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Latest research – 10

2022-12-29T11:05:41+02:0029 december, 2022|

Interview Cansu de Muijnck, by Maud van Gerwen (board member)

Cansu is a PhD student doing doctoral research on hereditary opticus atrophies (including ADOA). She works with Camiel Boon, Arthur van Bergen and Mies van Genderen, all specialists in this field.

Cansu is originally from Turkey and came to the Netherlands four years ago for love. It took her a year to get her medical degree recognised here and she then worked in various positions in a hospital.  A year and a half ago, she started her PhD in Ophthalmology. She officially works at the UMC Utrecht, but all the research takes place at the AMC and at Bartiméus. The AMC and Bartimeus are centres of expertise for hereditary eye diseases.  

Cansu explains that her research consists of two parts. ‘First: In 40 per cent of people with hereditary opticopathy, no abnormal gene has been found with the regular diagnostic tests. We will check whether we can still find an abnormal gene.  Secondly, sometimes a gene abnormality has been identified but is very rare. Little is known about the clinical characteristics that go with it then. We are going to describe those characteristics. We will also look at the electrophysiological characteristics of hereditary opticopathy, by measuring the signals the optic nerve transmits to the brain. ‘

I notice that Cansu keeps referring to ‘opticopathy’ where we more often speak of ‘opticus atrophy.’  She explains to me that opticopathy means ‘disease of the optic nerve’ and opticus atrophy means a ‘dead optic nerve’.

How do you know someone has a hereditary defect if you can’t find a genetic defect? ‘By looking at family circumstances. If it is more common in the family, you safely assume it is hereditary. But it’s still an assumption. That’s why we always talk about a suspicion of hereditary opticopathy if no genetic abnormality has yet been identified by genetic testing. You can also try to rule out other causes. If it is not inflammation, brain tumour, excessive alcohol consumption etc, it could be something hereditary’

‘If there is an abnormality on the OPA1 or OPA3 gene, we speak of ADOA. But of course, there are many more genes where something can be wrong. Nowadays, we test for 34 genes. In the past, this number was 3. As soon as an article is published, it is changed again. In France, they are already testing for 80 genes.’

Cansu will spend four years on her research. That is the time allowed for a PhD. She now is one and a half years into it. ‘Last time, I arranged all the consent for the genetic part of the study. I have just started patient inclusion.’ Cansu also writes articles. She is involved with research on ‘Wolfram-Like syndrome’. This is like ADOA but caused by a different gene. An article will be soon published by her.

What do you hope to have achieved with your research in four years’ time? ‘I hope to find the cause of disease for some patients. Knowing where your disease comes from is important to many people.  If you know on which gene there is an abnormality and you know what symptoms go with it, you can make a better prognosis for someone. ‘Also, Cansu wants to build up a lot of knowledge about Wolfram-Like syndrome.’ That is the second most common abnormality after the OPA1 gene.

Cansu is still looking for patients to participate in her study. If you are interested, please get in touch. Taking part means taking blood once.

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Latest Research – 9

2022-09-11T10:09:53+02:0019 mei, 2022|

Red light therapy

Glen Jeffery, email interviewed by Peter Makai

Recently, several companies have started to offer red light glasses https://eye-power.co.uk/, www.eyecharger.com.au which supposedly reduces vision loss in ageing eyes, through influencing mitochondria. Since ADOA is a mitochondrial disease, we were naturally curious if it can be safe and possibly beneficial for ADOA patients. ADOA is caused by a damaged gene (OPA1) causing several problems in the mitochondria within the so-called retinal ganglion cells, the cells which transmit information between the eyes and the brain. Mitochondria are primarily responsible for energy production by making a substance called ATP. ATP is produced within the mitochondrial membrane, where the OPA1 gene is necessary for several functions. If there is insufficient ATP, the mitochondria is damaged. When damaged, mitochondria release a substance signaling cell death, and vision loss. (meer…)

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Latest research – 8

2022-09-11T10:11:05+02:001 maart, 2022|

In late 2021, one of our contacts at Stoke Therapeutics sent us their financial results and company updates. Among other things, this states:

STK-002 is a proprietary antisense oligonucleotide (ASO) in preclinical development for the treatment of Autosomal Dominant Optic Atrophy (ADOA). Stoke believes that STK-002 has the potential to be the first disease-modifying therapy for people living with ADOA. STK-002 is designed to upregulate OPA1 protein expression by leveraging the non-mutant (wild-type) copy of the OPA1 gene to restore OPA1 protein expression with the aim to stop or reverse vision loss in patients with ADOA. Stoke has generated preclinical data demonstrating proof-of-mechanism and proof-of-concept for STK-002.

The entire piece can be read here.

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Latest research – 7

2021-10-02T23:25:32+02:002 oktober, 2021|

The optic nerve death in ADOA is usually caused by a fault on the OPA1 gene, which takes care of producing the OPA1 protein. Looking into the research around ADOA, we found several researchers who have actually succeeded in editing the OPA1 gene under laboratory conditions. This is very important, as correcting the protein stops the slow cell-death in ADOA and the slow visual decline.

The lead geneticist of the study, professor Michael Cheetham from the UCL Institute of Ophthalmology was kind enough to summarize the study in layman’s terms, give some pointers on what can we expect from the research, and how this work may eventually contribute to a medication.

Can you please describe the research in layman’s terms?
Inherited changes in the OPA1 gene produce a faulty protein, which leads to altered energetics and cell death in the optic nerve cells, causing ADOA. Our team corrected the changes in the gene in some patient derived stem cells using the newly developed crispr/cas9 method of gene editing. Correction of the gene fault corrected the protein, restored the energetics and reduced the cell death under lab conditions. 

What’s the conclusion in one or two sentences?
The study shows that correcting the inherited changes in the gene can rescue the defects caused by the faulty protein in the optic nerve cells. We have shown this targeting the part of the OPA1 gene causing the ADOA+ mutation.

Can you please explain in a bit more detail how you edited the OPA1 gene (technical)?
Genetic faults in gene called OPA1 are the most common reason for people to have ADOA. The OPA1 gene encode a large protein called OPA1 which basically is a switch that regulates the energy activity of the optic nerve cell using a factor called GTP.  The changes in OPA1 that cause ADOA are spread across the gene and affect different part of the protein and usually mean no protein is made.  Sometimes spelling mistakes (which change one building block for another) in the part of the protein that binds the GTP lead to a faulty protein that is produced and can affect how the other normal copy of the protein works.  These individuals can have more widespread symptoms with other tissues affected called DOA+.  It was one of these changes in the OPA1 protein that we corrected in this study.  This is important because this approach not only produces that second needed copy but it also removes the faulty ‘bad’ protein and stops it having a bad effect in the optic nerve cell. 

While a number of mutations on the OPA1 gene cause ADOA, in this study we targeted a very specific part of the OPA1 gene to correct the OPA1 proteins. This is mainly the way the CRISPR technology we used works – it is a great breakthrough for research because it enables us to target almost anywhere in the genome using something called a guide RNA, which directs an enzyme Cas9 to cut a specific place, and a repair template which then replaces the damaged part of the gene through a process called homology directed repair (HDR). This HDR is something cells do to correct mistakes in their DNA as they grow. 

But the downside of this method is that it is very specific – this is very much an approach that has to be developed and tested for each different DNA change.  The good news is that we have recently been able to target other changes in OPA1 with new guides and repair templates, but the ability to target multiple or different targets with the same guide would mean that they would have to be very close together (and most of the time they are not).  However, some of the inherited changes in OPA1 are quite common so for people that share the same change the same tools can be used. 

(meer…)

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Latest research – 6

2021-07-11T23:29:58+02:0011 juli, 2021|

PYC Therapeutics: Article for ADOA (Autosomal Dominant Optic Atrophy) European Association

ADOA remains an area of significant unmet need, and with the advent of precision medicine there is increasing optimism around RNA and DNA therapies for ADOA. PYC Therapeutics, an RNA drug development company, is hoping to apply its RNA technology, known as PPMO, to many inherited retinal diseases. The company recently announced the development of a potential drug for certain sub-types of ADOA.

“ADOA is a monogenic disease, which is a disease caused by a mutation in a select gene. The gene OPA1, has been identified as a common driver of ADOA in patients,” PYC’s Chief Scientific Officer Professor Sue Fletcher said.

“Usually, people have 2 copies of the OPA1 gene – one from each parent. Some people have mutations in one copy of the OPA1 gene, which means some cells do not produce enough OPA1 protein. The lack of protein is what is believed to drive ADOA in these patients and is known as a haploinsufficiency.

PYC’s team is now working to develop a potential PPMO that can increase the amount of OPA1 protein produced by the healthy copy of the OPA1 gene. The concept is that if we can restore the level of OPA1 protein above the disease threshold, we may slow or even stop vision loss,” Prof Fletcher said.

PYC’s PPMOs are a combination of two critical components: 1) the ‘PMO’ (which stands for phosphorodiamidate morpholino oligomer), is the drug cargo and when delivered to the cells, will help correct the disease process; and 2) the peptide ‘P’ delivers the PMO to the target cell and helps carry it into the cell – where the PMO is needed. Together they form a ‘P-PMO’.

“We have designed a number of PMO candidates that show promising early results in correcting the OPA1 protein haploinsufficiency in cells derived from ADOA patients. We have seen more than 100% protein upregulation in patient fibroblasts, and this is exciting,” Dr Grainok, the scientist leading PYC’s ADOA program, said.

Patient-derived fibroblasts are cells widely used in the early stages of drug development because they are easily accessible and typically allow screening of multiple PMO candidates in the context of a patient’s individual genetic background.

Dr Janya Grainok is leading a team of five scientists to evaluate PYC’s ADOA candidate in several pre-clinical models. Dr Grainok is the co-inventor of VP-001 – PYC’s other leading drug candidate to treat RP11 – and experienced as both a medicinal biochemist and molecular geneticist working across retinal disease. Dr Grainok’s expertise spans PMO design and drug validation strategies.

Dr Grainok and her team are supported by Professor Fletcher, co-inventor of three FDA approved drugs for the treatment of Duchenne muscular dystrophy (DMD). PYC’s Scientific leadership team includes Dr Kim Rice, a molecular geneticist who has deep knowledge and experience of oligonucleotide design and Dr Carla Jackson who has vast experience with stem cells and retinal organoids.

Dr Grainok said that once the PMOs are designed, the research to test for the safety and effectiveness of the PMO is performed using human stem cells.

“Stem cells can be used to make almost any of the cell types found within the organs of the human body, including the light-sensitive cells in the retina. A unique type of stem cell, called induced pluripotent stem cells (iPSCs), can be made from an adult’s own skin cells,” Dr Jackson said.

“As iPSCs contain all of the genetic information of the donor individual, the tissues that these stem cells can create allow the study of development and disease processes in that particular individual,” Dr Jackson said.

Dr Jackson said that stem cells can be instructed to make three-dimensional miniature versions of the human retina, called retinal organoids. “Retinal organoids are comparable to the light-sensitive tissue that grows naturally during human eye development, but they can be grown and studied entirely in the laboratory.

“This means that if iPSCs are made from a patient with inherited retinal disease, then the retinal organoids made from these can be used to directly study the events leading to visual loss in that patient. This allows the reasons underlying visual loss to be untangled, as well as the testing of new treatments.”

iPSC retinal models are becoming the gold standard in pre-clinical drug development and provide an extremely useful insight into a drug’s effectiveness before entering clinical studies in people.

Alongside these efficacy models, PYC will also evaluate safety, distribution, and duration of effect in animal models before entering clinical trials. This work is expected to occur across 2021 and 2022.

“Our goal is to develop a therapy to treat ADOA that is very safe and highly effective, obtain market authorisation for the therapy and get this treatment into patients with ADOA, alter the course of their disease and change lives,” Prof Fletcher said.

“We are a purpose-driven company with scientists who are passionate and working around the clock to achieve these goals.”

Professor Fletcher said that in the past, the development of a drugs of this nature could take 15 to 20 years. In recent times advances in technology, data generation and sharing, has seen that treatments can be developed, approved, and delivered to patients much more rapidly.

“We would hope that the process of developing a drug from concept to being available in the clinic for patients would take a third of that time. This may be ambitious on our part, however we urgently want to develop safe and effective treatments for people living with ADOA.”

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Latest research – 5

2021-03-30T09:16:40+02:0025 maart, 2021|

In our last newsletter of February 2021, we reported what kind of studies are currently ongoing. We also reported that there are studies on Glaucoma and Leber, among others, which are expected to be very interesting for us as ADOA patients. This is because the underlying problem has strong similarities. For example, we found an article about a study into Glaucoma and we put a number of questions to the researcher involved. The research focuses on the possibility of getting new healthy (RGC) cells in the eye. These cells have long branches to the brain and are what provide of your vision (this is a very brief summary of how this works, but it is the core of the story!). Here is a short report of the questions and  answers we received from the relevant researcher;

We spoke with Thomas V Johnson. He is a clinician-scientist and neuroscientist who, in addition to an ophthalmologist, eye surgeon and glaucoma specialist, also runs a translational science laboratory at Johns Hopkins Wilmer Eye Institute. They are studying the potential of stem cell transplantation to be used to achieve retinal ganglion cell (RGC) replacement and optic nerve regeneration for patients with optic neuropathies, including ADOA. In addition to running his own laboratory, he is co-director of the Hopkins Optic Nerve Regeneration Initiative.

Mr. Johnson answered the following questions for us;

Does this research also apply to ADOA and ADOA +?
Our work is very applicable to patients with ADOA. We envision that transplantation of stem cell-derived RGCs into the eye would have the potential to repopulate RGCs lost to a number of different optic neuropathies, including: ADOA, glaucoma, ischemic optic neuropathy, optic neuritis, Leber optic neuropathy, traumatic optic neuropathy. neuropathy and others.

What phase are you in now? And how long would it take to really get a therapy or medicine (also for ADOA)?
We are currently in the preclinical stage. We work with human stem cells and create human RGCs in the lab, but our scientific transplantation work is currently being performed in animal models of optic neuropathies, including rodents and non-human primates. Knowing when our successes in the laboratory and the safety of our approaches will provide enough supportive data to move forward with human clinical trials is a major challenge. We currently expect this possibility in 8-10 years. Of course, the faster we can conduct experiments in the laboratory (made possible with research funding from foundations and donors to support more scientists in laboratory doing the work), the sooner we expect to be able to conduct human clinical trials. Clinical trials in human patients would likely take about 2-4 years, and only if those studies demonstrated safety and efficacy, would RGC transplantation therapy become more generally available to patients on a widespread basis. 

Do you expect stabilization or improvement of your vision?
If our stem cell-derived neuronal transplantation approach works, we expect to see not only vision stabilization, but actual vision improvement / return. Vision loss in optic nerve disease develops as a result of RGC death and optic nerve atrophy. The aim of our work is to transplant human stem cell- derived RGCs into eyes with optic nerve damage and have these new RGCs integrate into the eye and send signals to the brain. By ‘replacing’ the damaged or degenerated RGCs, these transplanted neurons can be the first therapy capable of actually restoring vision in optic nerve disorders, including ADOA

What would a treatment look like?
At this point it is probably too early to know much detail about what the treatment would entail. However, I expect that much of the prep work prior to surgery will take place in a tissue engineering laboratory where human stem cells are manipulated and differentiated into donor replacement RGCs. A patient would then undergo transplantation of the donor RGCs into the eye during surgery in the operating room, which would likely require a number of other existing standard surgeries to prepare the eye for transplantation including: pars plana vitrectomy (removal of the gel from the center of the eye) and possibly internal limiting membrane peeling. During the same surgery, donor RGCs would then be transplanted into the eye using a vehicle/carrier such as a gel or scaffold, and the patient would wake up and go home to return for clinical follow-up. While recovery from surgery to the patient’s pre-operative level of vision may not take too long (days or a few weeks), it would likely require months for the donor RGCs to generate new connections between the eye and brain, and actually begin to restore the vision that had been lost to ADOA or another optic nerve disease. Again, at this point in time these details are primarily conjecture, but this is the direction in which we envision our scientific work is heading. 

You can read the entire research here: https://www.ophthalmologytimes.com/view/a-rift-in-the-retina-may-help-repair-the-optic-nerve 

Would you like to donate so that we can collect money for research?
That’s possible!

You can do so by transferring an amount to our account number:
NL80ABNA0833674641 in the name of Cure ADOA Foundation.

Or make a donation on our special DONATION PAGE

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The latest research – 4

2021-03-25T22:43:25+02:0013 maart, 2021|

The following is a brief report on a study done by one of our Medical Advisory Board members, among others: René de Coo.

In a collaborative effort between the Department of Ophthalmology at Maastricht University Hospital and the Neuromuscular and Mitochondrial Diseases (NeMO) expertise center at Maastricht University (MUMC+), biomarkers for mitochondrial diseases are being sought.

What are biomarkers? Can they be of use for mitochondrial diseases? Are they important for ADOA?

Biomarkers are biological markers, or pointers. A comparison: if you want to know if you have enough gasoline in the tank of your car, you look to see if the gauge is green, then the tank is sufficiently full; if it is orange, you need to find a gas station, and red warns that you will come to a stop (or you are already at a stop).

(meer…)

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The latest research – 3

2021-03-25T22:44:24+02:0013 maart, 2021|

Over the past few years, a number of people from the foundation have been active in searching for studies that are being done on ADOA worldwide. The positive news is that compared to about 5 years ago, there are a surprising number of new studies that can be found that are related to ADOA. In addition, there are also studies that do not directly have ADOA as their main topic but do have related conditions such as Leber and Glaucoma. The researchers we spoke to about these related studies indicated in most cases that if these studies were successful, a relatively short period of time might be needed to make it applicable to ADOA as well. But by relatively short we still mean a period of several years.

(meer…)

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Latest research – 2

2021-03-25T22:45:37+02:0012 maart, 2021|

The same person familiar with the Stoke Therapeutics research has contacted a research team from Italy and Greece this time. This in response to the article below and with the goal of getting a simpler explanation of what they do and an estimate of what the expectations are for the future. There is research being done by these researchers on ADOA for 18 years!!!

The research is called Inhibition of autophagy curtails visual loss in a model of autosomal dominant optic atrophy. And through either of these links you can read it in full: https://www.nature.com/articles/s41467-020-17821-1 or https://rdcu.be/b840e

With the answers to our mails to the researchers and by means of having the medical paper read carefully by an acquaintance who is knowledgeable about such studies, we have come to the following report;

ADOA is caused by a defect in the OPA1 gene. This causes mitochondria (energy factories of our cells) to malfunction. Because they are not working properly, self-destruction mode (autophagy) is turned on and they die. In addition to providing energy, mitochondria are also important in the optic nerve to relay signals from the eye to the brain. So if there are not enough of them, those signals cannot be passed on.

The researchers have shown in mutant cells that this self-destruction mode is a big problem and if they turn it off, there are as many mitochondria in the nerve cells as in healthy cells. They’ve also done this in mice. They made a mouse model where some of the optic nerve cells don’t have an OPA1 gene. As a result, the mice lose much of their vision when they reach 4 months of age. If they then turn off part of that self-destruct gene as well they see that the mice just keep their sight when they are 4 months old. They keep their sight until at least 12 months (they haven’t looked any longer). What is important though is that they have already turned off the self-destruction mode from birth. They don’t cure the mutation, nor do they restore sight.

The way they used in the paper at this time is not applicable to humans. In the interview they talk about drugs/substances that they want to start testing to see if that has the same effect. That is especially very interesting because they might be able to use that for humans. Furthermore, they also said that they don’t expect vision to get better again but that it won’t get worse. So not cure but delay/stop.

Because you have to take the medicine for the rest of your life you could use a pump under the skin. This is just an idea and unfortunately they are still far from that.

Nor can the researchers predict when there might be a therapy. They think they will need five years to test the drugs. Suppose something works super well then a clinical trial could be organized. But this also takes a number of years depending on a lot of factors. So this is also really unpredictable.

The researchers also indicated that this approach will probably and unfortunately not work for ADOA+ since other processes play a role here.

We will continue to monitor this research!

Would you like to donate so that we can collect money for research?
That’s possible!

You can do so by transferring an amount to our account number:
NL80ABNA0833674641 in the name of Cure ADOA Foundation.

Or make a donation on our special DONATION PAGE

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The latest research

2021-03-25T22:48:49+02:0011 maart, 2021|

An acquaintance of ours decided to approach Stoke Therapeutics, a pharmaceutical company which recently published a study on a possible treatment for ADOA. Someone was willing to talk to him and answered a few questions! Please note that all answers are the interpretation of the interviewer and not necessarily that of Stoke Therapeutics.

As a public company, why are you guys focusing on ADOA?
The treatment of ADOA as they envision it closely parallels a study they are doing to remedy certain epilepsy variants (Dravet syndrome). In addition, there are a number of conditions that can be approached in the same way, although the final drug will be different. All in all, they think they can address several conditions with this technique.

Is ADOA-plus also included in the research?
No unfortunately ADOA-plus is not included. The underlying cause in ADOA-plus is just a bit more complicated than in ADOA and therefore it will not work. I will come back to this in the next question. 

What does this research entail?  (explained as simply as possible)
Everyone consists of 50% DNA from their father and 50% DNA from their mother. Everyone has two OPA1 genes. The OPA1 gene ensures that a protein is produced that ensures proper functioning of the mitochondria. In people with ADOA one of the OPA1 genes, which can originate from either the mother or the father, has an error, or rather a mutation. Sometimes such a mutation occurs out of the blue, without the parents passing on a mutated gene. Stoke Therapeutics thinks it has the solution to this process by stimulating the healthy OPA1 gene to make more proteins to compensate for the mutated OPA1 gene. In ADOA-plus, there may be more going wrong than just 1 mutation in the OPA1 gene, but exactly how is not yet fully understood. Because sufficient stimulation is required and there may be more going on in ADOA-plus, the idea is that this does not work in this patient group. He also mentioned something along the lines that in that case you run the risk of stimulating other substances with the result that things get worse.

Which phases does the research consist of?
The research consists of a number of phases. The current research consists of testing on rabbits. Here they have successfully demonstrated that more proteins are produced by the healthy gene after their treatment. Whether this also has the desired effect on stabilization or improvement of vision they cannot measure with rabbits. They expect to start the next phase next year. In this phase they will research the risks and/or side effects that the treatment may entail. This phase is expected to take 1 to 1.5 years. Then they can start testing on humans.  This last phase is split into three. First they test on a small group of adults, then on children under 18, and then on a large patient group. Each subphase normally takes 1.5 to 2 years. Stoke Therapeutics can look

In a nutshell, the phases (as of now) look like the following;

  • Testing on animals (as good as completed)
  • Toxicology studies (start in 2021), duration 1 to 1.5 years
  • Adults, duration 1.5 to 2 years
  • Children, duration 1.5 to 2 years
  • Large study group of patients, duration 1.5 to 2 years

Do you expect stabilization or improvement of vision after treatment?
In principle, it is expected that stabilization of vision will be achieved. However, there are also weak cells that may start functioning better again, which may also lead to a small improvement, but they cannot make any serious statements about this yet. 

What will a possible treatment look like?
Each patient will receive an injection directly into his eye once or twice a year. This will be done with a very thin hypodermic needle. This will have to continue for life.

In summary, this research is still in its infancy, but the initial results are favorable. However, they are in the early stages of their research on OPA1 and as a company they have not yet decided to continue with this research. This depends on the ongoing studies. In any case, we are very curious about the future of this therapy and hope that it can be a godsend for a large portion of our fellow sufferers. Unfortunately, they think in advance that this is not going to be a solution for people with ADOA-plus, but it is possible that there is another solution on the way for these patients. It is nice to know that research is being done and that we are not being forgotten.

Would you like to donate so that we can collect money for research?
That’s possible!

You can do so by transferring an amount to our account number:
NL80ABNA0833674641 in the name of Cure ADOA Foundation.

Or make a donation on our special DONATION PAGE

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