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carlos55
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21 Nov 2022, 4:13 pm

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Why precision medicine could be the next frontier in treating autism
Swiss-based Stalicla is banking on an AI-driven precision medicine discovery platform to deliver needed therapies in the autism space.

The numbers behind autism spectrum disorder are staggering. According to the CDC, one in 44 American children is impacted by autism spectrum disorder (ASD) — but today’s treatments provide little relief. Drugs such as antipsychotics or antidepressants can help manage certain symptoms such as irritability or repetitive behaviors, yet no treatments have emerged that target the core of the disease.

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Lynn Durham, founder, CEO, Stalicla
Permission granted by Lynn Durham

Part of the challenge is that ASD is not one condition but many, each with different underlying factors, said Lynn Durham, founder and CEO of Stalicla, a Swiss clinical stage biotech developing precision therapeutics for ASD and other neurodevelopment disorders. In fact, as many as 100 different gene variants may play a role in ASD risk.

“One of the things that you know when you see hundreds of people with autism is that when you’ve seen one person with autism, you’ve seen one person with autism,” Durham said.



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This is why the company is banking on a precision medicine approach to the disorder. With the help of its AI-driven discovery platform called Databased Endophenotyping Patient Identification, or DEPI, Stalicla can sort ASD patients into subtypes and develop therapeutic drugs tailored to each group.

So far, the results of this approach have been trending in the right direction. Last spring Stalicla announced the successful completion of phase 1b trials for its lead candidate, STP1, a combo therapy that contains a PDE inhibitor and an NKCC1 inhibitor. The therapy targets a subgroup called ASD phenotype 1, which makes up some 20% of ASD cases. In the trial, STP1 not only hit its safety targets, but showed promise in improving important neurological and behavioral clinical measures.

“We have the first clinical efficacy results on our pipeline, showing the strongest target engagement data that has ever been reported in the field,” Durham said. The drug will now move into phase 2.

Stalicla also has a second candidate called STP2 heading into phase 2 trials. It’s designed to treat a second subgroup, ASD phenotype 2, which comprises 15% to 20% of ASD cases. Also in the pipeline are drugs for three additional ASD phenotypes, 3, 5 and 6, which Stalicla is pursuing through third-party partnership agreements.

Here, Durham discusses a potential timeline for its drug development aims and why she has zeroed in on creating new treatments for ASD.

This interview has been edited for style and brevity

PHARMAVOICE: Why did Stalicla set out with a focus on autism?
LYNN DURHAM: I have a life-long involvement with the neurodevelopmental disorder community. Both my brother and son have autism. And I wanted to make a change in the field and shift the field away from behaviorally defined indications that don’t offer any, or offer very little insight into the underlying genetic and molecular theology of the disease to be able to start stratifying patients and enabling the advancement of precision medicine in the field.

What is your overall goal for Stalicla?

We want the company to prove the feasibility of precision medicine for neurodevelopmental and neuropsychiatric disorders. The company is built on a mission to enable the advancement and the standardization of precision medicine for patients with neurodevelopmental disorders and neuropsychiatric disorders. Today, neuropsychiatry is the least evidence-based discipline in medicine and this needs to change because the brain is profoundly biological and there’s no reason not to apply biologically driven treatment strategies for these populations.

Can you tell me a little bit about the technology that you’re using?

We are integrating multiple sets of data, beyond behavioral data. So obviously, genetic (data). But also, other types of omics data, as well as electronic health record-related data, for example, comorbidities that have a convergence in terms of the underlying genes and pathways that are involved, and a family disease history. The whole idea here is to take a systems biology approach to autism, considering the genes and molecular pathways that are involved in the development and the functioning of the CNS (central nervous system) are also involved in other organs and diseases. So, we’re talking about systems diseases, rather than pure brain diseases.

How will patients eventually know that they’re in one of the categories that might be helped by the drugs that you are working on?

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We are not only developing a drug, we’re developing biomarkers to be able to bring them into companion diagnostics. So that one day, instead of recruiting patients on biologically supported phenotypes, we will recruit patients on the basis of blood-based biomarkers. Just like we do for breast cancer.

Can you tell me some more about your research findings to date?

The most advanced clinical trials that we have were in the phase 1b on the STP1 asset. We found extremely strong target engagement measured by EEG (electroencephalography) and ERP (event-related potentials) in specific areas of the brain related to social interaction and executive function. And we know, for instance, that the changes in processing speed, which we measured as an effect of STP1 treatment, are the earliest predictors of changes in social communication endpoints. That was measured previously in behavioral intervention.

Did patients in the studies note any differences in behavior or social interactions?

It’s difficult, because phenotype1 patients are mild-to-moderate, severely affected patients. The mean IQ for phenotype 1 patients is 65. So, their self-awareness about the treatment is limited. But we’re very much focused on choosing endpoints that are not overly influenced by placebo (so) we integrated computerized panels (and) computerized boxes as outcome measures. One of them is called the NIH toolbox and it’s a computerized measurement. It’s absolutely quantifiable and it’s not subject to placebo. So, what we’re seeing are early changes in sub items of cognition, such as processing speed (and) reaction time, that are building bricks to larger scale change, which will result hopefully in changes in social communication end points.

What is the potential timeline for when people might have access to these medications?

For STP1, we’re talking about 2027. For STP2, we’re talking about 2028. And for subsequent assets, or at least future assets, we’re also talking about 2027. This (STP1) phase 1b has been really a pivotal moment for Stalicla because it allowed us to mature our pipeline profile and to increase the probability that these products will get to market.

Why do you think creating treatments for ASD is so important?

I think that neuropsychiatric disorders are a pressing societal issue, because we’re not addressing them in a biologically driven manner, and because when someone’s brain is not functioning, that puts individuals in a very weak position in terms of their self-determination, dignity and safety. And that is our role. We have to address this as a society, and it will have major impact on us as a society to be able to support people in the functioning of their brains to bring more dignity and self-determination. So, it’s a major ethical and societal and economic issue.


https://www.pharmavoice.com/news/precis ... am/632494/

These are quite bold claims & achievements if true.

We may be seeing the beginning of the end of autism as one condition or label with some treatment paths for those that want it.

Her opinion regarding
Quote:
and because when someone’s brain is not functioning, that puts individuals in a very weak position in terms of their self-determination, dignity and safety.
is spot on.


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autisticelders
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27 Nov 2022, 3:53 pm

very interesting thanks for this post. watching with interest


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carlos55
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15 Dec 2022, 3:31 am

Da_Zero_A_Dieci wrote:
Thank you very much because we didn't talk about artificial intelligence, but about genetics and markers in blood reactive protein C and others.

Based on which a disease such as major depression would immediately have the drug tailored to the patient.
Precision medicine is the medicine of the future
Although the concept of precision medicine is not recent (it dates back, in fact, to 1952), however it is starting from the sequencing of the human genome and the development of modern technologies that it represents an innovation in the health sector, destined to produce increasingly large changes in the research and treatment of serious diseases.

But while it offers many new opportunities, however, the personalization of medicine also poses new problems.



What is Precision Medicine
Precision medicine is personalized and targeted medicine, which takes into account individual differences in terms of genetics, microbiome, lifestyle, environment, etc. It is therefore based on the identification of the specific characteristics of the individual subject, made possible by the great variety of physiological parameters detectable thanks to the advanced technologies now available, for the identification of the most suitable treatments, in particular for the treatment of pathologies still today difficult to treat, of which the identification of the target marker to be hit with the drug is not always immediate.Here, for example, it is practiced in Milan.
I can't tell you if it has any effects because it's a theme 70 years old enough not to have had any significant effects.

The question would be: what is more successful about artificial intelligence, which has existed in robotics for many years?
In the last 11 years, self-aware robots have been created in Silicon Valley, i.e. they learn on their own and build independent reasoning methods from humans.

ON TED TV I remember videos as early as 2011.
I had also read about the ethics of equalization between self-aware robots and humans.
The development of precision medicine started with the identification of the profound link between the genome and neoplasms which, in turn, promoted the search for new drugs and targeted therapeutic strategies. Today, personalized medicine is also evolving for other pathologies, such as type 1 diabetes, cirrhosis of the liver and epilepsy.



The institutes and governments that support the development of Precision Medicine
The American government (during Obama's presidency) was one of the first to commit itself to the development of research in the service of precision medicine, allocating funds and involving researchers, doctors, pharmaceutical companies, etc. The short-term investment was aimed at targeted treatments for widespread pathologies, while in the long-term it was aimed at researching data to search for personalized therapies for an ever-increasing number of pathological conditions.

In Europe, the attention of the European Commission to Precision Medicine started in 2013 with the publication of the report “Use of '-omics' technologies in the development of personalized medicine” and, subsequently, with the creation of a platform for life sciences in order to facilitate meetings between funders and researchers interested in this new approach.The topic of personalized care has also aroused the interest of Eastern countries, which are identifying possibilities for international collaboration and market expansion.



The critical issues of precision therapies
Although today genetic tests are more accessible than in the past and in many healthcare facilities there are registers of personal data of patients, for the individualized therapeutic approach to establish itself and become a routine practice, it will be necessary to overcome the critical issues connected to it.

First, a precision strategy must be supported by evidence of efficacy and safety deriving from research and experience.

It is also necessary to know how to manage and not waste limited health resources, increase the knowledge of health personnel for the application of new diagnostic and treatment techniques, inform patients and family members not only about the potential of personalized medicine but also about the risks it can entail.


Thanks i suppose the million dollar question with autism and genetics is would such a genetic treatment "cure" or at least go some way of curing the issue causing the autism?

Assuming there are many different autisms that lead to an overlap of symptoms, some may be caused by fixable things like autoimmune disorders such as the generation of folate antibodies that prevent this vital nutrient to the brain (attached).

Others that cause problems with managing & the communicating of brain cells may be fixable too. More serious forms that effect brain architecture may be more difficult to fix although they will probably be prevented

https://www.futuremedicine.com/doi/10.2 ... -2017-0109


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carlos55
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16 Dec 2022, 6:43 am

Da_Zero_A_Dieci wrote:
^Having recognized autism as having a biological origin with a significant hereditary component, research has focused on identifying the precise genetic causes, i.e. specific genes underlying autism spectrum disorders. The analysis of the whole genome and the cytogenetic studies carried out on families with at least two members affected by this condition has allowed to identify a certain number of genes most frequently associated with autism, located on different chromosomes such as 15, 16 , 22, and the X chromosome. However, the knowledge deriving from this type of study is rapidly evolving and the involvement of genes located on different chromosomes cannot be excluded. In general, to date, genetic analysis has failed to prove evidence of single-gene involvement associated with autism, and there is consensus in indicating a complex genetic origin characterized by the involvement of many genes. Some of these genes are involved in the production of important molecules involved in the development and maintenance of nervous networks: these are proteins involved in the functioning of the nerve synapse (that is, the structure that allows nerve cells to communicate with each other), the factors that regulate the expression of genes neurotransmitters and their receptors (i.e. the molecules that transmit the nerve signal from one nerve cell to another through the synapse) and genes involved in brain development.

Research is needed
Attention to the autistic syndrome has increased significantly in recent decades but, despite this, little is still known. There is a strong need to intensify and expand basic and clinical research to improve knowledge of this syndrome in terms of its incidence, causes and development. Increasing information is the only way to identify potential therapies, possibly applicable in early stages of development.

Galileo Galilei stated the following:-"a body not subjected to forces remains in its state of rest or uniform rectilinear motion until an external force intervenes to interrupt it".
The two-million-dollar question here is whether genetics in its quiet state, which then ends around age 2, is itself a problem and a solution.
That is, if we lend that state of stillness by acting on genetics can we always be free from incorrect modifications?
Something that is modified leads to other modifications in a chain.
Simple genetics would give me a maybe yes, but here we are dealing with complex genetics, too many variables intervene together.
That said: I'm glad to finally see a discussion on this topic.
I've been writing about it in the forums for years.
Among other things, it would be economically, socially, and pragmatically convenient for the States.
To pharmaceutical companies maybe not so much.
Precision medicine would reduce the vocabulary of drugs to a minimum!
Although DNA is represented with the Fibonacci golden system (Double Helix is ​​part of the PHI), it is very complex in terms of interactions and functioning.It is necessary to act on the Architecture of the "Brain" before those bonds are formed and a dysfunctional synergy is established.
I don't think it's easy.
I am also thinking of research concerning BDNF, which stimulates the survival and differentiation of some neurons and synapses belonging to the central nervous system (CNS) and peripheral (PNS)


Thanks for your comment the issue maybe for some, not necessarily the genes but things acting on them preventing them from performing their role.

One day we`ll find out, hopefully we`ll all still be around by then


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16 Dec 2022, 10:27 am

I don't want to be cured and I suspect many others with mild severity likely feel the same way.

I don't think I'm the problem. I think people are the problem.

I was very fortunate that my parents, after realizing I was doing "weird" stuff, decided I wasn't being bad...I was just like that ("weird"). So they decided not to punish me. I am so glad! They let me be me...avoiding much "damage" in the process. I muddled through life reasonably successfully.

Ideally I suspect many young mild Autistics (including myself) could do even better in life if there was some tailored parenting advice for them that accommodated the Autistic differences. I suspect there could of been some useful lessons on how to survive in the Allistic world without trying to remove my Autism. (I think I would've called them "infiltration lessons"!)

Image

Note: Autism is not well understood. The mild Autism "disorder" I got is likely different from the Autism "disorder" many others here have.


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17 Dec 2022, 4:38 pm

Double Retired wrote:
I don't want to be cured and I suspect many others with mild severity likely feel the same way.

I don't think I'm the problem. I think people are the problem.

I was very fortunate that my parents, after realizing I was doing "weird" stuff, decided I wasn't being bad...I was just like that ("weird"). So they decided not to punish me. I am so glad! They let me be me...avoiding much "damage" in the process. I muddled through life reasonably successfully.

Ideally I suspect many young mild Autistics (including myself) could do even better in life if there was some tailored parenting advice for them that accommodated the Autistic differences. I suspect there could of been some useful lessons on how to survive in the Allistic world without trying to remove my Autism. (I think I would've called them "infiltration lessons"!)

Image

Note: Autism is not well understood. The mild Autism "disorder" I got is likely different from the Autism "disorder" many others here have.


Some do want curing some don't, its a medical conundrum similar to the one highlighted by the COVID jab, most people recognised in the end that people shouldn't be forced to have a medical procedure but it should be there for those that do want it.

I will also repeat the quote again at the top:-

Quote:
and because when someone’s brain is not functioning, that puts individuals in a very weak position in terms of their self-determination, dignity and safety.


Anyone lower down the spectrum is basically helpless in this regard & they have no freedom. I leave you with a brief depressing story:-

In the UK there is a show documentary every week about the job of the emergency services, police, ambulance & fire, i think its called "911 what your emergency"?

I don't usually watch it but this particular weak about a month ago it featured an autistic man of about 30, he had become lost when taken out of his care home for the day on a shopping trip.

There was a police hunt for him, there was a report on Facebook of a man several miles away knocking on doors and behaving strangely, some people were messaging, calling him a potential predator, weirdo and to watch their kids.

In the end many hours later, he was found by the police safe miles away, he was asked on camera why he went for a wander, he said he sometimes gets bored at his care home.

His mother sent him back that night saying she didn't want him to get too used to being at her home & you later saw him sitting in his residential home looking miserable.

Very sad diabolical situation for a man so young who should be free


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17 Dec 2022, 8:27 pm

^ I’m partially sorry that I missed that episode, Carlos. Heartbreaking about his situation, in that he’d likely be a whole lot happier if it were possible for him to remain living with his mother. Sadly, he needs to separate himself in this regard for both his mother’s & his own sake, as no-one lives forever. Independence, wherever possible, is crucial.

So far as “treatment” goes … Much of the behaviour of autistic children/adults that is seen as a problem and is frequently targeted for “treatment, cure & correction” is actually symptomatic of the need for structure. If a disturbed autistic person is given the structure they need and crave, then the anxiety-driven problem behaviour disappears.