Tag: gene therapy

Categories : Genetics OphthalmologyTags :

Gene Therapy for Inherited Blindness Results in 100-fold Vision Improvement

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People with a rare genetic mutation that causes significant vision loss early in childhood experienced a 100-fold improvement in vision after receiving a corrective gene therapy. Some patients even experienced a 10 000-fold improvement in their vision after receiving the highest dose of the therapy, according to researchers from the Perelman School of Medicine at the University of Pennsylvania who co-led the clinical trial published in The Lancet.

“That 10 000-fold improvement is the same as a patient being able to see their surroundings on a moonlit night outdoors as opposed to requiring bright indoor lighting before treatment,” said the study’s lead author, Artur Cideciyan, PhD, a research professor of Ophthalmology and co-director of the Center for Hereditary Retinal Degenerations. “One patient reported for the first time being able to navigate at midnight outdoors only with the light of a bonfire.”

A total of 15 people participated in the Phase 1/2 trial, including three paediatric patients. Each patient had Leber congenital amaurosis as the result of mutations in the GUCY2D gene, which is essential to producing proteins critical for vision. This specific condition, which affects less than 100 000 people worldwide and is abbreviated as LCA1, causes significant amount of vision loss as early as infancy.

All subjects had severe vision loss with their best measure of vision being equal or worse than 20/80 – meaning if a typically-sighted person could see an object clearly at 80 feet (24m), these patients would have to move up to at least 20 feet (6m) to see it. Glasses provide limited benefit to these patients because they correct abnormalities in the optical focusing ability of the eye, and are unable to address medical causes of vision loss, such as genetic retinal diseases like LCA1.

The trial tested different dosage levels of the gene therapy, ATSN-101, which was adapted from the AAV5 microorganism and was surgically injected under the retina. For the first part of the study, cohorts of three adults each received either a low, mid, ore high dose. Evaluations were held between each level of dosage to ensure that they were safe before upping the dosage for the next cohort. A second phase of the study involved only administering the high dosage levels to both an adult cohort of three and a paediatric cohort of three, again after safety reviews of the previous cohorts.

Improvements were noticed quickly, often within the first month, after the therapy was applied and lasted for at least 12 months. Observations of participating patients are also ongoing. Three of six high-dosage patients who were tested to navigate a mobility course in varying levels of light achieved the maximum-possible score. Other tests used eye charts or measured the dimmest flashes of light patients perceived in a dark environment.

Of the nine patients who received the maximum dosage, two had the 10 000-fold improvement in vision.

“Even though we previously predicted a large vision improvement potential in LCA1, we did not know how receptive patients’ photoreceptors would be to treatment after decades of blindness,” said Cideciyan. “It is very satisfying to see a successful multi-center trial that shows gene therapy can be dramatically efficacious.”

Primarily, the study sought to determine the safety of the gene therapy and its varying dosage levels. Researchers did find some patients had side effects, but the overwhelming majority were related to the surgical procedure itself. The most common side effect was conjunctival haemorrhage, the breakage of small blood vessels underneath the clear surface of the eye, which healed. Two patients had eye inflammation that was reversed with a course of steroids. No serious side effects were related to the study drug.

This work comes on the heels of another successful ophthalmological trial at Penn restoring sight in patients with a different form of LCA. Earlier in 2024, CRISPR-Cas9 gene editing was used to improve the sight of many patients with a form of LCA tied to mutations in the CEP290 gene. Co-led by one of the new paper’s co-authors, Tomas S. Aleman, MD, professor in ophthalmology and co-director with Cideciyan of the Center for Hereditary Retinal Degenerations, the study used similar tests and was the first time children were involved in any gene editing work.

“The treatment success in our most recent clinical trials together with our earlier experience brings hope for a viable treatment for about 20 percent of infantile blindness caused by inherited retinal degenerations,” Aleman said. “The focus now is on perfecting the treatments and treating earlier manifestations of these conditions once safety is confirmed. We hope similar approaches will lead to equally positive outcomes in other forms of congenital retinal blindness.”

Moving forward, approval of this experimental medicine for clinical use requires a randomised controlled trial.

Source: University of Pennsylvania School of Medicine

Categories : Genetics Medical Research & TechnologyTags :

Scientists Develop a Way to Turbocharge Genetic Therapy

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Gene therapy, the idea of fixing faulty genes with healthy ones, has held immense promise. But a major hurdle has been finding a safe and efficient way to deliver those genes.

Now, researchers at the University of Hawaiʻi’s John A. Burns School of Medicine (JABSOM) have made a significant breakthrough in gene editing technology that could revolutionise how we treat genetic diseases. Their new method offers a faster, safer, and more efficient way to deliver healthy genes into the body, potentially leading to treatments for hundreds of conditions.

Current methods can fix errors in genes, but they can also cause unintended damage by creating breaks in the DNA. Additionally, they struggle to insert large chunks of genetic material such as whole genes.

The new technique, developed by Dr Jesse Owens along with his team Dr Brian Hew, Dr Ryuei Sato and Sabranth Gupta, from JABSOM’s Institute for Biogenesis Research and Cell and Molecular Biology Department, addresses these limitations. They used laboratory evolution to generate a new super-active integrase capable of inserting therapeutic genes into the genome at record-breaking efficiencies.

“It’s like having a “paste” function for the human genome,” said Dr Owens. “It uses specially engineered ‘integrases’ to carefully insert healthy genes into the exact location needed, without causing breaks in the DNA. This method is much more efficient, with success rates of up to 96% in some cases.”

“This could lead to faster and more affordable treatments for a wide range of diseases, potentially impacting hundreds of conditions with a single faulty gene,” said Dr. Owens.

Faster treatment development and a broader application

The implications of this research extend beyond gene therapy. The ability to efficiently insert large pieces of DNA has applications in other areas of medicine.

When making cell lines to produce therapeutic proteins, the gene encoding the protein is usually randomly inserted into the genome, and it rarely lands in a location in the genome that is good for production. This is like searching for a needle in a haystack. Additionally, finding a cell with the gene inserted correctly and producing the desired protein can take many months.

Instead of searching for a needle in a haystack, Dr Owens’ technique makes a stack of needles. It delivers the gene directly to the desired location, significantly speeding up the development process.

“JABSOM takes pride in nurturing talented researchers like Jesse Owens, whose work has the power to create a global impact,” said Sam Shomaker, dean of the University of Hawaiʻi John A. Burns School of Medicine. “This research, conducted in our lab in the middle of the Pacific, has the potential to significantly improve the way we treat genetic diseases.”  

Dr Owens’ team is exploring how this technique could accelerate the development and manufacture of biologics and advanced therapies such as antibodies. Currently, finding the right cell line for efficient production can be a time-consuming process. However, Dr Owens’ new genome engineering tool can reduce the cell line development timeline and accelerate the manufacture of life-saving therapeutics. 

Source: University of Hawaii at Manoa

Categories : Genetics PaediatricsTags :

Gene Therapy Restores Hearing in Children with Hereditary Deafness

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A new study co-led by investigators from Mass Eye and Ear, a member of Mass General Brigham, demonstrated the effectiveness of a gene therapy towards restoring hearing function for children suffering from hereditary deafness.

In a trial of six children taking place at the Eye & ENT Hospital of Fudan University in Shanghai, China, the researchers found the novel gene therapy to be an effective treatment for patients with a specific form of autosomal recessive deafness caused by mutations of the OTOF (otoferlin) gene, called DFNB9. With its first patient treated in December 2022, this research represents the first human clinical trial to administer gene therapy for treating this condition, with the most patients treated and longest follow-up to date. Their results are published in The Lancet.

“If children are unable to hear, their brains can develop abnormally without intervention,” said Zheng-Yi Chen, DPhil, an associate scientist in the Eaton-Peabody Laboratories at Mass Eye and Ear and associate professor of Otolaryngology–Head and Neck Surgery at Harvard Medical School. “The results from this study are truly remarkable. We saw the hearing ability of children improve dramatically week by week, as well as the regaining of their speech.”

Hearing loss affects more than 1.5 billion people worldwide, with congenital deafness making up about 26 million of those individuals. For hearing loss in children, more than 60% stem from genetic reasons. DFNB9 for example, is a hereditary disease caused by mutations of the OTOF gene and a failure to produce a functioning otoferlin protein, which is necessary for the transmission of the sound signals from the ear to the brain. There are currently no FDA-approved drugs to help with hereditary deafness, which has opened the door for new solutions like gene therapies.

In order to test this novel treatment, six children with DFNB9 were observed over a 26-week period at the Eye & ENT Hospital of Fudan University. The Mass Eye and Ear collaborators utilised an adeno-associated virus (AAV) carrying a version of the human OTOF gene to carefully introduce the gene into the inner ears of the patients through a special surgical procedure. Differing doses of the single injection of the viral vector were used.

All six children in the study had total deafness, as indicated by an average auditory brainstem response (ABR) threshold of over 95 decibels. After 26 weeks, five children demonstrated hearing recovery, showing a 40-57 decibel reduction in ABR testing, dramatic improvements in speech perception and the restored ability to conduct normal conversation. Overall, no dose-limiting toxicity was observed. While following up on the patients, 48 adverse events were observed, with a significant majority (96%) being low grade, and the rest being transitory with no long-term impact.

Trial findings will also be presented February 3rd at the Association for Research in Otolaryngology Annual Meeting.

This study provides evidence towards the safety and effectiveness of gene therapies in treating DFNB9, as well as their potential for other forms of genetic hearing loss. Moreover, the results contribute to an understanding of the safety of AAV insertion into the human inner ear. In regard to the usage of AAVs, the success of a dual-AAV vector carrying two pieces of the OTOF gene is notable. Typically, AAVs have a gene size limit, and so for a gene like OTOF that exceeds that limit, the achievement with a dual viral vector opens the door for AAV’s use with other large genes that are typically too big for the vector.

“We are the first to initiate the clinical trial of OTOF gene therapy. It is thrilling that our team translated the work from basic research in animal model of DFNB9 to hearing restoration in children with DFNB9,” said lead study author Yilai Shu, MD, of the Eye & ENT Hospital of Fudan University at Fudan University. Shu previously served as a postdoctoral fellow in Chen’s lab at Mass Eye and Ear. “I am truly excited about our future work on other forms of genetic hearing loss to bring treatments to more patients.”

The researchers plan to expand the trial to a larger sample size as well as track their outcomes over a longer timeline.

“Not since cochlear implants were invented 60 years ago, has there been an effective treatment for deafness,” said Chen. “This is a huge milestone that symbolises a new era in the fight against all types of hearing loss.”

Source: Massachusetts Eye and Ear Infirmary

Categories : Genetics UncategorizedTags :

Dual Testosterone Blockers More Effective in Treating Prostate Cancer

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Credit: Darryl Leja National Human Genome Research Institute National Institutes Of Health

Combining testosterone-blocking drugs in patients with prostate cancer relapse prevents the spread of cancer better than treatment with a single drug, a multi-institution, Phase 3 clinical trial led by UC San Francisco researchers has found.

The approach can extend the time between debilitating drug treatments without prolonging the time it takes to recover from each treatment.

Prostate cancer affects 1 in 8 men, and is usually treated with one of several testosterone-lowering drugs for a set period of time.

“This adds to a growing body of evidence in favour of more intensive testosterone-blocking therapy in patients with higher-risk prostate cancer,” said Rahul Aggarwal, MD, professor in the UCSF School of Medicine and lead author of the paper.

The researchers’ findings were published in the Journal of Clinical Oncology. They were first announced in September 2022 at the annual meeting of the European Society for Medical Oncology.

A case for intensifying prostate cancer treatment

The new study focused on patients who had surgery for prostate cancer, and yet the cancer relapsed and was detected through a sudden jump in the blood levels of a protein called prostate-specific antigen (PSA).

“We looked at patients who had a fast rise in their PSA – an indicator of a higher-risk form of relapsed prostate cancer,” Aggarwal said.

“Our goal was to test several different hormone therapy strategies to find the best approach in terms of delaying the cancer’s progression.”

Between 2017 and 2022, 503 patients were randomly assigned to take a single testosterone-lowering therapy chosen by their oncologist, or to combine it with one or two other testosterone-lowering drugs.

The additional drugs were already FDA-approved for other cancers but hadn’t been tested in this way with prostate cancer.

The patients stayed on the assigned therapy for a year. Whether given singly or in combination, the drugs caused their testosterone to plummet.

That put the brakes on their cancer but also caused fatigue, hot flashes, decreased libido and other problems for patients, according to Aggarwal.

Compared to the prostate cancer patients who only received a single drug therapy during their year of treatment, patients who received either one or two additional drugs stayed cancer-free, with low PSA levels, for longer.

Once off the treatment, patients who took the combination therapies saw their testosterone levels recover just as fast as others who took the single drug.

The researchers are following up with a more detailed analysis of how patients fared on the different treatments – which side effects they experienced and for how long, and how they felt overall as they recovered.

“New cancer therapies must clear a high bar to make their way to patients,” Aggarwal said. “With the evidence in this study and others, combination hormone therapy should be considered a standard of care in prostate cancer patients with high-risk relapse after prior treatment.”

Source: University of California – San Francisco

Categories : Genetics Regenerative MedicineTags :

Backdoor to the Inner Ear Allows Delivery of Gene Therapy

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An international team of researchers has developed a new method to deliver drugs into the inner ear, according to a new study in Science Translational Medicine. The discovery was possible by harnessing the natural flow of fluids in the brain and employing a little-understood backdoor into the cochlea. When combined to deliver a gene therapy that repairs inner ear hair cells, the researchers were able to restore hearing in deaf mice.

“These findings demonstrate that cerebrospinal fluid transport comprises an accessible route for gene delivery to the adult inner ear and may represent an important step towards using gene therapy to restore hearing in humans,” says lead author Barbara Canlon, professor at Karolinska Institutet.

The number of people worldwide predicted to have mild to complete hearing loss is expected to grow to around 2.5 billion by mid-century.  The primary cause is the death or loss of function of hair cells found in the cochlea – which relay sounds to the brain – due to mutations of critical genes, aging, noise exposure, and other factors. 

While hair cells do not naturally regenerate in humans and other mammals, gene therapies have shown promise and in separate studies have successfully repaired the function of hair cells in neo-natal and very young mice.

“However, as both mice and humans age, the cochlea, already a delicate structure, becomes enclosed in the temporal bone. At this point, any effort to reach the cochlea and deliver gene therapy via surgery risks damaging this sensitive area and altering hearing,” says Barbara Canlon.

In the new study, the researchers describe a little-understood passage into the cochlea called the cochlear aqueduct. The cochlear aqueduct is a thin boney channel no larger than several strands of hair. 

Channel for spinal fluid

A new study shows that the cochlear aqueduct acts as a conduit between the cerebrospinal fluid found in the inner ear and the rest of the brain. 

Scientists are developing a clearer picture of the mechanics of the glymphatic system, the brain’s unique process of removing waste. Because the glymphatic system pumps cerebrospinal fluid deep into brain tissue to wash away toxic proteins, researchers have been eyeing it as a potential new way to deliver drugs into the brain, a major challenge in developing drugs for neurological disorders. 

The new study represented an opportunity to put the drug delivery potential of the glymphatic system to the test, while at the same time targeting a previously unreachable part of the auditory system.   

Employing several imagining and modeling technologies, the researchers were able to develop a detailed portrait of how fluid from other parts of the brain flows through the cochlear aqueduct and into the inner ear.

The team then injected an adeno-associated virus into the cisterna magna, a large reservoir of cerebrospinal fluid found at the base of the skull. 

The virus found its way into the inner ear via the cochlear aqueduct and delivered a gene therapy that expresses a protein called vesicular glutamate transporter-3, which enables the hair cells to transmit signals and rescue hearing in adult deaf mice. 

“This new delivery route into the ear may not only serve the advancement of auditory research but also prove useful when translated to humans with progressive genetic-mediated hearing loss,” says Barbara Canlon.

Source: Karolinska Institutet

Categories : Genetics NeurologyTags :

Gene Therapy Partially Restores Cone Function in Achromatopsia

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University of College London researchers have used gene therapy to partially restore the function of cone receptors in two children with achromatopsia, a rare genetic disorder which can cause partial or complete colourblindness.

The findings, published in Brain, suggest that treatment activates previously dormant communication links between the retina and the brain, thanks to the developing adolescent brain’s plastic nature.

The academically-led study has been running alongside a phase 1/2 clinical trial in children with achromatopsia, using a new way to test whether the treatment is changing the neural pathways specific to the cones.

Achromatopsia is caused by disease-causing variants to one of a few genes. As it affect the cones in the retina, are responsible for colour vision, people with achromatopsia are completely colourblind, while they also have very poor vision and photophobia. Their cone cells do not send signals to the brain, but many remain present, so researchers have been seeking to activate the dormant cells.

Lead author Dr Tessa Dekker said: “Our study is the first to directly confirm widespread speculation that gene therapy offered to children and adolescents can successfully activate the dormant cone photoreceptor pathways and evoke visual signals never previously experienced by these patients.

“We are demonstrating the potential of leveraging the plasticity of our brains, which may be particularly able to adapt to treatment effects when people are young.”

The study involved four young people with achromatopsia aged 10 to 15 years old.

The two trials, which each target a different gene implicated in achromatopsia, are testing gene therapies with the primary aim of establishing that the treatment is safe, while also testing for improved vision. Their results have not yet been fully compiled so the overall effectiveness of the treatments remains to be determined.

The accompanying academic study used a novel functional magnetic resonance imaging (fMRI) mapping approach to separate emerging post-treatment cone signals from existing rod-driven signals in patients, allowing the researchers to pinpoint any changes in visual function, after treatment, directly to the targeted cone photoreceptor system. They employed a ‘silent substitution’ technique using pairs of lights to selectively stimulate cones or rods. The researchers also had to adapt their methods to accommodate eye movements due to nystagmus, another symptom of achromatopsia. The results were compared to tests involving nine untreated patients and 28 volunteers with normal vision.

Each of the four children was treated with gene therapy in one eye, enabling doctors to compare the treatment’s effectiveness with the untreated eye.

For two of the four children, there was strong evidence for cone-mediated signals in the brain’s visual cortex coming from the treated eye, six to 14 months after treatment. Before the treatment, the patients showed no evidence of cone function on any tests. After treatment, their measures closely resembled those from normal sighted study participants.

The study participants also completed a test to distinguish between different levels of contrast. This showed there was a difference in cone-supported vision in the treated eyes in the same two children.

The researchers say they cannot confirm whether the treatment was ineffective in the other two study participants, or if there may have been treatment effects that were not picked up by the tests they used, or if effects are delayed.

Co-lead author Dr Michel Michaelides (UCL Institute of Ophthalmology and Moorfields Eye Hospital), who is also co-investigator on both clinical trials, said: “In our trials, we are testing whether providing gene therapy early in life may be most effective while the neural circuits are still developing. Our findings demonstrate unprecedented neural plasticity, offering hope that treatments could enable visual functions using signalling pathways that have been dormant for years.

“We are still analysing the results from our two clinical trials, to see whether this gene therapy can effectively improve everyday vision for people with achromatopsia. We hope that with positive results, and with further clinical trials, we could greatly improve the sight of people with inherited retinal diseases.”

Dr Dekker added: “We believe that incorporating these new tests into future clinical trials could accelerate the testing of ocular gene therapies for a range of conditions, by offering unparalleled sensitivity to treatment effects on neural processing, while also providing new and detailed insight into when and why these therapies work best.”

One of the study participants commented: “Seeing changes to my vision has been very exciting, so I’m keen to see if there are any more changes and where this treatment as a whole might lead in the future.

“It’s actually quite difficult to imagine what or just how many impacts a big improvement in my vision could have, since I’ve grown up with and become accustomed to low vision, and have adapted and overcome challenges (with a lot of support from those around me) throughout my life.”

Source: University College London

Categories : Genetics Medical Research & TechnologyTags :

Quantum Leap for Genetic Disease Therapy with Baculovirus DNA Repair Kit

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DNA repair
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Genetic mutations behind a genetic kidney disease affecting children and young adults have been fixed in patient-derived kidney cells with a high-capacity DNA ‘repair kit’. The advance, developed by University of Bristol scientists, is published in Nucleic Acids Research.

In this new study, the international team describe how they created a DNA repair vehicle to genetically fix faulty podocin, a common genetic cause of inheritable Steroid Resistant Nephrotic Syndrome (SRNS).

Podocin is a protein normally located on the surface of specialised kidney cells and is essential for kidney function. Faulty podocin, however, remains stuck inside the cell and never makes it to the surface, terminally damaging the podocytes. Since the disease cannot be cured with medications, gene therapy which repairs the genetic mutations causing the faulty podocin offers hope for patients.

Typically, human viruses have been utilised in gene therapy applications to carry out genetic repairs. These are used as a ‘Trojan Horse’ to enter cells carrying the errors. Currently dominating systems include lentivirus (LV), adenovirus (AV) and adeno-associated virus (AAV), which are all relatively harmless viruses that readily infect humans. Their viral shells however restrict the amount of cargo they can carry and deliver, namely the DNA kit necessary for efficient genetic repair. This limits the scope of their application in gene therapy.

By applying synthetic biology techniques, the team led by Dr Francesco Aulicino and Professor Imre Berger, re-engineered baculovirus, a insect virus which has a nearly unlimited cargo capacity.

“What sets apart baculovirus from LV, AV, and AAV is the lack of a rigid shell encapsulating the cargo space.” said Dr Francesco Aulicino, who led the study. The shell of baculovirus resembles a hollow stick, simply lengthening when the cargo increases. This allows a much more sophisticated tool-kit can be delivered by the baculovirus.

First, baculovirus had to be equipped to penetrate human cells which it normally would not do. “We decorated the baculovirus with proteins that enabled it to enter human cells very efficiently.” explained Dr Aulicino. The scientists then used their engineered baculovirus to deliver much larger DNA pieces than was previously possible, and build these into the genomes of a whole range of human cells.

The DNA in the human genome comprises 3 billion base-pairs making up ~25,000 genes, which encode for the proteins that are essential for cellular functions. If faulty base-pairs occur in our genes, faulty proteins are made which can make us ill, resulting in hereditary disease. Gene therapy promises repair of hereditary disease at its very root, by rectifying such errors in our genomes. Gene editing approaches, in particular CRISPR/Cas-based methods, have greatly advanced the field by enabling genetic repair with base-pair precision.

The team used patient-derived podocytes carrying the disease-causing error in the genome to demonstrate the aptitude of their technology. By creating a DNA repair kit, comprising protein-based scissors and the nucleic acid molecules that guide them – and the DNA sequences to replace the faulty gene, the team delivered with a single engineered baculovirus a healthy copy of the podocin gene concomitant with the CRISPR/Cas machinery to insert it with base-pair precision into the genome. This was able to reverse the disease-causing phenotype and restore podocin to the cell surface.

Professor Imre Berger explained: “We had previously used baculovirus to infect cultured insect cells to produce recombinant proteins for studying their structure and function.” This method, called MultiBac, has been highly successful to make very large multiprotein complexes with many subunits, in laboratories world-wide. “MultiBac already exploited the flexibility of the baculovirus shell to deliver large pieces of DNA into the cultured insect cells, instructing them to assemble the proteins we were interested in.” When the scientists realised that the same property could potentially transform gene therapy in human cells, they created this new DNA repair kit.

Dr Aulicino added: “There are many avenues to utilise our system. In addition to podocin repair, we could show that we can simultaneously correct many errors in very different places in the genome efficiently, by using our single baculovirus delivery system and the most recent editing techniques available.”

Source: University of Bristol

Categories : Diseases, Syndromes and Conditions GeneticsTags :

Once-off Gene Therapy Reduces Haemophilia B Bleeding in Patients

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A single gene therapy injection could dramatically reduce the bleeding risk faced by people with haemophilia B, according to the results of a Phase I/II clinical trial published in the New England Journal of Medicine.

Low levels of the factor IX (FIX) protein, needed for clot formation, are behind haemophilia B. The FIX protein gene is on the X chromosome, so the severe form of haemophilia B is much more common in men, though it can occur in women due to X chromosome inactivation.

To prevent excessive bleeding, patients with haemophilia B typically need regular replacement therapy consisting of weekly injections of recombinant FIX. Despite advances in treatment, patients may continue to see debilitating joint damage.

The new treatment, from University College London, Royal Free Hospital and biotechnology company Freeline Therapeutics, is a type of adeno-associated virus (AAV) gene therapy candidate, called FLT180a, is being developed to treat severe and moderately severe cases of haemophilia B.

The Phase I/II multi-centre clinical trial, called B-AMAZE, and the related long-term follow up study found that a single treatment with FLT180a led to sustained production of FIX protein from the liver in 9 of 10 patients, across four different dose levels, removing the need for regular replacement therapy.

Out of 17 male patients aged 18 or over who underwent screening, 10 with severe or moderately severe haemophilia B took part in the 26-week trial of FLT180a, will be followed-up to assess safety and durability of FIX expression for 15 years.

Lead author Professor Pratima Chowdary of the Royal Free Hospital said: “Removing the need for haemophilia patients to regularly inject themselves with the missing protein is an important step in improving their quality of life. The long term follow up study will monitor the patients for durability of expression and surveillance for late effects.”

One patient, Elliott Mason, told the BBC: “I’ve not had any treatment since I had my therapy, it’s all a miracle really, well it’s science, but it feels quite miraculous to me.

“My life is completely normal, there’s nothing that I have to stop and think ‘how might my haemophilia affect this?’.”

AAV gene therapy works uses a packaging from the proteins found in the outer coat of the virus to deliver a functional copy of a gene directly to patient tissues. Newly synthesised proteins are released into the blood and a one-time infusion can have long-term effects.

Over several weeks to several months, patients took immunosuppressive drugs to prevent their immune systems from rejecting the therapy, and all reported known side effects.

Though the therapy was well tolerated, patients all experienced adverse events, with an abnormal blood clot in one who received the highest FLT180a dose and had the highest levels of FIX protein.

Professor Amit Nathwani, who co-authored the study, said: “Gene therapy is still a young field that pushes the boundaries of science for people with severe genetic diseases.

“The B-AMAZE long-term data add to the growing body of evidence that gene therapy has the potential to free patients from the challenges of having to adhere to lifelong therapy or could provide treatment where none exists today.”

In nine out of the ten patients, the treatment led to a sustained increase in FIX protein production, which led to a decrease in excessive bleeding. They also no longer required weekly injections of FIX protein.

After 26 weeks, five patients had normal levels of FIX protein, three had low but increased levels, and one patient treated at the highest dose had an abnormally high level.

Pamela Foulds, MD, Chief Medical Officer of Freeline, said: “The B-AMAZE long-term data continue to support our confidence that a single dose of FLT180a could protect people with haemophilia B from bleeding and the need for lifelong FIX replacement through durable expression of FIX at protective levels.”

Source: EurekAlert!

Categories : Metabolic DisordersTags :

‘Gene Silencing’ Therapy Cuts Lipoprotein(a) by Up to 98%

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DNA repair
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Findings from a new show that an experimental ‘gene silencing’ therapy reduced blood levels of lipoprotein(a) by up 98%. This is significant as lipoprotein(a) is a key cardiovascular risk driver which is determined largely by genetics and not modifiable lifestyle factors, and which cannot be lowered by current medical means.

Findings from the Cleveland Clinic-led phase 1 trial were published in the Journal of the American Medical Association.

Trial participants receiving higher doses of SLN360 – a small interfering RNA (siRNA) therapeutic that ‘silences’ the gene responsible for lipoprotein(a) production – saw their lipoprotein(a) levels  drop by as much as 96%-98%. Five months later, these participants’ lipoprotein(a) – also known as Lp(a) – levels remained 71%-81% lower than baseline.

The findings suggest this siRNA therapy could be a promising treatment to help prevent premature heart disease in people with high levels of Lp(a), which is estimated to affect 64 million people in the United States and 1.4 billion people worldwide.

“These results showed the safety and strong efficacy of this experimental treatment at reducing levels of Lp(a), a common, but previously untreatable, genetically-determined risk factor that leads to premature heart attack, stroke and aortic stenosis,” said the study’s lead author Steven E. Nissen, MD “We hope that further development of this therapy also will be shown to reduce the consequences of Lp(a) in the clinical setting through future studies.”

Lp(a) has similarities to LDL. Lp(a) is made in the liver, where an extra protein called apolipoprotein(a) is attached to an LDL-like particle. Unlike other types of cholesterol particles, Lp(a) levels are 80 to 90% genetically determined. The structure of the Lp(a) particle causes the accumulation of plaques in arteries, which play a significant role in heart disease. Elevated Lp(a) greatly increases the risk of heart attacks and strokes.

Although cardiovascular risk-reduction therapies that lower LDL cholesterol and other lipids exist, there are treatments to lower Lp(a). Since Lp(a) levels are genetically determined, lifestyle changes such as diet or exercise have no effect. In the current study, the siRNA therapy reduces Lp(a) levels by “silencing” the gene responsible for Lp(a) production and blocking creation of apolipoprotein(a) in the liver.

In the APOLLO trial, researchers enrolled 32 participants with Lp(a) levels above 15 nmol/L, with a median level of 224nmol/L (75nmol/L or less is considered normal). Eight participants received a placebo and the remaining received one of four doses of SLN360 via a single subcutaneous injection. The doses were 30mg, 100mg, 300mg and 600mg. Participants were closely observed for the first 24 hours after their injection and then followed up for five months.

Compared to baseline, participants receiving 300mg and 600mg of SLN360 experienced a maximum of 96% and 98% reduction in Lp(a) levels, and a reduction of 71% and 81% at five months. Those receiving a placebo saw no change in Lp(a) levels. The highest doses also reduced LDL cholesterol by about 20%-25%. There were no major safety consequences reported and the most common side effect was temporary soreness at the injection site. The study was extended and researchers will continue to follow participants for a total of one year.

Source: Cleveland Clinic

Categories : Genetics Neurodegenerative DiseasesTags :

Phase 1 Clinical Trial of a Gene Therapy for Alzheimer’s

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Researchers at University of California San Diego School of Medicine have received a grant to conduct a first-in-human Phase 1 clinical trial of a gene therapy for treating Alzheimer’s disease (AD) or Mild Cognitive Impairment (MCI), a condition often preceding dementia.

Gene therapy is an experimental technique that uses genes or gene products for the treatment or prevention of diseases by altering the DNA of living cells. Viral vectors are commonly used to insert the DNA changes into the target cells’ nuclei, but non-viral vectors also exist though they are generally less efficient.

The clinical trial, developed by principal investigator Mark Tuszynski, MD, PhD, professor of neuroscience and director of the Translational Neuroscience Institute at UC San Diego School of Medicine, delivers the brain-derived neurotrophic factor (BDNF) gene into the brains of qualifying trial participants where it is hoped it will stimulate BDNF production in cells.

BDNF belongs to a family of growth factors (proteins) found in the brain and central nervous system that support existing neurons and promote growth and differentiation of new neurons and synapses. BDNF is particularly important in brain regions susceptible to degeneration in AD.

“We found in earlier studies that delivering BDNF to the part of the brain that is affected earliest in Alzheimer’s disease — the entorhinal cortex and hippocampus — was able to reverse the loss of connections and to protect from ongoing cell degeneration,” said Tuszynski. “These benefits were observed in aged rats, aged monkeys and amyloid mice.”

The three-year-long trial seeks to recruit 12 participants with either diagnosed AD or MCI to receive AAV2-BDNF treatment, with another 12 persons serving as a control group over that period.

This will be the first safety and efficacy assessment of AAV2-BDNF in humans. A previous gene therapy trial from 2001 to 2012 using AAV2 and a different protein called nerve growth factor (NGF) found increased growth, axonal sprouting and activation of functional markers in the brains of participants.

“The BDNF gene therapy trial in AD represents an advance over the earlier NGF trial,” said Tuszynski. “BDNF is a more potent growth factor than NGF for neural circuits that degenerate in AD. In addition, new methods for delivering BDNF will more effectively deliver and distribute it into the entorhinal cortex and hippocampus.”

Source: UC San Diego