for in vitro and in vivo applications, and published in Scientific Reports.

Gene therapy is a relatively new approach that has been gaining popularity in clinical practice as a way to treat diseases caused by genetic mutations. It involves delivering a functional version of a gene to correct or replace a faulty gene within specific cells in the body.

In order to deliver the corrected version of the gene to cells, researchers use special viral vectors that work as carriers. Adeno-associated viruses, or AAVs, are one of the most used viral vectors in gene therapy due to their ability to infect and deliver the corrected gene to both dividing and non-dividing cells, without causing any harm to patients.

Gene therapy already is being used as a form of SMA treatment. The recent approval of Zolgensma (AVXS-101), a gene therapy co-developed by AveXis and Novartis, for the treatment of all types of SMA in newborns and toddlers up to the age of 2, was a historical landmark that highlighted the potential of AAV-based gene therapies to treat rare genetic disorders.

Most protocols recommend AAV purification from producer cells, grown in large cell stacks or cell culture factories to obtain sufficient AAVs for animal experiments. However, producer cells also release large quantities of AAV into the culture medium, which often remains unused, the investigators said.

In this study, researchers from the Boston University School of Medicine (BUSM) described a new protocol that allows them to maximize the quantity of AAVs that can be purified from producer cells and their culture medium in a fast, efficient and economic way.

With the new protocol, which involved several separation and purification laboratory techniques, they managed to obtain up to one milliliter of AAVs at a concentration of 10101011 viral genome copies per microliter, using five times less the number of producer cells normally used in conventional protocols.

They also showed the AAVs produced with the new protocol were viable and retained their ability to efficiently infect and deliver modified genes to cells in vitro and in vivo (outside and inside an organism, respectively).

Our protocol helps to produce AAVs efficiently and economically in regular laboratories so that researchers can easily conduct pre-clinical trialsforgene therapy, Markus Bachschmid, PhD, assistant professor of medicine at BUSM and corresponding author of the study, said in a press release.

Several labs in the Boston area and Japan have already tested this new protocol and found it useful, said Reiko Matsui, MD, assistant professor of medicine at BUSM and co-corresponding author of the study. Our hope is that many laboratories can adapt these procedures to accelerate research and promote gene therapy.

Joana is currently completing her PhD in Biomedicine and Clinical Research at Universidade de Lisboa. She also holds a BSc in Biology and an MSc in Evolutionary and Developmental Biology from Universidade de Lisboa. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells cells that make up the lining of blood vessels found in the umbilical cord of newborns.

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Ana holds a PhD in Immunology from the University of Lisbon and worked as a postdoctoral researcher at Instituto de Medicina Molecular (iMM) in Lisbon, Portugal. She graduated with a BSc in Genetics from the University of Newcastle and received a Masters in Biomolecular Archaeology from the University of Manchester, England. After leaving the lab to pursue a career in Science Communication, she served as the Director of Science Communication at iMM.

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New Method Produces High Quantities of Viral Vectors for Gene Therapy - SMA News Today

News Release

Wednesday, October 2, 2019

Forward-oriented design might boost treatment effectiveness and broaden use.

Researchers at the National Institutes of Health have developed a new and improved viral vectora virus-based vehicle that delivers therapeutic genesfor use in gene therapy for sickle cell disease. In advanced lab tests using animal models, the new vector was up to 10 times more efficient at incorporating corrective genes into bone marrow stem cells than the conventional vectors currently used, and it had a carrying capacity of up to six times higher, the researchers report.

The development of the vector could make gene therapy for sickle cell disease much more effective and pave the way for wider use of it as a curative approach for the painful, life-threatening blood disorder. Sickle cell disease affects about 100,000 people in the United States and millions worldwide.

Our new vector is an important breakthrough in the field of gene therapy for sickle cell disease, said study senior author John Tisdale, M.D., chief of the Cellular and Molecular Therapeutic Branch at the National Heart, Lung, and Blood Institute (NHLBI). Its the new kid on the block and represents a substantial improvement in our ability to produce high capacity, high efficiency vectors for treating this devastating disorder.

Researchers have used virus-based vehicles for years in gene therapy experiments, where they have been very effective at delivering therapeutic genes to bone marrow stem cells in the lab before returning them to the body. But theres always room for improvement in their design in order to optimize effectiveness, Tisdale noted. He compared the new virus-based vehicle to a new and improved car that is also far easier and cheaper for the factory to produce.

The study was supported by the NHLBI and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), both part of the NIH. It was published online today in Nature Communications.

Sickle cell disease is an inherited blood disorder caused by a mutation, or misspelling, in the beta-globin gene (or -globin gene). This mutation causes hemoglobin, the main ingredient of blood cells, to produce sickle-shaped cells that can stick to the walls of blood vessels, causing blockage, pain, anemia, organ damage, and early death. With gene therapy, doctors modify the patients bone marrow hematopoietic (blood-producing) stem cells in the lab by adding a normal copy of the beta-globin gene through the use of a viral vector. They then reinfuse the modified stem cells into the patient to produce normal, disc-shaped red blood cells.

For the past 30 years, researchers have been designing these beta-globin vectors in a reverse structural orientation, meaning the therapeutic genes incorporated into the virus are translated, or read, from right to left by the viral vector-making machinery much like reading an English sentence backwards. The reason for the reverse orientation is the sensitive expression of a key molecular component of the vector called intron 2. This segment is required for high-level beta-globin gene expression but gets clipped out during the normal vector preparation process if it is left in the natural, forward direction. Gene therapy trials using reverse-oriented vectors for sickle cell disease and beta-thalassemia have largely been encouraging, the researchers said, but this complicated gene translation process has made vector preparation and gene-transfer efficiency more difficult.

About 10 years ago, Tisdale and Naoya Uchida, M.D., Ph.D., a staff scientist in his lab, searched for an improved delivery vehicle like designing a better car and decided to undertake a radical redesign of the beta-globin vector. They came up with a unique work-around design that left intron 2 intact and created the new forward-oriented beta-globin vector. In contrast to the old vector, the gene sequence, or message, of the new beta-globin vector is read from left to right like reading a normal sentence making the gene translation approach less complicated, Tisdale explained.

The researchers tested the new vectors in mice and monkeys and compared the results to reverse-oriented vectors. They found that the new vectors could transfer a much higher viral load up to six times more therapeutic beta-globin genes than the conventional vectors and had four to 10 times higher transduction efficiency, a measure of the ability to incorporate corrective genes into repopulating bone marrow cells. The new vectors also showed a capacity for longevity, remaining in place four years after transplantation. Researchers also found that they could be produced in much higher amounts than the conventional vectors, potentially saving time and lowering costs associated with large-scale vector production.

Our lab has been working on improving beta-globin vectors for almost a decadeand finally decided to try something radically differentand it worked, Tisdale said. These findings bring us closer to a curative gene therapy approach for hemoglobin disorders.

The new vector, for which the NIH holds the patent, still needs to undergo clinical testing in humans. Already an estimated 27 people with sickle cell disease have undergone experimental gene therapy using conventional vectors. Through its Cure Sickle Cell Initiative, NIH is working to accelerate the development of these and other new genetic therapies, including gene editing, with the goal of finding a cure for the disease. The initiative is part of NIHs larger multi-pronged approach to reducing the burden of blood disorders. People with sickle cell disease can visit clinicaltrials.gov to find a clinical trial that is actively enrolling.

About the National Heart, Lung, and Blood Institute (NHLBI):NHLBI is the global leader in conducting and supporting research in heart, lung, and blood diseases and sleep disorders that advances scientific knowledge, improves public health, and saves lives. For more information, visitwww.nhlbi.nih.gov.

About the National Institutes of Health (NIH):NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

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NIH researchers create new viral vector for improved gene therapy in sickle cell disease - National Institutes of Health