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First patient treated in clinical study for gene therapy for Usher syndrome type 1B

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On September 16, 2024, AAVantgarde Bio, a biotechnology company from Italy, announced that the first patient has been treated in a clinical study investigating the safety and efficacy of a new gene therapy for patients with retinitis pigmentosa as a result of Usher Syndrome type 1B (USH1B). 

This clinical study, named LUCE-1, has been set up to examine how safe and effective the new gene therapy AAVB-081 is in individuals with Usher syndrome type 1B. In this condition, patients lose their hearing and sight due to a hereditary mutation in the MYO7A gene. The study is in phase 1/2, meaning it is still in an early stage and primarily focused on testing safety.

 How does the gene therapy work?
The new treatment, AAVB-081, utilizes a specialized technique designed to deliver larger genes like MYO7A into the eye. This is done by packaging two halves of the gene into viral carriers, known as AAV vectors, which together complete the MYO7A gene inside the cell. The idea is that this therapy restores the production of the Myo7A protein, which may help stabilize the patient’s vision.

Previously successful results achieved
The technology behind this gene therapy was developed by Professor Alberto Auricchio at the TIGEM institute in Naples. As the first-in-human study with this therapy has only just commenced, no data on the results are as yet available. However, scientists have previously studied the therapy in small and large animal models and demonstrated up to 40% improvement in the gene function. As animal eyes have many differences compared to human eyes, comment on the success of the therapy in humans will only be available after the clinical trials. .

First patient
The first patient in the LUCE-1 study has been treated at the University Hospital of Campania in Naples, under the guidance of Professor Francesca Simonelli, an expert in ophthalmology and gene therapy. In the coming period, more patients will be treated, and the results will be evaluated.

This study offers hope for individuals with Usher syndrome type 1B, a group of patients for whom there are currently no treatments available to preserve their vision. The success of this therapy would be a significant step forward in the fight against this progressive disease.

More information

AAVantgarde Bio continues to work closely with researchers to further develop this promising therapy and hopes to assist more patients soon. Stichting Ushersyndroom is regularly updated by AAVantgarde, and we share this valuable information with our supporters through our website, newsletter, and social media. The full results of the study will be announced once the study is completed and the data analysed, although this will take several years.

For further information about the LUCE-1 study:
https://clinicaltrials.gov/study/NCT06591793?term=aavantgarde&rank=2

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Hope for Usher patients  

HOPE FOR USH1B PATIENTS

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CLINICAL TRIAL BY AAVANTGARDE TO COMMENCE

AAVantgarde, an international biotechnology company based in Italy and co-founded by Professor Alberto Auricchio, is dedicated to overcoming the limitations of adeno-associated virus (AAV) vectors in gene therapy. AAVantgarde has developed its own AAV-based large gene delivery platform for retinitis pigmentosa associated with Usher syndrome type 1b (USH1B), utilizing DNA recombination known as dual hybrid AAV.

By the end of March/beginning of April, the first participant will undergo treatment with the dual hybrid AAV designed by AAVantgarde, marking an exciting period ahead.

Usher Syndrome Type 1B (USH1B) is a genetic disorder characterized by congenital deafness, impairment of the vestibular system, and retinitis pigmentosa (RP). It affects approximately 1 in 50.000 people. The condition is caused by mutations in the MYO7A gene, responsible for producing a protein called MYO7A, which plays a crucial role in various cellular processes, including melanosome localization in the retinal pigment epithelium (RPE) and rhodopsin transport in photoreceptor cells.

Motor Protein
MYO7A is an actin-based motor protein responsible for transporting various substances within the cell. These proteins move along thin fibers called microtubules in a manner resembling walking, with two “feet” that alternately bind to the fiber.

Here you can see a short animation of ‘a walking motor protein’:

Motor proteins consist of a head and a tail portion. The head houses the actual motor and consumes energy. The ‘tail side’ contains docking sites where various molecules can be attached. Because MYO7A is a motor protein, the challenge lies in delivering the entire protein healthily to the eye.

Dual Hybrid AAV
Traditional adeno-associated virus (AAV) gene therapy approaches have limitations due to the size of the genes they can deliver. A newer strategy, known as double hybrid AAV gene therapy, aims to address this challenge. In this approach, splice donor and acceptor signals are separately inserted into two AAV vectors, with recombination designed by AAVantgarde. Recombination involves rearranging genetic material to form a single AAV genome that leads to the production of a full-length functional protein.

Watch the presentation on AAVantgarde’s programs here.

Phase 1 and 2 of the Clinical Trial
The first participant is expected to be treated within Q2 2024, with a total of 15 participants to be treated in the study. Safety and effectiveness will be tested at various dosages, with the first results expected to be available by 2025.

In preparation for this clinical trial, a natural history study has been conducted in subjects at Naples, Madrid, and Rotterdam. This study is essential for establishing inclusion criteria and measuring the effectiveness of the treatment.

 

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Does this mutation cause blindness? It does, doesn’t, does!

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Janine Reurink ends long lasted controversy with major implications for healthcare


Initially there was no doubt a specific mutation in the USH2A gene caused the eye disease retinitis pigmentosa. Spanish research undermined that clarity and left patients in limbo. Until new research by PhD candidate Janine Reurink made it abundantly clear that the cause is indeed to be found in that USH2A gene. A textbook example of science in action.

We know of ten different genes that can cause Usher syndrome if they contain a mutation. Mutations in these genes eventually lead to deafness and blindness in patients with Usher syndrome. Mutations in Usher genes sometimes ‘generate’ other disorders as well. For example, a specific mutation in the Usher2A gene (USH2A) causes the eye disease retinitis pigmentosa (RP) when inherited from both father and mother. This mutation causes one spot in the USH2A protein to change the amino acid cysteine to phenylalanine, another amino acid. All this was genetically and clinically fine-tuned at the end of the last century. If you had such a specific double mutation in the USH2A gene, you didn’t have Usher syndrome but RP and the clinical problems were limited to blindness.

Smoldering controversy
Then suddenly a publication appeared about a Spanish family with RP. It wrote that researchers had found two individuals with exactly those specific USH2A mutations. But without any vision problem, which after all is an essential characteristic of RP! Erwin van Wijk, who has been researching Usher syndrome at the Radboudumc for over more than ten years: “That caused rather a lot of commotion among researchers and patients, because it meant this specific mutation could not be the cause of RP! Everyone who had previously received this diagnosis had apparently been misdiagnosed. So the real cause had to be found somewhere else in the genes.”
The publication causes many clinical genetics centers around the world to stop diagnosing RP on the basis of this USH2A mutation and all these patients should actually be re-screened. This also applies to Nijmegen. In the meantime, doubts continued. Was the screening in this Spanish family complete and reliable enough? – the results were never confirmed in any other study. Requests from different research groups to check the DNA of those families were not granted. Thus, a smoldering controversy about the value of the Spanish research ensued..

No alternatives mutations found
In recent years, Van Wijk and colleagues developed a promising therapy for a number of mutations in Usher genes. This therapy is based on a technique in which a piece of the RNA is ‘taped off’ (exon skipping). This prevents the mutation from being read and creates a protein that once again functions properly. These therapeutic ‘genetic patches’ can also be used for the specific USH2A mutation, but based on the Spanish family research the causal link with the eye disease is being questioned. As long as it’s unclear whether or not this mutation causes RP, no health insurance company will ever reimburse such a therapy. So a conclusive answer is needed. That proof was exactly what Janine Reurink set out to provide as part of her doctoral research.
Reurink: “First of all, we looked at several patients with the USH2A mutation to see if another explanation could be found for the disorder. To do this, we mapped their entire genome and examined it on all sides. The result? We did not find any alternative genetic explanation. Based on our research, the USH2A mutation remains the only possible explanation.”

Crystal clear evidence
In Nijmegen, much Usher research is done in zebrafish. This time it was also used for additional research, looking for as much evidence as possible. Reurink: “With the CRISPR/Cas9 system, a molecular scissors with which pieces of DNA can be very precisely cut away and replaced, we made a zebrafish with exactly the same mutation as in humans. Analysis of retinal cells in the eye of these fish showed that the corresponding proteins are then no longer or hardly produced. Normal production is really very thoroughly disturbed by the mutation. What’s more: as a result, other essential proteins for vision no longer end up in the right places. We also made an ERG, a kind of brain film for the eye. It demonstrated with crystal clarity that vision is really affected in zebrafish with this mutation. In short, extensive genetic bio-molecular and functional research clearly shows that the USH2A mutation is indeed the underlying cause of this form of retinitis pigmentosa. In terms of a detective novel, we now really have tracked down the culprit.”

Impact on healthcare
The research by Reurink and colleagues has been published in NPJ Genomic Medicine. For people with RP with a USH2A mutation, it’s clear now that this is the real causative, pathogenic mutation. Further search for a (non-existent) cause is no longer necessary. Meanwhile, the clinical genetics laboratories at Radboudumc have adjusted their diagnostics accordingly. Something that many more laboratories worldwide are likely to do in the near future. Moreover, patients are now eligible for therapy as soon one is available. A nice example of PhD research with impact on healthcare.

Radboudumc
Promotion Janine Reurink – USH2A-associated disease. Genetics, pathogenesis and treatment
Thursday April 6, 2023 at 12.30 pm

New research: testing gene therapy

With extra large vectors on mini retinas 

Prof. Dr. Jan Wijnholds and promovendus Rossella Valenzano

Stichting Ushersyndroom [ Dutch Usher Syndrome Foundation] is funding the majority of the new research “Genetic drugs preventing blindness due to loss of USH2A function” which has recently started. The research team led by Jan Wijnholds, who works at the Leiden University Medical Center (LUMC), will test two treatment methods on ‘mini-retinas’ made from human stem cells. The researchers want to determine if the light sensitive cells in the mini-retinas can be activated by the light-sensitive cells after administration of gene therapy. Can the USH2a gene in the retina be replaced or is it also possible to repair the defective gene at the same time?

 

Gene therapy looks very promising and developments in this area are moving very quickly. It is a treatment method for hereditary disorders where healthy copies of genes, with errors (= mutations) have been found, in patients are replaced or repaired in the cells of an organ.

Research shows that after gene therapy, the retina can make normal connections with other cells, which can lead to a light response again. After delivering a healthy copy of the gene or repairing the gene, the retina makes the proteins it needs to see properly. With gene therapy you treat the entire gene so that it does not matter what kind of mutations you have.

Means of transport for the large USH2A gene
In gene therapy, a healthy copy of the gene is delivered to a specific location in the retina of the eye using a molecular truck, or a means of transport. This is usually done using a virus that has first been rendered harmless so that a vector remains, a kind of ‘packaging’. The most commonly used vector is the adeno-associated viral vector (AAV).
However, there is a problem. The USH2A gene is much too large for a normal AAV vector, so another alternative must be sought to deliver the large healthy copy of the USH2A gene into a patient’s eye.

Large trucks as vector
Previously, in collaboration with Dr Manuel A.F.V Gonçalves (Department of Chemical Cell Biology), the researchers in Jan Wijnholds’ lab at the LUMC, have developed new vectors into which very large genes fit, the so-called High-Capacity Adenoviral Vectors (HcAdV).
The large USH2A gene fits completely into this vector. As a result, this vector can serve as a molecular truck and can be used as a vector for gene therapy.

Mini retinas
In the research project “Genetic drugs preventing blindness due to USH2A function”, human mutant USH2A iPSC retinal organoids are used to test several new high-DNA capacity gene therapy vectors. These USH2A ‘organoids’ are ‘mini-retinas’ made from cell lines derived from USH2A patients.

These ‘mini-retinas’ are used because they allow to study the effect of loss of USH2A protein (Usherin) in the cilium of the photoreceptor. The cilium transports the essential proteins in the retina. These ‘organoids’, made from patient cell lines, could also be used in the future to test gene therapy for retinal disorders due to mutations in other Usher genes.

Replace gene and/or edit gene
In the research project of Jan Wijnholds, two types of gene therapy are being tested on the ‘mini retinas’. The first type of therapy candidate is an HcAdV vector containing a healthy copy of the USH2A gene that, after delivery, replaces the defective USH2A gene in the retina. We call this gene replacement therapy. The healthy copy of the gene must activate the gene in the photoreceptors of the ‘mini retinas’, the ‘organoids’.

The second type of therapy candidate is an HcAdV vector containing ‘a repair kit’ and, after delivery into the retina, repairs the defective USH2A gene in the eye itself. This is also known as gene editing therapy, CRISPR-Cas9 is used for this. CRISPR are pieces of DNA with codes that can detect the defective gene. The Cas9 is an enzyme that ‘cuts’ out the defective gene and ‘sticks’ a new healthy piece of DNA in it.

Both the CRISPR and Cas9 are transported in a cassette and delivered into the retina by an HcAdV vector. The USH2A gene is edited and repaired at its destination.

Promises for large groups of patients
Both technologies for genetherapeutic application are not dependent on the type of mutations in the USH2A gene. If the USH2A gene is found to be expressed in the light-sensitive cells of the mini-retinas thanks to one or both techniques, the treatment may become available to all patients with USH2A. When more money becomes available for research for these two techniques , the research team of Jan Wijnholds could also test these for other Usher genes, and could possibly also be a solution for patients with mutations in Usher genes other than USH2A.

The mission of Stichting Ushersyndroom
Annouk van Nunen, secretary of Stichting Ushersyndroom, is very pleased with the start of this research. Stichting Ushersyndroom’s mission is “In 2025, Usher Syndrome will be treatable!”.Annouk: “We want all patients to have a realistic prospect in 2025 of a treatment that can slow down, stop or even restore the further deterioration of their hearing and vision”.

The big challenge for scientists is to explore multiple research routes in order to eventually develop a treatment for all people with Usher syndrome. Stichting Ushersyndroom therefore stimulates as many lines of research as possible, so that people with Usher Syndrome can make their dreams come true. “It is fantastic that so much research is being done into Usher Syndrome in the Netherlands. This type of research is hopeful for all USH2A patients. But if it works, it could also be a solution for patients with mutations in other Usher genes, Annouk van Nunen.

This four-year study, which started in November, has been budgeted at € 250.000. Stichting Ushersyndroom is contributing € 85.000 to this research. Other funds that have contributed are: Rotterdamse Stichting Blindenbelangen, LSBS, Stichting Blindenhulp and a partial contribution from the LUMC Ophthalmology Departmen