The ANOVA ALS Stem Cell Secretome
Treatment Programme Germany

ALS, also known as motor neuron disease (MND) or Lou Gehrig's disease, progressively destroys the motor neurons that control voluntary movement. ANOVA IRM has been treating people with ALS since 2016 — before a manufacturing authorisation under Section 20c AMG became necessary — and today manufactures MSC secretome (MSEC) in its own facility under official authorisation and officially inspected good professional practice (GFP). GFP is the German counterpart of Good Tissue Practice (GTP) in the US. A registration with the US FDA is, on its own, no official confirmation that the rules are met. In Germany, by contrast, GFP is a condition of the official authorisation and is regularly inspected by the authorities. MSEC is cell-free: it contains the signalling molecules released by the patient's own mesenchymal stromal cells, not the cells themselves. It is administered intrathecally, by lumbar puncture into the cerebrospinal fluid. The programme is offered alongside — never instead of — guideline-based care such as riluzole; see current ALS treatment options.

Amyotrophic lateral sclerosis (ALS) is a progressive disease of the motor neurons — the nerve cells that carry movement signals from the brain and spinal cord to the muscles. As upper and lower motor neurons degenerate, muscles weaken and waste (atrophy), affecting mobility, speech, swallowing (dysphagia) and breathing. Early signs often include muscle twitching (fasciculations), weakness in a hand or foot, slurred speech (dysarthria) or cramps.

ALS usually begins in the arms or legs (limb-onset or spinal-onset ALS) or in the muscles for speech and swallowing (bulbar-onset ALS). It progresses at very different speeds; clinicians distinguish fast and slow progressors. About 90% of cases occur without a known family history (sporadic ALS, sALS); the remaining 10% are familial (familial ALS, fALS). Diagnosis rests on clinical examination, electromyography (EMG) and nerve conduction studies, with MRI to exclude other causes. To date no cure is known for amyotrophic lateral sclerosis or motor neuron disease.

Progression is often described with the King's staging system: stages 1 to 3 reflect how many body regions are affected, stage 4 the need for feeding support (gastrostomy) or breathing support.

Common symptoms include weakness in a hand, arm or leg, muscle wasting, cramps and twitching, stiffness, slurred speech, difficulty swallowing and shortness of breath.

More details can be found below in our scientific section on amyotrophic lateral sclerosis.

ANOVA offers autologous MSC secretome (MSEC) therapy for amyotrophic lateral sclerosis. The programme contains MSC secretome, TUDCA, senolytic therapy, gut microbiome analysis and, where appropriate, HAL robotic exoskeleton training. Each component is selected individually; the programme is not a fixed package.

Stem cells are thought to act mainly through soluble factors, together called the secretome, which includes exosomes and many other factors. In ALS and MND, the loss of motor neurons is accompanied by inflammation in their immediate surroundings, driven by supporting cells such as microglia and astrocytes. MSEC is given intrathecally, so the spinal cord and the nerve roots are the structures it reaches best, and it is intended to influence that environment rather than to replace motor neurons.

The signalling molecules released by the patient's own mesenchymal stromal cells, given intrathecally into the cerebrospinal fluid. Laboratory and animal studies suggest they may dampen inflammation and help nerve cells survive. Small external early clinical studies (phase 1/2) with related MSC products given intrathecally mainly examined safety; MSEC itself has not yet been tested in a clinical trial in ALS.

A naturally occurring bile acid under investigation for possible neuroprotective effects; the evidence and why we still use it are set out in the clinical and scientific section below. It is prescribed individually as a pharmacy-compounded preparation (Rezepturarzneimittel) and is not an approved ALS treatment.

Intended to reduce senescent (biologically aged) cells, which release inflammatory signalling molecules. Evidence in ALS so far comes only from laboratory and animal studies; a small external phase 1 study in Alzheimer's disease examined safety. No senolytic compound is approved for ALS, and we do not name individual substances on this website.

Analysis of the gut–brain axis, with personalised dietary or probiotic advice where clinically indicated. External observational studies have found differences in the gut microbiome of people with ALS; that changing it influences the disease has not been proven by clinical studies.

A robotic leg exoskeleton driven by the patient's own residual muscle signals. In an external randomised controlled crossover trial in slowly progressive neuromuscular diseases, including ALS, it improved walking distance; a small external ALS study showed improved step frequency. An optional adjunct, not a substitute for the components above.

Of the 86 people treated at ANOVA IRM for ALS or MND with MSEC at that time, 69 had enough follow-up data to analyse. In this group, functional decline on the ALSFRS-R was on average about 30% slower than reference rates reported for no treatment, and about 23% slower than reference rates reported for riluzole. This is an early signal, not proof: the finding is not statistically significant, there is no control group, and our patients may not be a typical group.

The full analysis, including every limitation, is in our ALS real-world data report.

Which tests are used to diagnose ALS or MND?

The diagnosis rests on clinical examination, electromyography (EMG) and nerve conduction studies. MRI of brain and spinal cord, with contrast where needed, serves mainly to exclude other causes, and the El Escorial and Gold Coast criteria structure the assessment. Function is tracked with the ALSFRS-R and breathing with forced vital capacity (FVC); genetic testing and neurofilament light chain (NfL) may be added.

What do we review before ALS or MND treatment at ANOVA IRM?

Before any treatment decision we review your neurological findings, your ALSFRS-R score and your respiratory function. We also assess whether you are fit for the brief sedation required for tissue collection. Where relevant we add genetic testing and gut microbiome analysis.

• Standard: an MRI of the abdominal wall to exclude a hernia is required before the liposuction, taken no more than four weeks beforehand. It can be done at home or at ANOVA IRM.
• Optional: CT guidance for the intrathecal application at ANOVA IRM, used while the dose is given.
• Optional: further MRI scans, with or without contrast, where your ALS or MND situation calls for them — for example to reassess the spine before an application or to follow up another finding.

Imaging can be carried out in-house. The full diagnostic pathway is described on our diagnostics page.

ANOVA IRM has manufactured MSEC under German regulatory authorisation and official inspection since 2018 and has treated more than 86 people with ALS (September 2026). Why an autologous tissue preparation used only for our own patients requires no marketing authorisation is set out on our regulatory status page.

Initial evaluation can begin remotely, by phone or video, without travel to Germany. Treatment itself requires an in-person visit to Offenbach am Main, less than 20 minutes from Frankfurt Airport. You receive an individual written cost estimate before any treatment decision.

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MSEC treatment for ALS at ANOVA IRM costs approximately €20,000–€36,000, depending on the number of doses used. It requires a two-day outpatient visit to Offenbach, Germany, for tissue collection, followed by further visits for the applications according to your individual treatment plan. It is available to people with early-to-mid stage ALS who can breathe unassisted.

1. 01
   Initial evaluation

   Remote, by phone or video — typically 2 weeks to a few months

2. 02
   Preliminary screening

   In your home country, to avoid an unnecessary journey

3. 03
   First visit — bloodwork and tissue collection

   Two-day outpatient visit to Offenbach: bloodwork first, then — if the results are in order — mini-liposuction under brief sedation

4. 04
   Production and quality control

   Approximately 4 weeks; yields 10 doses per production cycle

5. 05
   Storage

   Up to 2 years, allowing an extended personalised schedule

6. 06
   Application schedule

   Set individually: two doses at the start, then one dose every 4–6 weeks, or two doses every 3 months

We treat people in the early to mid stage of ALS who can breathe unassisted and are medically fit for the brief sedation required to collect fat tissue. We treat both fast and slow progressors. Every treatment recommendation follows a full clinical evaluation: medical history, neurological status, ALSFRS-R, respiratory function and, where relevant, genetic or microbiome testing.

What are the contraindications for ALS or MND treatment?

Our treatments are experimental. We treat only people for whom, after medical assessment, we consider the benefit-risk balance to support treatment.

Applies to all ANOVA treatments:

• Active cancer within the last two years
• Under the age of legal majority
• Pregnancy or breastfeeding
• Active infectious disease (hepatitis A, B, C, HIV, syphilis or other)

Specific to ALS:

• Unable to breathe unaided, or requiring a ventilator
• Difficulty breathing in the supine position
• Dysphagia (severe difficulty swallowing)
• Psychiatric disorder that would prevent informed consent or cooperation

What screening is needed before you travel for ALS or MND treatment?

Before you travel, a preliminary screening in your home country — usually a blood test for medical or infectious-disease factors that would prevent treatment — helps you avoid an unnecessary journey.

What happens at your first ALS or MND visit to Offenbach, Germany?

The first treatment visit takes about two days in Offenbach, on an outpatient basis. It begins with bloodwork at ANOVA IRM; if the results are in order, a small amount of abdominal fat tissue is collected by mini-liposuction under brief sedation. From this point to the first secretome application is usually four to six weeks.

How is your MSEC for ALS or MND produced and quality-controlled?

Mesenchymal stromal cells are isolated from the collected tissue and expanded under controlled conditions in our own facility in Offenbach, under official authorisation and officially inspected good professional practice (GFP). These cells are then used to produce your MSEC preparation — the signalling molecules they release, not the living cells. Production and quality control take approximately four weeks and yield 10 doses per production cycle. Each patient batch is tested with methods validated according to the European Pharmacopoeia (Ph. Eur.) and GMP, and released under a documented procedure; the released secretome is stored at −80 °C and keeps for up to two years.

How often is MSEC applied in ALS or MND?

Because ALS is a chronic, progressive disease for which there is currently no cure, we recommend a longer-term treatment using all 10 doses produced rather than a single application; see the timeline above.

The schedule is set individually for each patient, for example:

• At the start: two intrathecal doses.
• If you live close by: a single MSEC dose every 4 to 6 weeks.
• If you live further away: a double dose every 3 months — about five visits over 15 months for the 10 doses produced.
• Standard route for ALS: intrathecal, by lumbar puncture into the cerebrospinal fluid. This is intended to bring the secretome closer to the spinal cord and brain than an infusion into the bloodstream, which would have to cross the blood–brain barrier.
• Individual alternative: intravenous, if you specifically wish it or if systemic treatment is medically necessary.

Intrathecal applications are standard procedures when performed by experienced physicians; where the anatomy requires it, ANOVA IRM uses CT guidance from its in-house radiology. The benefit-risk assessment of intrathecal administration is set out on a separate page.

MSEC treatment for ALS costs approximately €20,000 to €36,000 and is billed according to the German Medical Fee Schedule (GOÄ). The base package — the mini-liposuction and the first three MSEC doses — costs approximately €20,000; each further dose is charged separately at approximately €2,250 to €2,350 depending on the application route. Because we recommend using all 10 doses over a longer period for a chronic, progressive disease such as ALS, most treatment plans end up at the upper end of this range. The total also depends on additional examinations and your sedation or anaesthesia preferences. You receive an individual written estimate before any treatment decision. Travel, accommodation and other personal expenses are separate. Experimental ALS treatment is generally self-funded; you can still ask your insurer about possible reimbursement. All prices are subject to change.

Because ALS is a chronic, progressive disease, a double liposuction can be recommended: it yields 20 doses, which can be used over the current shelf life of two years from a single collection. The cost is correspondingly higher and is shown in your individual estimate.

Why does the cost of ALS or MND treatment vary with the application route?

All treatments at ANOVA IRM are billed according to the German Medical Fee Schedule (Gebührenordnung für Ärzte, GOÄ); within it, the cost varies mainly with the route of application. For ALS we mainly administer MSEC intrathecally, because in our assessment it is most likely to act there: the cerebrospinal fluid is a small, closed compartment in direct contact with the spinal cord and brain. We use intravenous administration only if you specifically wish it or if systemic treatment is medically necessary. The exact cost of your treatment plan is set out in your individual written cost estimate.

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ALS is now widely regarded as a complex disorder involving multiple interacting pathways rather than a single mechanism.^[29] Onset is limb (spinal) or bulbar, and the rate of progression differs widely between fast and slow progressors.^[30] Diagnosis follows criteria such as El Escorial and Gold Coast. Function is measured on the ALSFRS-R and respiratory function on forced vital capacity (FVC); neurofilament light chain (NfL) is used as a biomarker of neuronal damage.^[30]

What causes ALS, and what are the risk factors?

The cause is not known in most cases. ALS is understood as a complex disorder in which genetic predisposition and environmental factors interact. What triggers the disease and what drives its progression are two different questions; the next section deals with progression.^{[28],[29],[30]}

• Age: onset is most common between 55 and 75 years.
• Sex: men are affected somewhat more often than women, and the difference narrows with age.
• Family history: about 10% of cases are familial, with variants in genes such as SOD1, C9orf72, TARDBP and FUS.^[29]
• Genetic variants without family history: the same variants are also found in some people with no affected relatives.
• Discussed, not established: smoking, military service, intense physical activity and certain occupational exposures have been discussed as risk factors; the evidence is mixed.^[30]

What drives the progression of ALS or MND?

The cause of ALS is unknown, and the drivers of progression are a separate question. Motor neurons are thought to be where the disease begins, while the cells around them — microglia and astrocytes — shape how fast it advances. They maintain a local inflammatory response and release mediators that add to the damage.^[17],[18]

Further processes contribute: oxidative stress, mitochondrial dysfunction, impaired protein homeostasis and disturbed energy metabolism.^{[20],[23],[29]} This is where our programme aims — at the course of the disease, not at its cause, and not at a cure.

Riluzole can modestly prolong survival, with benefit varying between individuals, and may cause gastrointestinal symptoms and elevated liver enzymes.^{[1],[2],[3],[4],[5]} Edaravone is approved in several countries for selected patients.^[6] Tofersen is approved for patients with a SOD1 mutation.^[7] Sodium phenylbutyrate with taurursodiol showed a benefit in an external phase 2 trial that was not confirmed in the external phase 3 trial; the product has since been withdrawn.^[12],[13] Multidisciplinary supportive care remains essential throughout: physiotherapy, occupational therapy, speech and language therapy, nutritional support including PEG feeding where needed, and respiratory support such as non-invasive ventilation (NIV) and cough assistance.^[30] The ANOVA programme is offered alongside these therapies, not in place of them.

How is ALS or MND diagnosed, and what do we not do ourselves?

The diagnosis of ALS or MND is made by neurologists, not by us. The standard work-up includes clinical examination, electromyography (EMG) and nerve conduction studies, MRI of brain and spinal cord to exclude other causes, blood tests, sometimes examination of the cerebrospinal fluid, and genetic testing where indicated. Assessment follows the El Escorial and Gold Coast criteria, and progression is tracked with the ALSFRS-R and lung function.

What we do ourselves is imaging: MRI with or without contrast, and CT guidance for an intrathecal application. This is carried out at the Institut für Bildgebende Diagnostik in the same building, which also belongs to Dr. Stehling. We do not perform EMG, nerve conduction studies or the neurological diagnosis itself; please bring these findings from your neurologist.

MSC secretome (MSEC)

MSEC uses the signalling molecules released by mesenchymal stromal cells — growth factors, cytokines, extracellular vesicles — rather than living cells.^[10],[11] Small external phase 1 and phase 1/2 studies with related MSC products given intrathecally mainly examined safety and reported acceptable tolerability.^[8],[9] External phase 3 trials with two such cell products (NurOwn, NeuroNata-R) did not meet their primary endpoints in the full study population.^[34] MSEC itself has not yet been tested in a clinical trial in ALS; our own real-world data are set out in section 4.

What is the efficacy hypothesis behind MSC secretome in ALS and MND?

ALS is regarded as a non-cell-autonomous disease: the onset is thought to lie in the motor neurons, while supporting cells drive the progression. Activated microglia and astrocytes maintain a local inflammatory response, migrate to the site of injury and release inflammatory mediators.^[17]

In the SOD1-G93A mouse model, removing three factors released by microglia — IL-1α, TNFα and C1q — markedly extended survival, which identifies the microglia-to-astrocyte axis as a strong driver of progression.^[18] Astrocytes also carry the main glutamate transporter EAAT2, and its loss alone causes severe motor neuron damage.^[17]

The hypothesis behind MSEC is that its soluble factors influence this environment rather than the motor neuron itself. Two limitations belong with it: anti-inflammatory approaches have so far had only modest effects in ALS, and the cause of the disease remains unknown. Our aim is to slow progression, not to cure the disease.

TUDCA

A bile acid studied for possible effects on mitochondrial function, endoplasmic reticulum stress and apoptosis.^{[12],[14],[15]} In the external phase 3 trial TUDCA-ALS, TUDCA added to riluzole showed no benefit over placebo after 18 months; the results were reported in 2024.^[16] TUDCA is not an approved ALS treatment.

Why do we still use TUDCA? Talk to us about it.

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Gut microbiome

External observational studies report differences in gut microbiome composition between people with ALS and healthy individuals; that changing the microbiome influences ALS has not been proven by clinical studies.^[19]–[23]

Cellular senescence and senolytics

Senescent cells stop dividing but continue releasing inflammatory signalling molecules.^[25],[26] In animal models, senolytic compounds have reduced the number of senescent cells; a small external phase 1 study in Alzheimer's disease examined safety.^[24] In an ALS mouse model, removing senescent cells with engineered immune cells did not improve motor function or survival.^[27] No senolytic compound is approved for ALS, and we do not name individual substances on this website.

HAL robotic exoskeleton training

An external multicentre randomised controlled crossover trial across nine Japanese hospitals found that cybernic treatment with HAL significantly improved ambulatory function in patients with slowly progressive rare neuromuscular diseases.^[31] In a small external ALS study, a full course of HAL training significantly improved gait cadence on the 10-metre walk test, although gait speed and step length were not significantly affected.^[32] A small external study in limb-girdle muscular dystrophy found HAL-supported treadmill training safe and feasible.^[33]

Talk to us about current changes or additions to the programme. For a number of conditions ANOVA IRM also offers infusion therapies alongside the components described above.

In 2026 we had treated 86 people with a diagnosis of ALS or MND with MSEC since 2016 and tracked functional ability on the ALSFRS-R. Of these, 69 had enough follow-up data; these were analysed. In this group, decline was on average about 30% slower than published reference rates for no treatment and about 23% slower than published rates for riluzole.

What this does not yet tell us

• It is not statistically significant. With this number of patients we cannot rule out chance.
• There is no control group. We compare our patients with published rates from other studies, not with a matched untreated group.
• Our patients may not be a typical group. People who return for repeated treatments over months or years tend to be doing relatively well.
• ALS varies enormously between people, which makes small studies hard to interpret.

How this compares with riluzole

Riluzole's approval and status as standard of care rest on large controlled trials and real-world data showing a statistically significant survival benefit, together with decades of safety experience.^[1],[4] Its evidence base is substantially stronger than what we have for MSEC today. We say this plainly rather than imply the two are on equal footing.

What comes next

As a private treatment centre we are not in a position to sponsor a randomised clinical trial. We continue to treat individually, collect data on everyone we treat, and evaluate that data against the growing published literature, including its limitations.

MSEC is an autologous tissue preparation. ANOVA IRM manufactures it under a procurement authorisation (Section 20b AMG) and a manufacturing authorisation under Section 20c AMG, issued and regularly inspected by the Hessian State Office for Health and Care (HLfGP). The individual treatment attempt (individueller Heilversuch) concerns the administration only and follows full disclosure and informed consent; because the product is used only for ANOVA IRM's own patients, no authorisation under Section 4b, no marketing authorisation under Section 21 and no approval under Section 21a AMG is required. The full derivation is on our regulatory status page.

Questions people usually ask next. Each is answered in full on its own page.

• Who are we?
• Is ANOVA legal?
• Is stem cell therapy safe?
• What is MSC secretome (MSEC)?
• What is BMC (Bone Marrow Concentrate)?
• What are stem cells?
• What should I ask when looking for a stem cell treatment?
• Which conditions do we treat?
• Benefit-risk assessment of intrathecal administration
• Does the secretome pass the blood–brain barrier?
• HAL robotic exoskeleton training
• ALS treatment options — standard and emerging
• ALS real-world data report

Request a Consultation →

ANOVA IRM shares its premises in Offenbach with two further institutions owned by Dr. Stehling: the Institut für Bildgebende Diagnostik (IBDO), providing MRI and CT imaging, and the Vitus Prostate Center. Because imaging is carried out in the same building, condition-specific diagnostics — including CT-guided procedures — can be performed in-house rather than referred elsewhere. See diagnostics at ANOVA IRM.

Current standard therapy for ALS

• [1] Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. N Engl J Med. 1994;330(9):585–591. doi:10.1056/NEJM199403033300901. PMID: 8302340.
• [2] Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev. 2012;(3):CD001447.
• [3] Fang T, Al Khleifat A, Meurgey JH, et al. Stage at which riluzole treatment prolongs survival in patients with amyotrophic lateral sclerosis: a retrospective analysis of data from a dose-ranging study. Lancet Neurol. 2018;17(5):416–422. doi:10.1016/S1474-4422(18)30054-1. PMID: 29525492.
• [4] Andrews JA, Jackson CE, Heiman-Patterson TD, et al. Real-world evidence of riluzole effectiveness in treating amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2020;21(7-8):509–518. doi:10.1080/21678421.2020.1771734. PMID: 32573277.
• [5] Thakore NJ, Lapin BR, Mitsumoto H; PRO-ACT Consortium. Early initiation of riluzole may improve absolute survival in amyotrophic lateral sclerosis. Muscle Nerve. 2022;66(6):702–708. doi:10.1002/mus.27724. PMID: 36117390.
• [6] Writing Group; Edaravone (MCI-186) ALS 19 Study Group. Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2017;16(7):505–512. doi:10.1016/S1474-4422(17)30115-1. PMID: 28522181.
• [7] Miller TM, Cudkowicz ME, Genge A, et al. Trial of antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med. 2022;387(12):1099–1110. doi:10.1056/NEJMoa2204705. PMID: 36129998.

Mesenchymal stromal cells and regenerative medicine

• [8] Oh KW, Moon C, Kim HY, et al. Phase I trial of repeated intrathecal autologous bone marrow-derived mesenchymal stromal cells in amyotrophic lateral sclerosis. Stem Cells Transl Med. 2015;4(6):590–597. doi:10.5966/sctm.2014-0212. PMID: 25934946.
• [9] Petrou P, Gothelf Y, Argov Z, et al. Safety and clinical effects of mesenchymal stem cells secreting neurotrophic factor transplantation in patients with amyotrophic lateral sclerosis: results of phase 1/2 and 2a clinical trials. JAMA Neurol. 2016;73(3):337–344. doi:10.1001/jamaneurol.2015.4321. PMID: 26751635.
• [10] Gugliandolo A, Bramanti P, Mazzon E. Mesenchymal stem cells: a potential therapeutic approach for amyotrophic lateral sclerosis? Stem Cells Int. 2019;2019:3675627. doi:10.1155/2019/3675627. PMCID: PMC6431432.
• [11] Deng S, et al. Cell-based regenerative and rejuvenation strategies for treating neurodegenerative diseases. Stem Cell Res Ther. 2025;16:167. PMID: 40189500.

TUDCA and neuroprotection

• [12] Paganoni S, Macklin EA, Hendrix S, et al. Trial of sodium phenylbutyrate–taurursodiol for amyotrophic lateral sclerosis (CENTAUR, phase 2). N Engl J Med. 2020;383(10):919–930. doi:10.1056/NEJMoa1916945. PMID: 32877582.
• [13] PHOENIX trial of sodium phenylbutyrate–taurursodiol in ALS (ClinicalTrials.gov NCT05021536). Topline results, March 2024: primary endpoint not met, no significant difference in secondary endpoints; the product was subsequently withdrawn from the market. Manufacturer announcement; no peer-reviewed full publication as of September 2026.
• [14] Albanese A, et al. Tauroursodeoxycholic acid in patients with amyotrophic lateral sclerosis: the TUDCA-ALS trial protocol. Front Neurol. 2022;13:1009113. PMID: 36237618.
• [15] Lombardo FL, Spila Alegiani S, Mayer F, et al. A randomized double-blind clinical trial on safety and efficacy of tauroursodeoxycholic acid (TUDCA) as add-on treatment in patients affected by amyotrophic lateral sclerosis (ALS): the statistical analysis plan of TUDCA-ALS trial. Trials. 2023;24:792. doi:10.1186/s13063-023-07638-w.
• [16] TUDCA-ALS trial (ClinicalTrials.gov NCT03800524). Topline results, March 2024: the phase 3 trial did not meet its primary endpoint (ALSFRS-R slope after 18 months); no differences were seen in secondary endpoints including survival. Announcement by the TUDCA-ALS consortium; no peer-reviewed publication of the results was available as of September 2026.

Glia and non-cell-autonomous mechanisms

• [17] Lee J, Hyeon SJ, Im H, et al. Astrocytes and microglia as non-cell-autonomous players in the pathogenesis of ALS. Exp Neurobiol. 2016;25(5):233–240. doi:10.5607/en.2016.25.5.233. PMID: 27790057.
• [18] Guttenplan KA, Weigel MK, Adler DI, et al. Knockout of reactive astrocyte activating factors slows disease progression in an ALS mouse model. Nat Commun. 2020;11:3753. doi:10.1038/s41467-020-17514-9. PMID: 32719333.

Gut–brain axis and the ALS microbiome

• [19] Cryan JF, O'Riordan KJ, Cowan CSM, et al. The microbiota-gut-brain axis. Physiol Rev. 2019;99(4):1877–2013. doi:10.1152/physrev.00018.2018. PMID: 31460832.
• [20] Cryan JF, O'Riordan KJ, Sandhu K, Peterson V, Dinan TG. The gut microbiome in neurological disorders. Lancet Neurol. 2020;19(2):179–194. doi:10.1016/S1474-4422(19)30356-4. PMID: 31753762.
• [21] Dandamudi BJ, Dimaano KAM, Shah N, et al. Neurodegenerative disorders and the gut-microbiome-brain axis: a literature review. Cureus. 2024;16(10):e72427. doi:10.7759/cureus.72427.
• [22] Liu X, Liu Y, Liu J, et al. Correlation between the gut microbiome and neurodegenerative diseases: a review of metagenomics evidence. Neural Regen Res. 2024;19(4):833–845. doi:10.4103/1673-5374.382223. PMID: 37843219.
• [23] Yang EJ. The emerging role of the brain–gut axis in amyotrophic lateral sclerosis: pathogenesis, mechanisms, and therapeutic perspectives. Int J Mol Sci. 2025;26(17):8419. doi:10.3390/ijms26178419. PMID: 40943341.

Cellular senescence and healthy ageing

• [24] Gonzales MM, Garbarino VR, Kautz TF, et al. Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial. Nat Med. 2023;29(10):2481–2488. doi:10.1038/s41591-023-02543-w. PMID: 37679434.
• [25] Tan X, Gao N. The emerging role of cellular senescence in amyotrophic lateral sclerosis. Front Neurosci. 2025;19:1599492. doi:10.3389/fnins.2025.1599492.
• [26] Tsang VSK, Malaspina A, Henson SM. The metabolic intersection between immunosenescence and neuroinflammation in amyotrophic lateral sclerosis. J Inflamm (Lond). 2025;22:36. doi:10.1186/s12950-025-00460-y. PMID: 40866928.
• [27] Fang L, Bai Z, Yang D, et al. Elimination of senescent cells fails to attenuate disease progression in an ALS mouse model. Neurol Sci. 2026;47:411. doi:10.1007/s10072-026-09023-2.

Translational medicine and ALS genetics

• [28] Bedlack R, Li X, Evangelista BA, et al. The scientific and therapeutic rationale for off-label treatments in amyotrophic lateral sclerosis. Ann Neurol. 2025;97(1):15–27. doi:10.1002/ana.27126. PMID: 39503319.
• [29] Mejzini R, Flynn LL, Pitout IL, et al. ALS genetics, mechanisms, and therapeutics: where are we now? Front Neurosci. 2019;13:1310. doi:10.3389/fnins.2019.01310. PMID: 31866818.
• [30] van Es MA, Hardiman O, Chio A, et al. Amyotrophic lateral sclerosis. Lancet. 2017;390(10107):2084–2098. doi:10.1016/S0140-6736(17)31287-4. PMID: 28552366.

HAL robotic exoskeleton training

• [31] Nakajima T, Sankai Y, Takata S, et al. Cybernic treatment with wearable cyborg Hybrid Assistive Limb (HAL) improves ambulatory function in patients with slowly progressive rare neuromuscular diseases: a multicentre, randomised, controlled crossover trial for efficacy and safety (NCY-3001). Orphanet J Rare Dis. 2021;16(1):304. PMID: 34233722.
• [32] Morioka H, Hirayama T, Sugisawa T, et al. Robot-assisted training using hybrid assistive limb ameliorates gait ability in patients with amyotrophic lateral sclerosis. J Clin Neurosci. 2022;99:158–163. PMID: 35279589.
• [33] Sczesny-Kaiser M, Kowalewski R, Schildhauer TA, et al. Treadmill training with HAL exoskeleton — a novel approach for symptomatic therapy in patients with limb-girdle muscular dystrophy — preliminary study. Front Neurosci. 2017;11:449. PMID: 28848377.

Mesenchymal stromal cell products — phase 3

• [34] Cudkowicz ME, Lindborg SR, Goyal NA, et al. A randomized placebo-controlled phase 3 study of mesenchymal stem cells induced to secrete high levels of neurotrophic factors in amyotrophic lateral sclerosis (NurOwn). Muscle Nerve. 2022;65(3):291–302. doi:10.1002/mus.27472. PMID: 34890069.
• [35] Nam JY, Chun S, Lee TY, et al. Long-term survival benefits of intrathecal autologous bone marrow-derived mesenchymal stem cells (Neuronata-R®: lenzumestrocel) treatment in ALS: propensity-score-matched control, surveillance study. Front Aging Neurosci. 2023;15:1148444. doi:10.3389/fnagi.2023.1148444. PMID: 37122380 (manufacturer-affiliated study with an external control group from the PRO-ACT database; conditional approval by the Korean MFDS in 2013).
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General MSC, extracellular vesicle and secretome literature is maintained on the MSC secretome page; bone marrow literature on the BMC page.