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Inlaid Base Editors Slide Windows, Increase Efficiency

Inlaid Base Editors Slide Windows, Increase Efficiency | Vectorology - GEG Tech top picks | Scoop.it
Beam Therapeutics describes Inlaid Base Editors (IBEs) and their ability to convert the disease-causing sickle cell allele into a non-pathogenic variant.
BigField GEG Tech's insight:

Base editors are fusions of a deaminase and a Cas enzyme and modify DNA precisely and efficiently and avoid double-strand breaks with little off-target effect. This technology thus has many advantages but has obstacles such as a limitation of access to particular sites in the genome, which depends on the location of the protospacer adjacent motif (PAM) sequence and a short DNA sequence that is required for Cas9 to target an editing window. The Beam Therapeutics has therefore developed a new class of base editors called embedded base editors, which is a solution to the PAM problems, by repositioning the TadA deaminase in the middle of Cas 9 and not at the N or C terminal, so this allows the active site to be oriented around Cas 9 and decide where deamination will occur in the DNA. This new technology converts a pathogenic sickle cell hemoglobin allele into a natural variant.

However, in vivo core editors are big, hard-to-deliver cargo. That is why Beam Therapeutics recently acquired Guide Therapeutics, which has technological expertise in rapidly screening novel lipid nanoparticles with DNA barcodes. Beam Therapeutics’ treatments will likely be among the genome-editing treatments available to sickle cell patients in the future.

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Better choice of contraceptives can prevent breast cancer | EurekAlert! Science News

Better choice of contraceptives can prevent breast cancer | EurekAlert! Science News | Vectorology - GEG Tech top picks | Scoop.it
There is a strong link between hormonal contraceptives and breast cancer risk. The main culprit are progestins, synthetic mimics of the pregnancy hormone progesterone that stimulate cell growth in the breast. An EPFL study into the distinct biological effects of different progestins on the breast shows that contraceptive-related breast cancer can be prevented by more informed choices about the composition of contraceptives.
BigField GEG Tech's insight:

Proud to share the work of one of our long-standing partners who recently published in EMBO Molecular Medicine , study for which we have provided our expertise in vectorology.

This work has also been subject of a video allowing to hear the Professor Cathrin Brisken talk about this area.

 

https://www.embopress.org/doi/full/10.15252/emmm.202114314

https://www.youtube.com/watch?v=POV1vI4yI6Y

 

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In vivo adenine base editing of PCSK9 in macaques reduces LDL cholesterol levels - Nature Biotech

In vivo adenine base editing of PCSK9 in macaques reduces LDL cholesterol levels - Nature Biotech | Vectorology - GEG Tech top picks | Scoop.it
Most known pathogenic point mutations in humans are C•G to T•A substitutions, which can be directly repaired by adenine base editors (ABEs). In this study, we investigated the efficacy and safety of ABEs in the livers of mice and cynomolgus macaques for the reduction of blood low-density lipoprotein (LDL) levels. Lipid nanoparticle–based delivery of mRNA encoding an ABE and a single-guide RNA targeting PCSK9, a negative regulator of LDL, induced up to 67% editing (on average, 61%) in mice and up to 34% editing (on average, 26%) in macaques. Plasma PCSK9 and LDL levels were stably reduced by 95% and 58% in mice and by 32% and 14% in macaques, respectively. ABE mRNA was cleared rapidly, and no off-target mutations in genomic DNA were found. Re-dosing in macaques did not increase editing, possibly owing to the detected humoral immune response to ABE upon treatment. These findings support further investigation of ABEs to treat patients with monogenic liver diseases. Base editors are effective and safe for cholesterol reduction in non-human primates.
BigField GEG Tech's insight:

Low-density lipoprotein (LDL) can carry thousands of fat molecules,
such as cholesterol, and high levels of LDL in the blood are clinically associated with an increased risk of cardiovascular disease or atherosclerosis. By installing a point mutation through gene editing in the gene encoding an enzyme called PCSK9 that is involved in the uptake of LDL cholesterol from the blood into cells, an international team of researchers led by the University of Zurich succeeded in permanently lowering high levels of LDL cholesterol in the blood of mice and macaques. To control the delivery of the basic editing tool into the animals' livers, the researchers adapted the RNA technology used in the COVID-19 vaccines. However, instead of encapsulating an RNA encoding the SARS-CoV2 spike protein in lipid nanoparticles, they encapsulated an RNA encoding the adenine base editor. This study opens the possibility of curing patients with inherited metabolic liver diseases.

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New CAR T approach minimizes resistance, helps avoid relapse in non-Hodgkin's B-cell lymphoma 

New CAR T approach minimizes resistance, helps avoid relapse in non-Hodgkin's B-cell lymphoma  | Vectorology - GEG Tech top picks | Scoop.it
Early results from a new, pioneering chimeric antigen receptor (CAR) T cell immunotherapy trial led by researchers at the UCLA found using a bilateral attack achieves a more robust defense and helps avoid relapse.
BigField GEG Tech's insight:

Patients diagnosed with relapsed or refractory B-cell lymphoma tend to have poor outcomes with second-line therapies. CAR T cells have been a game changer for many people with this disease. However, 50% of patients relapse after six months. Researchers at the UCLA Jonsson Comprehensive Cancer Center have therefore developed a new CAR T cell-based immunotherapy for people with non-Hodgkin's B-cell lymphoma that allows for a bilateral attack by targeting CD19 and CD20 instead of a conventional approach by targeting only CD19, thereby minimizing resistance to treatment. This new approach allows for a more robust defense, helps avoid relapse and prevents antigen leakage. For the first clinical trial, T lymphocytes from 5 patients were collected, modified in the laboratory to produce anti CD19-CD20 CAR T cells and then reinjected into the patients. The results of the first clinical trial demonstrated a complete metabolic response with minimal toxicity in four of the five treated patients. The goal of the study was to determine a safe therapeutic dose.

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The NIH Somatic Cell Genome Editing program - Nature

The NIH Somatic Cell Genome Editing program - Nature | Vectorology - GEG Tech top picks | Scoop.it
PNA
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In an article published in the April 8 issue of Nature, the National Institutes of Health's Somatic Cell Gene Editing Consortium provided a detailed update on the progress of their nationwide effort to develop safer and more effective methods to edit the genomes of disease-relevant somatic cells and reduce the burden of disease caused by genetic changes.

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What scientists do and don’t know about the Oxford–AstraZeneca COVID vaccine - Nature

What scientists do and don’t know about the Oxford–AstraZeneca COVID vaccine - Nature | Vectorology - GEG Tech top picks | Scoop.it
Results confirming the vaccine’s strong protection against COVID-19 were welcomed following last week’s pause in roll-outs — but fresh questions have now emerged about the data.
BigField GEG Tech's insight:

After a pause in the use of AstraZeneca's vaccine in several European countries to investigate reports of blood clotting conditions in a number of vaccine recipients, the European Medicines Agency considers AstraZeneca's vaccine to be safe and the World Health Organization continues to recommend it. The vaccine has received regulatory approval in more than 100 countries but has not yet been approved in the United States. Amidst these uncertainties, this vaccine raises many questions. How effective is this vaccine?  How safe is it? How effective is it in the elderly? What is the optimal timing of doses? What impact will this week's confusion have on the U.S. rollout? How well does the vaccine perform against the variants? At this point, are we able to answer most of these questions correctly? What do we know and what do we not yet know? These questions are even more important as AstraZeneca will soon begin trials on next-generation vaccines against current variants of SARS-CoV-2 and will be available by the end of 2021. 

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Major European nations suspend use of AstraZeneca vaccine

Major European nations suspend use of AstraZeneca vaccine | Vectorology - GEG Tech top picks | Scoop.it
BERLIN (AP) — Germany, France and Italy on Monday became the latest countries to suspend use of AstraZeneca’s COVID-19 vaccine over reports of dangerous blood clots in some recipients, though the...
BigField GEG Tech's insight:

Germany, France and Italy on Monday became the latest countries to suspend use of AstraZeneca’s COVID-19 vaccine over reports of dangerous blood clots in some recipients, though the company and European regulators have said there is no evidence the shot is to blame.

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News: CRISPR Approaches to Duchenne Muscular Dystrophy

News: CRISPR Approaches to Duchenne Muscular Dystrophy | Vectorology - GEG Tech top picks | Scoop.it
CRISPR-Cas is seen as the holy grail in medicine for rare and incurable genetic diseases. In this piece, we take a look at what CRISPR can do for Duchenne muscular dystrophy.
BigField GEG Tech's insight:

Duchenne muscular dystrophy (DMD) occurs in approximately 1 in 3,500 to 5,000 live male births worldwide. It is an X-linked disease that results from mutations in the DMD gene that codes for dystrophin. DMD leads to progressive muscle weakness and muscle death, inflammation and loss of mobility before adulthood. Respiratory and cardiac dysfunctions occur in advanced stages of the disease and people with DMD usually die prematurely. In recent years, four gene targeting therapies have received FDA approval for DMD. All of these therapies are antisense olignonucleotides that work by binding to the transcript of pre-mRNA dystrophin. These exons skipping therapeutic strategies can theoretically treat more than 80% of DMD mutations, their efficacy has so far raised concerns, they do not treat cardiac dysfunction in DMD, and are not curative. However, an in vivo CRISPR therapy would treat DMD mutations at the genomic level, offering a permanent correction and circumventing the need for regular dosing. For example, research in Germany last year revealed that the suppression of exon 51 by CRISPR-Cas9 in pigs lacking exon 52 resulted in widespread expression of dystrophin in muscles, including the diaphragm and heart, prolonging survival and reducing the risk of irregular heart rhythm.

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Bluebird reveals new details on cancer cases in gene therapy trial

Bluebird reveals new details on cancer cases in gene therapy trial | Vectorology - GEG Tech top picks | Scoop.it
Executives shared an update on the biotech's investigation of the two cases at an investor conference, rather than via a statement or regulatory filing.
BigField GEG Tech's insight:

Bluebird bio has stopped two clinical studies of its gene therapy for sickle cell disease after one participant developed leukemia and researchers reported another has a cancer-like disease of the bone marrow. 

Bluebird is trying to determine where the vector integrated into the cell's genome, aiming to assess proximity to the genes that triggered the patient's cancer. The company will also examine whether the vector influenced gene expression, said chief scientific officer Phillip Gregory. 

 

Part of answer?

https://pubmed.ncbi.nlm.nih.gov/22523069/

https://pubmed.ncbi.nlm.nih.gov/19707188/

 

 

 

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CRISPR and Lentiviral Vector use to fix cell defects in two common blood disorders - Science

CRISPR and Lentiviral Vector use to fix cell defects in two common blood disorders - Science | Vectorology - GEG Tech top picks | Scoop.it
CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia
BigField GEG Tech's insight:

It is a double milestone: new evidence that cures are possible for many people born with sickle cell disease and another serious blood disorder, beta-thalassemia, and a first for the genome editor CRISPR.

Today in The New England Journal of Medicine (NEJM) and tomorrow at the American Society of Hematology (ASH) meeting, teams report that two strategies for directly fixing malfunctioning blood cells have dramatically improved the health of a handful of people with these genetic diseases

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News: A Single Cas9 Injection Could Mean a Lifetime of Treatment for Angelman Syndrome

News: A Single Cas9 Injection Could Mean a Lifetime of Treatment for Angelman Syndrome | Vectorology - GEG Tech top picks | Scoop.it

A CRISPR-Cas9 treatment reactivated a crucial gene in mice and human neurons — hinting at a possible one-time treatment for Angelman syndrome.

BigField GEG Tech's insight:

A treatment based on CRISPR-Cas9 reactivated a crucial gene in mice and human neurons suggesting a possible single treatment for Angelman syndrome.  This new approach would replace frequent and invasive injections of an existing therapy. Angelman syndrome is a genetic disease. It causes developmental delay, speech and balance problems, intellectual impairment and sometimes seizures. This syndrome is caused by a mutation that suppresses the copy of the UBE3A gene obtained by the mother. The paternal copy of the gene is naturally silenced. Patients therefore find themselves without a single functional copy of the UBE3A gene. This new gene editing therapy based on CRISPER-Case 9 awakens the dormant paternal copy of the gene by targeting and deactivating the UBE3A-ATS ligase that down-regulates its expression. 20 years after scientists first realized that Angelman Syndrome was treatable, this new treatment shows that the disease could be at least largely reversed at or around birth.

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Patient death in pivotal gene therapy trial rattles Sarepta partner already facing clinical hold –

Patient death in pivotal gene therapy trial rattles Sarepta partner already facing clinical hold – | Vectorology - GEG Tech top picks | Scoop.it
BigField GEG Tech's insight:

A child with mucopolysaccharidosis type IIIA (MPS IIIA) has died in Lysogene’s pivotal trial for its lead gene therapy. LYS-SAF302 is designed to deliver a functional copy of the SGSH gene directly to brain cells using the adeno-associated virus carrier, AAVrh10.

As Solid’s repeated trial suspensions have illustrated, safety fears continue to plague gene therapy developers relying on high doses of AAV vectors to deliver their supposed one-time cure. More recently, Astellas subsidiary Audentes reported the third death in its trial for X-linked myotubular myopathy, highlighting trouble ahead for a booming field that’s also clouded by durability and CMC challenges.

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Orchard licenses gene therapy tech from GSK

Orchard licenses gene therapy tech from GSK | Vectorology - GEG Tech top picks | Scoop.it
BigField GEG Tech's insight:

Orchard Therapeutics has licensed lentiviral stable cell line technology from GlaxoSmithKline for use in its hematopoietic stem cell gene therapies. GSK filed for patents on the technology before selling its rare disease gene therapy portfolio to Orchard in 2018.

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AAV used in gene therapies may pose cancer risk, dog study hints - Science

AAV used in gene therapies may pose cancer risk, dog study hints - Science | Vectorology - GEG Tech top picks | Scoop.it
Delivered DNA integrates into host genome, stabilizing protein production but stirring fears of mutating cell growth genes
BigField GEG Tech's insight:

Great publication in an internationally well-respected journal, about the integration of AAV genomes. This is a critical point because this type of event can induce genotoxicity effects which are harmful in gene therapy contexts. For far too long, this point has remained unclear, preventing its study and biasing the evaluation of the AAV biosafety level. This lack of clarity has also prevented comparisons with other viral vector options to design gene therapy strategies which would have been more relevant. For example, several publications showed very promising results with non-integrating lentiviral vectors in the field of eye gene therapy.

 

The issues of AAV integrations are even more important after the recent marketing authorizations of gene therapy products Luxturna and Zolgensma which are based on this type of viral vector.

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Enhancing CRISPR-Cas9 gRNA efficiency prediction by data integration and deep learning - Nature

Enhancing CRISPR-Cas9 gRNA efficiency prediction by data integration and deep learning - Nature | Vectorology - GEG Tech top picks | Scoop.it
The design of CRISPR gRNAs requires accurate on-target efficiency predictions, which demand high-quality gRNA activity data and efficient modeling. To advance, we here report on the generation of on-target gRNA activity data for 10,592 SpCas9 gRNAs. Integrating these with complementary published data, we train a deep learning model, CRISPRon, on 23,902 gRNAs. Compared to existing tools, CRISPRon exhibits significantly higher prediction performances on four test datasets not overlapping with training data used for the development of these tools. Furthermore, we present an interactive gRNA design webserver based on the CRISPRon standalone software, both available via
https://rth.dk/resources/crispr/

. CRISPRon advances CRISPR applications by providing more accurate gRNA efficiency predictions than the existing tools. High-quality gRNA activity data is needed for accurate on-target efficiency predictions. Here the authors generate activity data for over 10,000 gRNA and build a deep learning model CRISPRon for improved performance predictions.
BigField GEG Tech's insight:

When working with CRISPR, it is important to realize that there is always a difference between the gRNAs you use. Some work more efficiently and generate a high frequency of predicted modifications, while others are less efficient. Many of these differences are not obvious and are impossible to predict by simply looking at the sequences. Thus, in recent years, many efforts have been made to develop models that can help scientists select the most efficient gRNAs. Recently, researchers have created a new algorithm-based deep learning model, CRISPRon, from a novel approach that is based on studying a barcoded gRNA and its endogenous substitution site in a same lentiviral vector. In a single experiment, thousands of different lentiviral vectors can be used for transduction of human cells. The gene editing events are then studied and a massive parallel quantification of the editing activity of more than 10,000 gRNAs was obtained using this lentiviral library. This huge dataset was used to train the deep learning model, CRISPRon, and it was found that this new tool is significantly better at predicting gRNA efficiency than existing models.

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Partial recovery of visual function in a blind patient after optogenetic therapy - Nature

Partial recovery of visual function in a blind patient after optogenetic therapy - Nature | Vectorology - GEG Tech top picks | Scoop.it
BigField GEG Tech's insight:

Optogenetics may enable mutation-independent, circuit-specific restoration of neuronal function in neurological diseases. Retinitis pigmentosa is a neurodegenerative eye disease where loss of photoreceptors can lead to complete blindness. In a blind patient, the researchers combined intraocular injection of an adeno-associated viral vector encoding ChrimsonR with light stimulation via engineered goggles. 

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Inlaid Base Editors Slide Windows, Increase Efficiency

Inlaid Base Editors Slide Windows, Increase Efficiency | Vectorology - GEG Tech top picks | Scoop.it
Beam Therapeutics describes Inlaid Base Editors (IBEs) and their ability to convert the disease-causing sickle cell allele into a non-pathogenic variant.
BigField GEG Tech's insight:

Base editors are fusions of a deaminase and a Cas enzyme and modify DNA precisely and efficiently and avoid double-strand breaks with little off-target effect. This technology thus has many advantages but has obstacles such as a limitation of access to particular sites in the genome, which depends on the location of the protospacer adjacent motif (PAM) sequence and a short DNA sequence that is required for Cas9 to target an editing window. The Beam Therapeutics has therefore developed a new class of base editors called embedded base editors, which is a solution to the PAM problems, by repositioning the TadA deaminase in the middle of Cas 9 and not at the N or C terminal, so this allows the active site to be oriented around Cas 9 and decide where deamination will occur in the DNA. This new technology converts a pathogenic sickle cell hemoglobin allele into a natural variant.

However, in vivo core editors are big, hard-to-deliver cargo. That is why Beam Therapeutics recently acquired Guide Therapeutics, which has technological expertise in rapidly screening novel lipid nanoparticles with DNA barcodes. Beam Therapeutics’ treatments will likely be among the genome-editing treatments available to sickle cell patients in the future.

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Durable vision improvement after a single treatment with antisense oligonucleotide sepofarsen: a case report

Durable vision improvement after a single treatment with antisense oligonucleotide sepofarsen: a case report | Vectorology - GEG Tech top picks | Scoop.it
BigField GEG Tech's insight:

Leber congenital amaurosis due to CEP290 ciliopathy is being explored by treatment with the antisense oligonucleotide (AON) sepofarsen. One patient who was part of a larger cohort (ClinicalTrials.gov
NCT03140969

) was studied for 15 months after a single intravitreal sepofarsen injection. Concordant measures of visual function and retinal structure reached a substantial efficacy peak near 3 months after injection. At 15 months, there was sustained efficacy, even though there was evidence of reduction from peak response. Efficacy kinetics can be explained by the balance of AON-driven new CEP290 protein synthesis and a slow natural rate of CEP290 protein degradation in human foveal cone photoreceptors. Post hoc analyses and follow-up of a patient with Leber congenital amaurosis treated with the antisense oligonucleotide sepofarsen as part of a clinical trial indicates sustained improvement of vision 15 months after receiving a single dose of the drug.

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mRNA-Based CAR T-Cell Therapy Descartes-11 Moves Into Phase 2 Trial in Myeloma

mRNA-Based CAR T-Cell Therapy Descartes-11 Moves Into Phase 2 Trial in Myeloma | Vectorology - GEG Tech top picks | Scoop.it
A phase 2 clinical trial has been initiated to evaluate Descartes-11, an mRNA CAR T-cell therapy, as a consolidative therapy in patients with newly diagnosed, high-risk multiple myeloma who have residual disease after induction therapy.
BigField GEG Tech's insight:

Multiple myeloma is the second most common hematological malignancy in the world and remains difficult to treat despite numerous therapeutic advances and drug approvals. Patients continue to experience multiple relapses and complications of the disease, affecting many areas of the body, such as the bones, kidneys and immune system. An mRNA-based CAR-T cell therapy, named Descartes-11, has been developed as a consolidative therapy in newly diagnosed high-risk multiple myeloma patients who have residual disease after the first treatment.  Descartes-11 is engineered to express CAR molecules transiently rather than permanently, which may reduce some of the short- and long-term risks associated with traditional autologous CAR-T cell therapies. This therapy is the first mRNA-based cancer treatment to enter clinical development. Phase 1 data showed no evidence of cytokine release syndrome or neurotoxicity in patients with advanced multiple myeloma. Currently, the emergence of these adverse events remains a major challenge for CAR-T cell therapies in hematological malignancies. The Phase 2 trial (NCT04436029) will enroll approximately 30 patients with newly diagnosed multiple myeloma who remain weakly positive for residual disease after initial treatment. 

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News: CRISPR Enables Plug-and-Play Expression of Therapeutic Transgenes in Blood Cells

News: CRISPR Enables Plug-and-Play Expression of Therapeutic Transgenes in Blood Cells | Vectorology - GEG Tech top picks | Scoop.it
The group of Mario Amendola has used CRISPR-based editing of haematopoietic stem cells to generate a common platform for treating several rare genetic diseases. The method employs knock-in of transgenes that encode therapeutic proteins under control of the endogenous α-globin promoter.
BigField GEG Tech's insight:

Approximately 300 million people worldwide are affected by one of the 7,000 rare genetic diseases. In theory, CRISPR can treat most of these diseases by editing the genome in order to correct the specific genetic variances of each affected patient.  However, this would require to perform 7000 different treatments based on CRISPR but this would result in a very high price of treatments for most of these diseases as they affect only few people. This is why Mario Amendola's research group wants to use CRISPR to generate a universal solution: a common platform for the treatment of several rare genetic diseases. This idea is based on the fact that some rare diseases have in common the lack of expression of a specific protein in the blood.  M. Amendola therefore thought of using genome editing to ensure that blood cells provide a constant supply of the missing protein. The process uses a knock-in of transgenes that code for therapeutic proteins under the control of the endogenous a-globin promoter. The researchers tested their platform on four variants of rare genetic diseases such as Hurler syndrome. In each case, their treatment resulted in a 16 to 171-fold increase in mRNA expression, and protein levels increased by 2.5 to 4.5 times.

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Austria suspends AstraZeneca COVID-19 vaccine batch after death | Reuters

Austria suspends AstraZeneca COVID-19 vaccine batch after death | Reuters | Vectorology - GEG Tech top picks | Scoop.it
BigField GEG Tech's insight:

Austrian authorities have suspended inoculations with a batch of AstraZeneca's COVID-19 vaccine as a precaution while investigating the death of one person and the illness of another after the shots, a health agency said on Sunday.

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Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy | Science Translational Medicine

Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy | Science Translational Medicine | Vectorology - GEG Tech top picks | Scoop.it
BigField GEG Tech's insight:

Gene therapy using adeno-associated viral (AAV) vectors can be used for monogenic blinding diseases. Leber hereditary optic neuropathy (LHON) is caused by mutations in mitochondrial DNA (mtDNA), and a recombinant AAV, rAAV2/2-ND4, has shown therapeutic effects in a mouse model of LHON. Yu-Wai-Man et al. carried out a phase 3 clinical trial in 37 subjects with LHON bearing a MT-ND4 mutation. Although only one eye in each subject was treated, the authors reported sustained vision improvement in both eyes. Investigative analysis in nonhuman primates showed evidence of viral vector DNA transfer from the injected to the contralateral eye.

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Researchers restore lost sight in mice, offering clues to reversing aging - Science

Researchers restore lost sight in mice, offering clues to reversing aging - Science | Vectorology - GEG Tech top picks | Scoop.it
But many hurdles remain before approach can be tried in people
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Do old and damaged cells remember what it was like to be young? That’s the suggestion of new study, in which scientists reprogrammed neurons in mouse eyes to make them more resistant to damage and able to regrow after injury—like the cells of younger mice. The study suggests that hallmarks of aging, and possibly the keys to reversing it, lie in the epigenome, the proteins and other compounds that decorate DNA and influence what genes are turned on or off.

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CRISPR/Cas9 May Be Better Than Conventional Gene Therapy at Raising FIX Activity

CRISPR/Cas9 May Be Better Than Conventional Gene Therapy at Raising FIX Activity | Vectorology - GEG Tech top picks | Scoop.it

According to a study conducted on primates by Intellia Therapeutics, CRISPR/Cas9 would work better than conventional genetic therapy for increasing the activity of factor IX (FIX), the blood clotting protein that is missing in people with hemophilia B. Researchers have shown that CRISPR/Cas9-mediated gene insertion can lead to higher levels of FIX activity over time compared to conventional gene therapy that uses adeno-associated viral vectors (AAVs) to deliver modified genes to cells. According to the company, a six-week study demonstrated a successful increase in FIX activity, at or above normal limits, in the blood of non-human primates. FIX activity levels can be refined by adjusting several parameters, such as CRISPR/Cas9 doses. Also, in a mouse model of liver regeneration, the companies’ scientists demonstrated that unlike conventional gene therapy, CRISPR/Cas9 can allow gene constructs to remain active inside liver cells even as they divide and expand in order to restore the tissue that was lost. The researchers took part of the animals' livers to induce tissue regeneration. After 14 days, the activity levels of the artificial FIX fell by 85% with the gene delivered using standard gene therapy. In contrast, when CRISPR / Cas9 was used, FIX activity levels remained stable for at least 45 days.

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Getting gene therapy to the brain - Upenn

Getting gene therapy to the brain - Upenn | Vectorology - GEG Tech top picks | Scoop.it
Global CNS correction in a large brain model of human alpha-mannosidosis by intravascular gene therapy
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Using a large animal model of genetic brain disease, researchers led by John H. Wolfe of the School of Veterinary Medicine, Perelman School of Medicine, and Children’s Hospital of Philadelphia delivered an effective treatment across the blood-brain barrier to correct the whole brain.

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The ANCHOR system achieves a new performance by visualizing HIV1 retrotranscription and integration in living cells.

The ANCHOR system achieves a new performance by visualizing HIV1 retrotranscription and integration in living cells. | Vectorology - GEG Tech top picks | Scoop.it
Remodeling of the core leads HIV-1 pre-integration complex in the nucleus of human lymphocytes.
BigField GEG Tech's insight:

The ANCHOR system invented by NeoVirtech has been combined by GEG Tech to tag HIV-1 vectors (Lenti-ONE system) and generate autofluorescent lentivirus genomes able to be tracked in real time in living cells (1).

Following this proof of concept, the collaboration with Francesca Di Nunzio lab at the Pasteur Institute, has resulted a new breakthrough published in Journal of Virology (2): “We are very excited to be able to visualize the pre-integration complex and the fate of the HIV1 genome in living cells. The ANCHORTM technology is for us the state of the art technology allowing for the first time thorough investigation of HIV1 biology and response to antiviral treatment directly in living cells. The technology is the only one compatible with CLEM (correlative light-electron microscopy) to dissect the ultrastructural structure of the HIV1 particle. The fact that the ANCHORTM technology does not modify HIV1 virus biology offers an unprecedented view of the dynamics of this virus in living cells”.

Francesca Di Nunzio Ph.D, Pasteur Institute, Paris, France.

 

(1) https://www.linkedin.com/pulse/first-ever-live-tracking-hiv-1-(2) based-lentiviral-human-grandchamp/.

https://jvi.asm.org/content/early/2020/04/16/JVI.00135-20

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