Up to 40% of children in the “failed” phase 3 bumetanide trial were actually responders, according to AI reanalysis of the data – Treating autism in the real world

 

In some parts of the world even the words “treating autism” can still get you into trouble and some people have to go to quite extreme lengths to get their child’s developmental trajectory back on track.

I did note that in the US big changes have been made to their Interagency Autism Coordinating Committee (IACC) that coordinates all efforts within the Department of Health and Human Services (HHS) concerning autism. Now it includes some readers of this blog. Will this make a difference?

https://iacc.hhs.gov/ 

 

Over in France, the Bumetanide researchers Ben-Ari, Lemonnier and pals published their AI driven reanalysis of the “failed” phase 3 autism trial. They found that using AI they could actually predict who did actually respond; and many did. Nonetheless this large trial of all-jumbled-together kids with an autism diagnosis showed that overall bumetanide was no better than a placebo. Sounds strange to you? This is a common theme in autism trials because they do not narrow down a specific type of autism that they are trying to treat.

Over where I am, I keep getting positive reports of success. Some people are lucky and find that much of what works for my son works for theirs. There is a lot in this blog about other types of autism.

Why autism remains untreatable?

Autism is not simple to treat. Autism has no biological definition and measurement scales are all likely not fit for purpose. What would treatment success even mean?

From the perspective of severe autism with apparent ID (the old “Classic autism”) the biggest issues are to do with the slow rate of acquiring new skills. There are very well established tools to measure the skillset of such kids, such as  ABLLS (Assessment of Basic Language and Learning Skills). There are also non-verbal IQ tests. 

For young kids with classic autism you want them to add these basic skills ASAP, so that they can move on with their lives. In our case Bumetanide was the key to unlock new skill addition.

This is not what the phase 3 bumetanide trial was trying to measure.

Indeed one of the recurring comments from parents and teachers is the child has become more “present.” How do you quantify something like that?

For most children with autism in 2026, they do not have a problem with skill acquisition, they are a bit quirky, nervous, resistant to change, stim a bit, do not make friends. It is a very different condition. These issues are very real and genuinely concern some parents, but they are very different problems.

The modern cookie-cutter, protocol-driven, approach does work for most of medicine. But it will never work on an ill-defined category like autism. It actually becomes ridiculous when you look at all the varied types of autism. Even people with cerebral palsy or Down syndrome can be given an “autism” diagnosis on top, but they are completely different biological conditions.

Where to from here?

What does Ben-Ari do now?

Start again with another phase 3 trial? Paid for by who?  Will Servier come back and fund the second attempt?

In the meantime the clock keeps ticking.

I read Ben-Ari’s initial study and made my n=1 trial in 2012. My trial met its primary endpoint (Peter satisfied) and therapy started.

Academic performance went from complete basket-case to passing his high school public IGCSE exams a decade later.

Now it is 2026 and therapy still continues. No side effects,  heart ultrasound (echocardiogram) all normal.

Crazy world.

40% “disabled” at Stanford

I was surprised to read that almost 40% of undergraduates at Stanford University are claiming disability, to get extra time in exams. It does tell you a lot about the current generation of 20 year olds.

I would give them an E on their final diploma (I passed but needed Extra time). It is perfectly reasonable for a small number of clever students to need extra time, they might have a physical disability with their hands, be deaf, or blind, or dyslexic. It is perfectly reasonable to give some people extra time, but 40%?

It really is not fair on the remaining 60%. Maybe just give everyone an extra hour, those that finish early just leave early. They could get E on their results, for “I work fast and finish Early - hire me!"

What is annoying is the trivialization of the word disability.

40% of Stanford undergrads receive disability accommodations—but it’s become a college-wide phenomenon as Gen Z try to succeed in the current climate

So many people claim a disability like autism that theme parks in the US and Europe have had to roll back their privileged access schemes.

When I visited Charlotte International airport a while back and had to stand in a very long line for the passport control, I was amazed to see a never-ending procession of people appearing in wheelchairs to skip the queue. I have never seen this in Europe, but I suppose it will eventually come.

 

Back to those 40% in the Bumetanide trial.

New Analysis of the Bumetanide Phase 3 Trials: Were Responders Hidden in a “Failed” Study?

Approximately one-quarter to one-third of participants fit validated clinical profiles in which bumetanide showed statistically significant benefit on SRS-2, despite the overall trial being negative. The abstract itself says up to 40%.

Treating autism with Bumetanide: Identification of responders using Q-Finder machine learning algorithm

Bumetanide, a specific NKCC1 co-transporter inhibitor, restores deficient GABAergic inhibition implicated in various brain disorders, including Autism Spectrum Disorders (ASD). In keeping with this mechanism, nine successful phase 2 clinical trials, conducted by seven independent teams using an identical protocol, have shown significant improvements in ASD symptoms among individuals treated with Bumetanide. Despite these promising results, two large phase 3 clinical trials (over 400 children recruited in approximately 50 centers and covering age groups 2–6 and 7–17 years) failed with no significant difference between patients treated by placebo or Bumetanide. This failure may stem from the substantial heterogeneity of ASD symptom profiles across the study population, potentially diluting the overall observed treatment effect. To address this, we reanalyzed the phase 3 data using Q-Finder, a supervised machine learning algorithm, aiming to identify subgroups of patients who responded to the treatment. This analysis was based on clinical parameters collected at the baseline of trial and used the same standard endpoints and success criteria defined in the original phase 3 protocol. It enabled the identification of responder subgroups showing a statistically significant difference between placebo and Bumetanide treatment arms. We report detailed descriptions and statistical evaluations of these subgroups. The discovered responder subgroups, representing up to 40% of participants, were cross validated between the two study populations. These findings suggest that meaningful treatment responses can be uncovered within negative phase 3 trials, highlighting the limitations of a one-size-fits-all approach for heterogeneous conditions such as ASD. Machine learning appears to be a promising tool to support this precision medicine strategy.

The 2026 reanalysis published in Translational Psychiatry revisited the large Phase 3 bumetanide trials that previously failed to meet their primary endpoint.

The original Phase 3 trials included more than 400 children (ages 2–17) and found no significant overall difference between bumetanide and placebo on the primary outcome measure (CARS2).

This new study asked a different question:

Instead of “Did bumetanide work for everyone?”, could it have worked for specific subgroups that were diluted in the overall average?

To explore this, the authors used a supervised machine-learning algorithm (Q-Finder) to identify baseline clinical profiles associated with treatment response.

What They Found

The original overall result remains negative

Across the entire population:

• No significant benefit on the primary endpoint (CARS2).
• No meaningful average effect.

So the trial still officially failed.

Subgroups showing benefit were identified

When the data were stratified by symptom profiles at baseline, several subgroups showed:

• Statistically significant improvement on the SRS-2 (Social Responsiveness Scale)
• Treatment effects of roughly 12–17 points in validated groups
• Coverage of about 25–36% of participants in the largest responder profiles

Importantly, these findings were cross-validated between the younger and older trial cohorts.

A Consistent Feature of Responders

Across validated subgroups, one feature repeatedly appeared:

Mildly abnormal “adaptation to environmental changes” on CARS2

This domain reflects:

• Difficulty with transitions
• Rigidity around routines
• Stress with change

Responders were typically:

• Clearly autistic (often moderate–severe social symptoms)
• With repetitive behaviours
• But not globally or profoundly impaired across all domains

Interestingly, IQ did not emerge as a defining predictor of response.

Primary Endpoint vs Secondary Endpoint

A key nuance:

• No validated responder subgroups were found using the primary endpoint (CARS2).
• Validated subgroups were found using the secondary endpoint (SRS-2).

From a regulatory standpoint, this matters: trials are judged on their primary endpoint.

From a scientific standpoint, it suggests:

SRS-2 may have been more sensitive to the type of change bumetanide produces.

What This Means

This reanalysis does not prove bumetanide works broadly in autism.

It does suggest:

• Autism is highly heterogeneous.
• A one-size-fits-all trial design may dilute effects.
• A biologically or symptom-stratified approach may be necessary.
• Around one-quarter to one-third of participants may represent a responder subtype.

However, these findings are post hoc and exploratory.

To confirm them, a new trial would need to:

• Prospectively enroll only the identified responder phenotype.
• Use appropriate primary endpoints.
• Replicate the treatment effect.

Why This Matters for Autism Research

The study reflects a broader shift toward precision medicine:

• Rather than asking “Does this drug work for autism?”
• The better question may be:

“Which subtype of autism does it work for?”

Machine learning may help identify these subgroups, but prospective validation is essential.

The original Phase 3 trial remains negative at the population level.

This reanalysis suggests that meaningful responses may have been present in specific clinical subgroups — particularly children with:

• Mild adaptation abnormalities
• Repetitive behaviours
• Significant social impairment

Whether this represents a reproducible biological subtype remains to be tested in future trials.

Conclusion

In Rett syndrome a very expensive new drug called Trofinitide was approved, even though reports suggest it is only really effective in about 20% of these girls. I was really surprised.  It costs $300,000 to $900,00 a year depending on the girl’s weight.

It looks very odd that the large bumetanide failed, even though 25-40% were actually responders. By the way, my son’s bumetanide therapy has cost about $80 a year, for the last 13 years.

It does not fill you with great confidence.

I recently saw an article saying that “paracetamol/ acetaminophen does not, after all, increase the incidence of autism.” Well theoretically it should be harmful, by depleting glutathione, which is why it should be taken with NAC. We also know that NAC taken during pregnancy can significantly reduce the risk of miscarriage and this has been studied in a clinical trial.

N-acetyl cysteine for treatment of recurrent unexplained pregnancy loss

A controlled clinical trial studied N-acetylcysteine (NAC) in 168 pregnant women with a history of recurrent unexplained miscarriage. Women received either folic acid alone or folic acid plus NAC at 600 mg per day. In the NAC group, 52% of pregnancies continued beyond 20 weeks, compared with 27% in the control group. The take-home baby rate was 47% in the NAC group, compared with 21% in the control group. This represents more than a doubling of the live birth rate. NAC works by restoring glutathione, the cell’s main antioxidant, protecting placental and fetal tissue from oxidative stress. Oxidative stress is known to impair placental function and contribute to pregnancy loss. NAC was well tolerated, with no significant safety concerns reported. These results suggest that correcting oxidative stress can directly improve pregnancy outcomes in a defined high-risk group. This study illustrates how targeting a specific biological mechanism can dramatically change developmental outcomes.

If a professionally-managed autism trial cannot detect the 25-40% who responded to some extent, do you believe a study that effectively says nobody gets autism from pre-natal acetaminophen. Not even 1%? All you likely need to do is pair it with NAC to make the risk 0%.

For decades doctors refused to believe regressive autism existed. Once people started videoing their toddlers, it became impossible to doubt that some actually had developed speech and then lost it. Parents were not imagining it. It was just an inconvenient truth, and still is.

The plural of anecdote is data – I vote for that

 

Most of my interactions in the world of treating autism are with people I have never met, but you cannot help keep learning new things.

I was recently contacted by a mother who is computer programmer and so used to dealing with “exact sciences.” She had read my book and noted from it that genetic testing in autism often misses important genes. Her child’s report stated that there were no mutated autism genes found. She asked if I know how to analyse the raw data from the testing. That is a bit too technical for me, though I discovered you can upload that file to ChatGPT for analysis. I said that all I do is take the 10-20 genes highlighted in the full report and look them all up, regardless of whether they are obvious autism genes or not. Back came the very short list and after a couple of minutes “Bingo” there was the gene. It was not on the lab’s “autism list,” but in the research one of the genes is described as having potential to cause autism.

In a perfect world the testing lab would have an updated list that includes all the genes known to cause autism, or indeed intellectual disability. It is not the exact science the mother is used to, it is sloppy science. You must dig deeper than you thought would be really necessary.

I did meet, in real life, the parents of a young child with severe autism a week or two ago. They had tried all sorts of expensive therapies, from stem cell therapy to GcMAF from Japan. There was a scandal in the US and Europe a decade ago when GcMAF was marketed to treat cancer, autism and other conditions. In Japan it is still used in alternative clinics, but it is not an approved therapy or a regulated drug anywhere.

I was told that in Japan GcMAF is now made from a patient’s own blood and saw that it is marketed as a "personalized" or "natural" therapy. The process typically involves isolating the Gc protein (a vitamin D-binding protein) from the patient’s blood, chemically modifying it to activate macrophages, and then injecting it back into the patient. I have no idea if it works.

I dared not ask how much it cost, but I did ask if it helped. I suggested that in autism the cheapest and safest therapies are often the most effective.

One reader of this blog remains a fan of the original GcMAF that was produced by David Noakes' company Immuno Biotech. He later went to jail in the UK and then in France for selling an unlicensed medical product. In June 2015 Dr Jeffrey Bradstreet, a well-known autism doctor who used GcMAF, was found dead the day after his office in Buford, Georgia was raided by the FDA, searching for evidence of illegal medical practices related to unapproved drugs.

Japan seems to be more “anything goes” when it comes to alternative medicine. This is probably not what you would have expected. GcMAF is still marketed there to treat cancer and autism.

Safety

Safety should be the prime concern when treating autism. I recall being told the key insight a mainstream doctor took away from attending the Brain Foundation’s autism conference in California a while back was that “you actually can safely treat autism.”

The GcMAF mother did ask me if it was safe.

Using common existing drugs that have been repurposed for autism is safe, as long as they are used responsibly and care is taken regarding interactions and the listed side effects.

Drugs taken orally are often considered inherently safer than those administered via injection or infusion for several reasons, perhaps the key one is the barrier of the digestive system.

When drugs are taken by mouth, they pass through the liver before entering systemic circulation. The liver metabolizes some of the drug, which can detoxify harmful substances or reduce their potency. This serves as a protective mechanism. The stomach and intestines have mechanisms to break down and filter harmful substances, adding another layer of safety.

Injectable drugs require sterile preparation and administration to avoid infections. Oral drugs are less prone to contamination since they do not bypass the body's natural barriers.

Gene therapy can be risky, as was shown recently in a trial for Rett syndrome: 

Patient Death in Rett Syndrome Trial Forces Neurogene to Drop High-Dose Arm

Despite the death, the FDA has allowed Neurogene to forge ahead with the Phase I/II Rett syndrome trial, but using only the lower 1E15 vg dose of its investigational gene therapy NGN-401.

Neurogene revealed in an SEC filing on Thursday that a patient has died in its Phase I/II Rett syndrome clinical trial after being dosed with its investigational gene therapy.

The patient had been treated with the higher, 3E15-vg dose of NGN-401 when they experienced what was initially described only as a treatment-related serious adverse event (SAE). In a follow-up announcement on Monday, Neurogene disclosed that the patient had developed systemic hyperinflammatory syndrome—a known but severe side effect of adeno-associated virus gene therapies—and was in critical condition.

 

The plural of anecdote is data vs The plural of anecdote is not data

"The plural of anecdote is not data" is a commonly used phrase in scientific and analytical discussions. It highlights the idea that individual anecdotes, no matter how numerous, do not constitute reliable evidence or robust data without proper scientific methods like controlled observation, experimentation, and statistical analysis.

The phrase the plural of anecdote is not data turns out to have been a misquote. The original observation, by the political scientist Ray Wolfinger, was just the opposite: The plural of anecdote is data.

Ray Wolfinger said this to emphasize that anecdotes, when systematically collected and analyzed, can form the foundation of meaningful data sets.

Wolfinger's point was not to dismiss the importance of rigorous scientific methods but rather to highlight that even seemingly small, subjective observations—when aggregated and scrutinized—can reveal broader patterns and insights.

This perspective challenges the overly dismissive view of anecdotes in research, acknowledging their potential as the seeds of inquiry and evidence in contexts where comprehensive data collection may not yet exist.

Human biology is not an exact science

The phrase "human biology is not an exact science" reflects the inherent complexity and variability of biological systems, particularly in humans. Unlike the physical sciences, which often operate under strict laws and predictable outcomes, human biology involves numerous interacting factors, such as genetics, environment, lifestyle, and individual variability. This makes it challenging to predict outcomes with precision.

Key reasons include:

• Genetic diversity: Each person has a unique genetic makeup, leading to different responses to stimuli, medications, and conditions.
• Environmental influences: Diet, climate, socioeconomic status, and exposure to toxins vary widely among individuals and populations.
• Biological variability: Even within the same individual, factors like age, hormonal changes, and microbiome composition can cause variations.
• Unpredictable interactions: Complex systems, such as the immune response or neural activity, often defy simple cause-and-effect explanations.

As a result, human biology relies on probabilities, trends, and patterns rather than absolutes, making it a science of approximations and context-dependent insights.

Again, bumetanide works for some

Our reader A.W. recently completed a trial of bumetanide and in parallel the pediatrician made a trial on her own 5-year-old granddaughter with severe autism. Bumetanide did not work for A.W. but it did for the 5-year-old granddaughter. Notably her speech increased from single words to multiple words. Continued use will now certainly bring profound benefits as she grows up.

We see that human biology is not an exact science, but the situation is made worse by diagnostic stupidity. We know that there are many hundreds of biological dysfunctions leading to the umbrella diagnosis of autism. All autism is still lumped in together in these supposedly gold-standard randomized clinical trials. In layman’s terms you have to compare apples with apples, not apples with kiwis.

As a result, all large randomized clinical trials for core autism symptoms have failed and will likely continue to do so.  Even the large bumetanide trial failed. 

Meanwhile some people, now including A.W.’s pediatrician, will continue effectively treating a small number of children and adults with autism.    

Conclusion

When I presented my take at the recent autism conference in Abu Dhabi I did have a confrontation with the moderator of my session.

I presented the scientific logic behind treating autism but what he saw was someone dealing with anecdotes. He said he only believes in randomized clinical trials. 15 years ago I would also have thought like him—then came my epiphany.

I then learnt the benefit of tinkering with things you supposedly cannot fix but cannot just throw away and replace.

I do fix many other things. I had Monty’s two electric scooters in pieces several times recently, the last job was fixing the battery pack that malfunctioned. I have no previous experience, you just start tinkering, apply common sense and solve the problem. Having a spare scooter is an advantage.  I can always buy a third one.

In years only recently gone by you did discard “malfunctioning” young children into institutions. The doctor would then suggest you try again for another child and wish you better luck next time. Like buying scooter number two and discarding the first one.

Nowadays you keep such children at home, leave them untreated, and only later on put them into mini-institutions (AKA group homes).

I think it pays to tinker (play around fixing things) and improve functioning as much as possible. There is no guarantee of success, but you do have a fighting chance.

Wonder cures promoted in catchy 60 second videos on TikTok, Facebook and Instagram may not be your best choice. 

Can you safely take Bumetanide or Acetazolamide (Diamox) if you have a Sulfonamide allergy?

I was contacted by a reader in Italy whose child with autism may respond to bumetanide, but has a sulfonamide allergy and got a skin reaction (hives). She had to stop giving the drug, but wanted to know how she could re-start bumetanide.

Other readers have pointed out how they dare not try bumetanide because they know their child has a sulfonamide allergy. I think our longtime reader Tanya is one example.

 

Key Point to Note

Most people discover their sulfonamide after being giving an antibiotic in early childhood.

It is now well established that many (but not all) people with an allergy to sulfonamide antibiotics can safely take a sulfonamide diuretic like Bumetanide or Diamox/Acetazolamide. This is presented in case studies later in this post.

 

Sulfonamide Drugs

Many common drugs are “sulfonamides”. Their chemical structure includes a sulfonyl (–SO2) group attached to an amine group (–NH2). They include common antibiotics, like erythromycin, many diuretics (bumetanide, furosemide, acetazolamide (Diamox), some anticonvulsants (zonisamide) and some anti-inflammatory drugs (sulfasalazine).

 

Sulfonamide Allergy

Many parents discover early in their child’s life that their child has a sulfonamide allergy. Sometimes this is abbreviated to a “sulfa allergy.”

The symptoms of a sulfonamide allergy can vary but may include:

• Skin reactions (rash, hives, or itching)
• Fever
• Swelling
• Respiratory issues (shortness of breath)
• Anaphylaxis (in severe cases)

Usually the symptoms are minor, but once diagnosed the parents usually take note never to give their child any sulfonamide drug.

 

If you have the allergy must you avoid all sulfonamide drugs?

The standard assumption has been that if you have a sulfonamide allergy you cannot take Bumetanide or Acetazolamide (Diamox).

Upon further investigation in the research, this may not always be true.

 

What happens when there is no alternative drug?

When treating ion channel/transporter dysfunctions there may not be a non-sulfonamide alternative.

Acetazolamide (Diamox) is documented in the literature as a case in point. Bumetanide has not yet made it to the literature.

Furosemide fortunately has been researched and a safe desensitization protocol exists. Furosemide is a very similar drug to bumetanide.

 

Desensitization strategies

I did recently write about enzyme potentiated desensitization, which is an old, mostly overlooked, technique to overcome allergic reactions. I was interested in pollen allergy.

The best-known kinds of desensitization are allergy shots and more recently overcoming nut allergies, which gets media attention. 

Oral immunotherapy for peanut allergy in young children

The study also found that the youngest children and those who started the trial with lower levels of peanut-specific antibodies were most likely to achieve remission. 

“The landmark results of the trial suggest a window of opportunity in early childhood to induce remission of peanut allergy through oral immunotherapy,” says NIAID Director Dr. Anthony Fauci. “It is our hope that these study findings will inform the development of treatment modalities that reduce the burden of peanut allergy in children.”

 

I did wonder that if it works for nuts then why not bumetanide.

It turns out that I am not the first to consider desensitization to a drug allergy. The best known method is rapid drug desensitization (RDD), usually intravenous, which opens a window to be able to start taking a drug you are allergic to. Once you stop taking the drug, you then again become allergic to it.

The other approach is more like dealing with nut allergies, it is called slow drug desensitization (SDD) and involves taking a tiny initial dose and then slowly increasing it over weeks and months.

Drug desensitization is normally done in hospital as part of some therapy when you absolutely must have a drug that you are allergic to.

The paper below contains information on a very large number of common drugs where drug desensitization has been successfully carried out.

 

Desensitization for the prevention of drug hypersensitivity reactions

Drug desensitization is the temporary induction of tolerance to a sensitized drug by administering slow increments of the drug, starting from a very small amount to a full therapeutic dose. It can be used as a therapeutic strategy for patients with drug hypersensitivity when no comparable alternatives are available. Desensitization has been recommended for immunoglobulin E (IgE)-mediated immediate hypersensitivity; however, its indications have recently been expanded to include non-IgE-mediated, non-immunological, or delayed T cell-mediated reactions. Currently, the mechanism of desensitization is not fully understood. However, the attenuation of various intracellular signals in target cells is an area of active research, such as high-affinity IgE receptor (FcɛRI) internalization, anti-drug IgG4 blocking antibody, altered signaling pathways in mast cells and basophils, and reduced Ca²⁺ influx. Agents commonly requiring desensitization include antineoplastic agents, antibiotics, antituberculous agents, and aspirin/nonsteroidal anti-inflammatory drugs. Various desensitization protocols (rapid or slow, multi-bag or one-bag, with different target doses) have been proposed for each drug. An appropriate protocol should be selected with the appropriate concentration, dosage, dosing interval, and route of administration. In addition, the protocol should be adjusted with consideration of the severity of the initial reaction, the characteristics of the drug itself, as well as the frequency, pattern, and degree of breakthrough reactions.

Two categories of desensitization protocols are currently available: RDD and slow drug desensitization (SDD). RDD is recommended for immediate reactions, both allergic and nonallergic. The most widely used RDD protocol is doubling the dosage every 15 minutes until the therapeutic dose is achieved. SDD is recommended for type IV delayed hypersensitivity reactions with T cell involvement, and can be performed both orally and intravenously. There is as yet no consensus on SDD protocols, including the initial dose, dose increments between steps, and dosing interval. Further clinical experience and research are required to establish the role and efficacy of desensitization for delayed reactions.

H1 blockers, H2 blockers, and glucocorticoids can be used as premedication. Aspirin and montelukast block the end products of the arachidonic acid cascade and decrease the incidence and severity of BTRs. NSAIDs can help to control the symptoms of cytokine release syndrome. Glucocorticoids alone are not recommended because they cannot prevent the initial degranulation of mast cells. 

The desensitization process is known to be antigen-specific, as the level of drug-specific immunoglobulin E (IgE) decreases but the levels of other allergen-specific IgE remain consistent throughout the treatment period. However, the cellular and molecular mechanisms underlying drug desensitization are not yet fully understood.

Aspirin/NSAID desensitization is considered for patients with cardiovascular or musculoskeletal diseases who require aspirin or NSAID administration for prolonged periods.

The temporary tolerance to aspirin/NSAIDs lasts 48 to 72 hours after desensitization. Therefore, hypersensitivity reactions can recur 2 to 5 days after discontinuation if the therapeutic dose is not continued.

 

DHR to β-lactams, such as penicillin or cephalosporin, is more common than that to non-β-lactams. Desensitization can be performed for both immediate and delayed hypersensitivity reactions. The protocol should be selected based on patient characteristics, hospital capacity, and physician preferences. It is generally started with 1/1,000 of the therapeutic dose and then increased by 2 to 3-fold every 15 minutes to 5 hours. Oral administration is preferred due to its ease, safety, and effectiveness. Desensitization to penicillin and cephalosporins has been well established. Successful desensitization has also been reported for other β-lactams, such as carbapenem and monobactam, and non-β-lactams, such as vancomycin, clindamycin, metronidazole, macrolides, aminoglycosides, tetracycline, and ciprofloxacin.

Successful desensitization to other antimicrobials has also been reported for antifungals, such as amphotericin B, fluconazole, itraconazole, voriconazole, and micafungin, and for antivirals, such as acyclovir, valganciclovir, ribavirin, and nevirapine.

 

Furosemide desensitization

There is no literature specific to bumetanide but there is on the very similar drug furosemide.

 

RAPID ORAL DESENSITIZATION TO FUROSEMIDE

Furosemide is a commonly used loop diuretic that contains a sulfonamide group. Although there are rare reports of hypersensitivity to furosemide, severe reactions, including anaphylaxis, have been reported. Ethacrynic acid, the only loop diuretic without a sulfonamide moiety, is no longer available in oral formulation, thus posing a dilemma in the outpatient treatment of patients with furosemide allergy.

Published protocols for furosemide desensitization include rapid intravenous administration and oral protocols lasting 3 to 10 days.3–5 The oral protocols were performed in patients with non–type I hypersensitivity reactions. We present a rapid, oral protocol for desensitization in a patient with presumed type 1 furosemide allergy manifesting as urticaria.

 

Desensitization to sulfonamide-containing antibiotics has been extensively used, but desensitization to furosemide is uncommon. The oral protocols previously described took 3 to 10 days and were performed in patients with non–type I hypersensitivity reactions, one with pancytopenia and the other with pancreatitis. The patient with a type I hypersensitivity reaction underwent an intravenous desensitization protocol. Rapid oral desensitization to a loop diuretic has not been previously described. The potential advantages of oral desensitization are that it is probably safer than intravenous desensitization, it may be more cost-effective in terms of monitoring and staff requirements, and it may be possible to perform in an outpatient setting. We propose our protocol as a novel approach to furosemide desensitization therapy for patients with non–life threatening reactions to furosemide. Further progress in the diagnosis and treatment of hypersensitivity to sulfonamide drugs will require identification of the major antigenic determinant and standardization of skin testing and specific IgE testing.

I think we should say good work to Dr Naureen Alim, then at Baylor College of Medicine Houston, Texas.

If anyone wants to desensitize to a bumetanide allergy I think she is the one to contact for advice. She is easy to find via Google. 

Here is another case example. 

Desensitization therapy in a patient with furosemide allergy

Allergy to furosemide is a rare phenomenon. Desensitization to this sulfa-containing drug has not been frequently performed. We describe a patient with severe congestive heart failure and type I allergy to furosemide. Because of the severity of her condition, we decided to use a rapid intravenous desensitization protocol. Following the desensitization, the patient was treated with intravenous and oral furosemide with a dramatic improvement in her clinical state. We suggest that rapid desensitization may be a safe and effective way of introducing furosemide to allergic patients for whom loop diuretics are urgently indicated.

 

In the case of Acetazolamide, here is one published desensitization method:

  

Desensitization to acetazolamide in a patient with previous antimicrobial sulfonamide allergy

Acetazolamide is a carbonic anhydrase inhibitor that is frequently used in the management of idiopathic intracranial hypertension. Acetazolamide is a sulfonamide agent; specifically, it is a non sulfonylarylamine, which lacks the amine moiety found at the N4 position that is seen in sulfa antibiotics. 

Sulfonamide antibiotics contain a substituted ring at the N1 position that is thought to be the driving factor in immediate hypersensitivity reactions.  

Although sulfa allergies are commonly reported, there is no evidence to suggest cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics. However, patients can report a history of allergy to both categories of drugs. We present a rapid desensitization protocol to acetazolamide in a patient with history of immediate hypersensitivity reactions to both a sulfonamide antibiotic and acetazolamide. 

We formulated a 12-step intravenous protocol that was performed in the intensive care unit setting (Table 1). Informed consent was provided by the patient, and she tolerated the procedure well without any adverse reactions. The desensitization procedure took 395 minutes or approximately 6.5 hours. She was monitored overnight in the hospital and was observed the following morning after taking 500 mg of acetazolamide orally to ensure tolerance. She was thereafter able to continue her recommended dose of acetazolamide without any issues to date.

 

Allergy to a sulfonamide antibiotic does not always mean you will be allergic to the non-antibiotic sulfonamide drugs.

  

Use of Acetazolamide in Sulfonamide-Allergic Patients With Neurologic Channelopathies

The 3 patients had been considered for carbonic anhydrase inhibitor treatment but a pharmacist had refused to fill a prescription for acetazolamide for 1 patient and the other 2 patients were denied treatment because of the allergy history. All 3 patients were prescribed acetazolamide and had no adverse reaction. Two patients improved substantially and are continuing treatment. A review of the pharmacology literature suggests that cross-reactivity between antibiotic and nonantibiotic carbonic anhydrase inhibitors is unlikely. Moreover, a review of case reports does not suggest cross-reactivity. Previous reports in the ophthalmology literature also indicate that acetazolamide can be administered to patients with a history of antibiotic sulfonamide allergic reaction.

Conclusions

These 3 cases confirm that the carbonic anhydrase inhibitor acetazolamide can be given to patients with a history of allergic skin rash with antibiotic sulfonamide.

 

Acetazolamide has been used for the treatment of episodic ataxia type 2, with benefit in 50% to 75% of patients. In episodic ataxia type 1, acetazolamide was also effective in decreasing attack frequency. Acetazolamide is also effective in the periodic paralyses. Carbonic anhydrase inhibitors have been used to prevent altitude sickness, to lower intraocular pressure in open-angle glaucoma, and to treat refractory absence, myoclonic, and catamenial epilepsy as part of multidrug regimens. Acetazolamide has recently been used for hemiplegic migraine and idiopathic intracranial hypertension. 

The lack of available clinical or pharmacological evidence to support cross-reactivity between sulfonamide antibiotics and acetazolamide lends supports to the use of acetazolamide to treat patients with episodic ataxia and periodic paralysis. Of our 3 sulfonamide-allergic patients, 2 improved in symptoms after treatment with acetazolamide and none of the 3 had a hypersensitivity reaction. We conclude that a sulfonamide allergy should not be a contraindication to treatment with acetazolamide in patients with neurologic channelopathies. 

 

Acetazolamide and sulfonamide allergy: a not so simple story

 Allergies and adverse reactions to sulfonamide medications are quite common. Two distinct categories of drugs are classified as sulfonamides: antibiotics and nonantibiotics. The two groups differ in their chemical structure, use, and the rate at which adverse reactions occur. Cross-reactivity between the two groups has been implied in the past, but is suspect. Acetazolamide, from the nonantibiotic group, is routinely used in the prevention and treatment of high altitude issues and may not need to be avoided in individuals with a history of sulfonamide allergy. This review addresses the differences between the groups and the propensity for intergroup and intragroup adverse reactions based on the available literature. We also examine the different clinical presentations of allergy and adverse reactions, from simple cutaneous reactions with no sequelae through Stevens-Johnson syndrome and anaphylaxis, with risk for significant morbidity and mortality. We offer a systematic approach to determine whether acetazolamide is a safe option for those with a history of allergy to sulfonamides.

Sulfonamide-containing antibiotics are the second most frequent cause of allergic drug reactions, after the b-lactams (penicillins and cephalosporins). In one large study, the incidence of reactions to trimethoprim–sulfamethoxazole (TMPSMX) was 3% of patients exposed, compared with 5% for amoxicillin. The incidence of reactions to nonantibiotic sulfonamides is not well established; it is clearly less than with antibiotics.

 

There are several approaches to the use of sulfonamide drugs (specifically acetazolamide) in patients with past reactions to this class of medications. The choice of strategy depends on the type and severity of the previous reaction, as well as the class of drug (antibiotic versus non antibiotic) and the risk–benefit profile for the patient. However, regardless of the approach, the risks of subsequent reactions cannot be completely eliminated, and a thorough discussion between the medical provider and the patient should include this point so that an informed decision regarding the use of acetazolamide can be made. The safest approach for the patient with any prior reaction to a sulfa drug, multiple drug allergies, or penicillin allergy would be to avoid all drugs in the sulfonamide group, including acetazolamide.

 

Avoidance of the entire sulfonamide drug group is warranted for individuals whose previous reaction included a serious and/or life-threatening condition such as anaphylaxis, SJS, and TEN. Any form of reexposure to the precipitating drug or a sulfonamide in the same group is strictly contraindicated. Published evidence has shown that SJS/TEN can recur with even minor reexposures and may be more severe in the second episode. Even though SJS/TEN reactions are so far not associated with nonantibiotic sulfonamides, because of the severity and life-threatening nature of these reactions, a safe practice is to avoid all sulfonamides in patients with past SJS or TEN from sulfonamide containing medications.

 

This paper was published in a journal on high altitude medicine. That is why the suggested alternatives are staged ascents of the mountain and oxygen.

  

Conclusion

The first key point is that you can have an allergy to sulfonamide antibiotics and have absolutely no negative reaction to sulfonamide drugs like bumetanide and acetazolamide (Diamox).

If you do have a mild allergic reaction to a sulfonamide drug, there are desensitization strategies that are proven to work in many people.

It looks like rapid oral desensitization to bumetanide and acetazolamide is likely possible, based on what has been shown possible with furosemide and a wide variety of other drugs.

Clearly the level of sensitivity and hence the nature of the allergic reaction can vary massively from person to person, this is why rapid desensitization usually takes place in hospital.

If you opt for the slower process, much less is known, because it is not generally used. If you did it in hospital it would require a very long stay and so would be hugely expensive.

It is suggested that slow drug desensitization (SDD) should be much more long lasting and hopefully might become permanent – as is the hope for nut allergy treatment.

When posed the initial question by our reader wanting to use bumetanide, I was thinking along the lines of slow drug desensitization (SDD), because this is how you would treat a pollen allergy. If rapid oral desensitization will work for taking bumetanide once a day that would be great. To maintain the protection from allergy it might be safer to take a small second daily dose.

 

Here is a quick overview of desensitization options for sulfonamide allergy:

• Rapid Desensitization (RDD):
• Faster process (hours)
• Temporary tolerance achieved
• May be repeated if needed
• Slow Desensitization (SDD):
• Slower process (days, weeks, or months)
• Might offer a greater chance of longer-lasting
• Still requires close monitoring

Important Considerations:

• Always consult your doctor: They can assess your allergy severity, treatment options, and the suitability of desensitization if necessary.
• Desensitization is not without risks: It requires careful monitoring.

 

I for one found this an interesting investigation and with promise for parents of those with severe autism who have been unable to trial Bumetanide due to a sulfonamide allergy. 

Hopefully our reader Dr Antonucci will follow up on this and make a bumetanide desensitization protocol for those people with autism and a sulfonamide allergy. Maybe he has already done it. It looks very achievable.

Advances in personalized medicine to treat Autism/IDD – Rett syndrome as an example. Also, Piperine to upregulate KCC2, but what about its direct effect on GABAa receptors?

 

Source:  https://www.cell.com/neuron/pdf/S0896-6273(21)00466-9.pdf

Today’s post is drawn from a workshop I am invited to present at an autism conference in Abu Dhabi.

I decided to talk about advances in personalized medicine – no surprise there.  Since I have 2 ½ hours, I thought I will need some interesting examples to maintain the audiences interest.  One such topic is going to be Rett syndrome.

I regard Rett syndrome and all the other such syndromes in this blog as “single gene autisms” (monogenic autism).  If you apply the American DSM classification, from 2013 onwards Rett syndrome is no longer part of autism.  Hopefully there are no such purists attending in Abu Dhabi. 

Two gene therapies for Rett syndrome are currently undergoing human trials and one drug therapy has been FDA approved.  This looks very encouraging, so let’s dig a little deeper.

Rett syndrome can present with a wide range of disability ranging from mild to severe. 

Rett syndrome is the second most common cause of severe intellectual disability after Down syndrome.

Other symptoms may include:

•      Loss of speech

•      Loss of purposeful use of hands

•      Loss of mobility or gait disturbances

•      Loss of muscle tone

•      Seizures or Rett “episodes”

•      Scoliosis

•      Breathing issues

•      Sleep disturbances

•      Slowed rate of growth for head, feet and hands

Here are the new therapies: 

TSHA-102: This gene therapy, developed by Taysha Therapeutics, is a gene replacement therapy that aims to deliver a functional copy of the MECP2 gene to brain cells.  It utilizes an AAV-9 virus to carry the miniMECP2 gene product into cells for the body to produce more MeCP2 protein, which is deficient in Rett syndrome. As of February 2024, Taysha completed dosing for the first cohort (low dose) in their REVEAL Phase 1/2 adolescent and adult trial in Canada, with positive interim data on safety. They are also conducting trials in the US for both pediatric and adolescent/adult populations.

NGN-401: This gene therapy, by Neurogene Inc., employs a different approach. It uses an AAV9 vector to deliver a regulated version of the MECP2 gene called EXACT. This technology aims to control the amount of MECP2 protein produced by the gene, mitigating the risk of overproduction. NGN-401 is currently in a Phase 1/2 trial for girls with Rett syndrome aged 4 to 10 years old.

Daybue (trofinetide)

Daybue is the first and only FDA-approved treatment specifically for Rett syndrome in adults and children two years of age and older. It is not a gene therapy, but rather a medication taken orally.

The optimistic AI generated view:

Here's a breakdown of Daybue for Rett syndrome:

• Mechanism: The exact way Daybue works in Rett syndrome isn't fully understood, but it's believed to target neuroinflammation and support synaptic function.
• Dosage: The recommended dose is based on the patient's weight and is taken twice daily, morning and evening, with or without food.
• Administration: Daybue comes as an oral solution and can be taken directly or through a gastrostomy tube if swallowing is difficult.
• Efficacy: Studies have shown that Daybue can improve symptoms of Rett syndrome, including reducing scores on the Rett Syndrome Behavior Questionnaire (RSBQ) and showing improvement on the Clinical Global Impression-Improvement (CGI-I) scale.
• Side Effects: The most common side effects of Daybue are diarrhea and vomiting. Weight loss can also occur in some patients. It's important to consult with a healthcare professional for monitoring and managing any potential side effects.

Daybue is an expensive medication. Here's what we know about the cost:

• List Price: The list price of Daybue is around $21.10 per milliliter.
• Annual Cost: This translates to an estimated average annual cost of around $375,000 for patients.
• Dosage Variability: It's important to note that the dosage of Daybue is based on a patient's weight, so the annual cost can vary depending on the individual.

Insurance and Assistance Programs:

• The high cost of Daybue highlights the importance of insurance coverage. Whether insurance covers Daybue and to what extent will depend on your specific plan.
• The manufacturer, Acadia Pharmaceuticals, offers a copay program called Daybue Acadia Connect. This program may help eligible commercially insured patients pay $0 for their monthly prescription.

What are the parents' groups saying? 

Not as good as you might be expecting for $375,000 a year.

Affordable potential alternatives to Daybue/Trofinetide

Daybue/Trofinetide is the product of decades of research into a growth factor called IGF-1.

It is a complicated subject and as usual the abbreviations can be confusing.

As you will see below there already is an OTC product commercialized by one of the original researchers, Dr Jian Guan.

One Rett syndrome parent, who reads this blog, has trialed cGP and sees a benefit. You rather wonder why the Phelan-McDermid, Pitt Hopkins, Angelman and Prader-Willi parents don’t follow him and splash out 50 USD and make a trial.

 

 

Gene-therapy

Gene therapy is undoubtedly very clever and ultimately will likely be the best therapy.  It still may not be that silver bullet.

To be effective gene therapy needs to be given at a very young age, ideally as a fetal therapy prior to birth. Note that we saw that in the Rett mouse model they gave bumetanide to the pregnant mother just before birth.

Fetal therapy is not a crazy idea and much is already written about it; many pregnancies are terminated because genetic anomalies are detected prior to birth. Down syndrome is the best-known example. Fetal therapy is realistic for some disorders.

Girls with Rett syndrome are often diagnosed first with idiopathic autism and then years later with a more precise diagnosis of Rett syndrome. This is a common experience among readers of this blog.

Classic Rett syndrome 

The average age of diagnosis for this form is around 2.5 years old in the US and 5 years old in the UK.  Why do you think that is?

Research in mouse models has shown that the effect of gene therapy ranges from curative when given extremely young to more limited the later it is given.

Off-target effects

Gene therapy has the potential for off-target effects. This is a significant concern in the field and researchers are actively working on ways to minimize these risks. Here is a breakdown of what off-target effects are and why they matter:

During gene therapy, a modified gene is delivered to target cells with the aim of correcting a genetic defect.

Ideally, the modified gene integrates into the intended location in the genome.

However, there's a chance it might insert itself into unintended locations (off-target sites).

Potential Consequences of Off-Target Effects

Disrupting normal genes at off-target sites could lead to unpredictable and potentially harmful consequences. This could include triggering uncontrolled cell growth, which is a risk factor for cancer.

It can also cause unexpected side effects depending on which genes are accidentally disrupted.

Minimizing Off-Target Effects

Researchers are developing various strategies to improve the accuracy and specificity of gene therapy techniques.

This includes using more precise gene editing tools like CRISPR-Cas9 with optimized guide RNAs to reduce off-target edits.

Additionally, researchers are working on methods to detect and potentially repair any off-target modifications that might occur.

Over-expression of the target gene

Yes, there is a possibility that the replaced gene in gene therapy could overproduce the expressed protein. This can be a potential complication and researchers are working on ways to control the level of protein expression. Here's a breakdown of the concern:

• Gene Dosing: Ideally, gene therapy aims to deliver a functional copy of the gene at the right amount to compensate for the deficiency.
• Overproduction Risks: However, if the delivered gene is too active or multiple copies are inserted, it can lead to overproduction of the protein.

Consequences of Protein Overproduction:

• Overproduction of a protein can disrupt the delicate balance in the cell, potentially leading to cell dysfunction or even cell death.
• In some cases, the protein itself might have harmful effects if present in excessive amounts.

Controlling Protein Expression:

Researchers are developing several strategies to control protein expression in gene therapy:

• Promoter selection: Using promoters that have a weaker switch can help regulate protein production.
• Viral vectors: Engineering viral vectors to control the number of gene copies delivered to cells.
• Inducible systems: Developing gene therapy methods where the expression of the introduced gene can be turned on and off as needed.

The cost of gene therapy

•      Despite the high cost, gene therapy can be a cost-effective treatment for some diseases. This is because it can eliminate the need for lifelong treatment with other medications.

•      Here are some examples of the cost of currently available pediatric gene therapies:

•      Luxturna (gene therapy for Leber congenital amaurosis type 10): $425,000

•      Zolgensma (gene therapy for spinal muscular atrophy type 1): $2.1 million

•      Skysona (gene therapy for adrenoleukodystrophy): $3 million

Piperine to correct KCC2 expression in Rett syndrome?

One key feature of Rett syndrome is impaired cognition.

As regular readers are aware, there are many types of treatable intellectual disability (ID).

One type of treatable ID is caused when the GABA developmental switch fails to occur shortly after birth.  This creates an excitatory/inhibitory imbalance in neurons which impairs cognition and lowers IQ.

The faulty GABA switch is a feature of many types of autism, but far from all of them.

By using pharmaceuticals to lower chloride within neurons, you can compensate for the failure of the GABA switch.

This treatment can be achieved by:

1.     Blocking or down regulating NKCC1

2.     Up regulating KCC2

In the paper below they look at up regulating KCC2

Pharmacological enhancement of KCC2 gene expression exerts therapeutic effects on human Rett syndrome neurons and Mecp2 mutant mice

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the methyl CpG binding protein 2 (MECP2) gene. There are currently no approved treatments for RTT. The expression of K⁺/Cl⁻ cotransporter 2 (KCC2), a neuron-specific protein, has been found to be reduced in human RTT neurons and in RTT mouse models, suggesting that KCC2 might play a role in the pathophysiology of RTT.

Injection of KEEC KW-2449 or piperine in Mecp2 mutant mice ameliorated disease-associated respiratory and locomotion phenotypes. The small-molecule compounds described in our study may have therapeutic effects not only in RTT but also in other neurological disorders involving dysregulation of KCC2.

Thus, our data demonstrate that activation of the SIRT1 pathway or the TRPV1 channel enhances KCC2 expression in RTT human neurons.

Treatment with piperine (10 μM), an activator of the TRPV1 channel (51), induced a significant rise in KCC2 expression in cultured human neurons 

We already knew this was likely from earlier research from Ben Ari, see below for a reminder.  Is Piperine an interesting option for those restricted to OTC interventions?

Early alterations in a mouse model of Rett syndrome: the GABA developmental shift is abolished at birth

Genetic mutations of the Methyl-CpG-binding protein-2 (MECP2) gene underlie Rett syndrome (RTT). Developmental processes are often considered to be irrelevant in RTT pathogenesis but neuronal activity at birth has not been recorded. We report that the GABA developmental shift at birth is abolished in CA3 pyramidal neurons of Mecp2-/y mice and the glutamatergic/GABAergic postsynaptic currents (PSCs) ratio is increased. Two weeks later, GABA exerts strong excitatory actions, the glutamatergic/GABAergic PSCs ratio is enhanced, hyper-synchronized activity is present and metabotropic long-term depression (LTD) is impacted. One day before delivery, maternal administration of the NKCC1 chloride importer antagonist bumetanide restored these parameters but not respiratory or weight deficits, nor the onset of mortality. Results suggest that birth is a critical period in RTT with important alterations that can be attenuated by bumetanide raising the possibility of early treatment of the disorder.

One day before delivery, maternal administration of the NKCC1 chloride importer antagonist bumetanide restored these parameters but not respiratory or weight deficits, nor the onset of mortality. Results suggest that birth is a critical period in RTT with important alterations that can be attenuated by bumetanide raising the possibility of early treatment of the disorder.

Treating the mother prior to delivery with bumetanide was a partially effective therapy in the mouse model of Rett syndrome.

Piperine

Bumetanide is cheap and very possibly effective in human Rett syndrome, but it is a prescription drug.

Piperine is an OTC supplement and a compound found in black pepper. By activating the TRPV1 channel it causes an increase in expression of the KCC2 transporter that allows flow of chloride out of neurons. So piperine should lower chloride inside neurons.  Piperine can cross the blood brain barrier, so when taken orally it should have some effect on intracellular chloride.

Piperine is also a positive allosteric modulator of GABA_A receptors

This means that piperine multiplies the effect of whatever GABA is around. This means that in typical people piperine should have anti-anxiety effects.

Piperine was recently found to interact with a previously unknown  benzodiazepine-independent binding site.

Researchers are currently toying with the piperine molecule to try and separate the effect on TRPV1 from the effects on  GABA_A.  They want to create 2 new drugs.

1.     a selective TRPV1 activator

2.     a selective GABA_A modulator (PAM)

Piperine as an alternative or complement to Bumetanide?

One effect of piperine would be great to have (TRPV1 activator) but the second effect would not be helpful (positive allosteric modulator of GABAA).

The question is what is the net effect. Nobody will be able to answer that without a human trial.

I was advised long ago by one drug developer than it is best to focus on reducing flow into neurons via NKCC1, rather than increase its exit by KCC2, because nobody had yet been successful with KCC2; many have tried.  KCC2 plays a key role in neuropathic pain and that is why it has been researched.

Conclusion

We did see years ago that taking coffee with your bumetanide made sense. Coffee contains compounds that are OAT3 inhibitors and slow down the excretion of bumetanide from the body; coffee increases the effect of bumetanide. You can achieve something very similar by just increasing the dose of bumetanide.

Taking black pepper (piperine) with your bumetanide might be good, or might not be. It certainly would be easy to find out. As with Daybue/Trofinetide, the result is likely to vary from person to person. If GABA function, post- bumetanide, is still a bit excitatory amplifying GABA signaling will make autism worse. If GABA function has been shifted to inhibitory then amplifying GABA signaling will be calming.

Gene therapy will require much earlier diagnosis of single gene autisms.

“Precision medicine” therapies like Daybue/Trofinetide may not be that precise after all and large variations exist in the response, even among children with the same affected gene.

The huge expense means that for most of the world they will see no benefit from gene therapy or indeed “precision medicine.”

The low hanging fruit is to repurpose affordable existing drugs and get the benefit from their secondary effects.  This is what I term personalized medicine.

The research clearly indicates that some girls with Rett syndrome likely will benefit from Bumetanide therapy. For a young child this therapy would cost 50 US dollars/euros a year, if you pay the actual price for generics.

Why are they trialing genetic therapies for Rett instead of first doing the obvious thing and trialing cheap bumetanide? They will likely be able to sell the gene therapy for $2 million a shot.  There is little interest in trialing a $50 a year therapy.

Our new reader from Turkey, MÜCADELECI ANNE DENIZ ( = FIGHTING MOTHER DENIZ), likely does not have $2 million to spend, but seems to be on the way to creating her own personalized medicine therapy for her son. Good luck to her.

As to the cGP Max supplement, it seems to work for some and have no effect in others. Nobody has reported any side effects. It looks worth a try for Rett syndrome.  As a supplement it is not cheap, that is until you see what they charge for Daybue.