Therapeutic Strategies For Ataxia-Telangiectasia

Replace, Correct or Compensate for the Loss of the ATM Gene

Replacing, correcting, or compensating for the missing ATM protein represents the most direct and rational approach to treating A-T. Whether by delivering a functional copy of the gene, repairing the mutation, or enabling the body to bypass the defect and restore ATM activity, these strategies aim to address the root cause of the disease.

Examples

Use splice-switching antisense oligonucleotides to restore normal splicing patterns.
Use gene editing (with CRISPR, base editing, prime editing, Bridge editing, PRECISE editing, reprogrammed recombinases, etc.) to correct or bypass harmful mutations.
Use three separate adeno-associated viral vectors with split inteins to reconstitute the entire ATM protein post-translationally, delivering appropriate proportions of the three viral particles to each cell.
Replace the ATM gene using a non-viral delivery technology such as lipid nanoparticles, intra-cranial electroporation, polymer-based delivery, cell-penetrating peptides, exosomes and extracellular vesicles.
Instead of delivering DNA, use lipid nanoparticles to deliver ATM mRNA (either by intrathecal or intracerebroventricular injection, or by using nanoparticles engineered to cross the blood-brain barrier) to provide transient, functional ATM protein without genomic integration.
Use read-through compounds that enable ribosomes to bypass premature stop codons in mRNA (created by nonsense mutations) and then restore the production of full-length ATM protein, while overcoming challenges with read-through efficiency and preventing read-through of normal stop codons (which can be toxic) while assuring that the restored protein is properly folded and functional.
For patients with hypomorphic ATM mutations who express small amounts of residual ATM protein, or in combination with approaches that restore ATM expression:
- Enhance residual ATM function (pharmacologic chaperones or stabilizers for hypomorphic mutations)
- Modulate ATM regulatory proteins to alter expression or activity of proteins that activate or inhibit ATM, like TIP60 or the MRN complex
Target alternative DNA repair pathways by using drugs that boost ATR or DNA-PK to partially compensate for ATM deficiency.

Reduce Neuroinflammation

Neuroinflammation in A-T is not just a secondary byproduct of neurodegeneration. It is a primary, self-reinforcing pathology, driven by cytosolic DNA and innate immune activation, mitochondrial dysfunction and ROS, overactive microglia and toxic astrocytes, senescent cells secreting inflammatory factors and breakdown of immune tolerance and repair pathways. This creates a toxic CNS environment in which Purkinje neurons, already metabolically fragile, cannot survive. Targeting inflammation offers a promising route for mitigating A-T symptoms, possibly slowing or even halting cerebellar degeneration if timed early enough.

Examples

Target innate immune sensors with NLRP3 inflammasome inhibitors such as MCC950 or CVN392, modulating microglial activation to target inflammasome-driven IL-1β production implicated in neurodegeneration.
Activate the NRF2 pathway to boost antioxidant defenses, reduce oxidative stress and inflammation, and support mitochondrial health, via compounds like Skyclarys (omaveloxolone), dimethyl fumarate, sulforaphane, or bardoxolone.
Block necroptosis by inhibiting RIPK1/RIPK3/MLKL-mediated inflammatory cell death.
Prevent immune cell infiltration into the central nervous system, by targeting adhesion molecules or chemokine gradients using peripheral antibody therapeutics such as MITI001.
Block pro-inflammatory cytokines directly (e.g., IL-1β, IL-6, IL-8, TNF-α) using antibodies or receptor antagonists such as Anakinra (IL-1RA), tocilizumab (anti-IL-6R).
Inhibit the NF-κB pathway to reduce chronic inflammatory signaling in the brain and immune cells.
Use Rapamycin (also known as sirolimus), a potent inhibitor of mTOR, which is a central regulator of cell growth, metabolism, autophagy, and inflammation (which is often dysregulated in ATM deficient cells) as studies suggest that loss of ATM can lead to hyperactivation of mTOR, which contributes to neurodegeneration and oxidative stress. Inhibiting mTOR with rapamycin might counteract this hyperactivation, restoring some cellular homeostasis (although Rapamycin may not be safe for A-T children with immune deficiency).
Target the STING pathway using cGAS-STING inhibitors (e.g., with an experimental compound such as H-151), as ATM loss causes accumulation of cytosolic DNA and activates STING, and suppressing STING may reduce interferon-driven inflammation.
Treat A-T patients with corticosteroids such as Dexamethasone (e.g., EryDex) which have demonstrated some clinical benefit in A-T and are broadly anti-inflammatory, while confirming that long-term use will not have significant side effects.
Treat patients with non-steroidal anti-inflammatory drugs such as ibuprofen and naproxen which have general anti-inflammatory action but modest central nervous system penetration.
Target the JAK-STAT pathway with JAK inhibitors such as ruxolitinib or baricitinib to reduce cytokine signaling, as it may mitigate chronic immune activation in A-T.
Treat with anti-TNF therapies such as etanercept and adalimumab, as TNF-α is elevated in neuroinflammatory states and inhibition may protect neurons.
Treat with TLR4 antagonists such as TAK-242 to suppress innate immune activation driven by damage associated molecular patterns in ATM-deficient cells.
Treat with minocycline, an anti-inflammatory antibiotic with brain penetration and anti-apoptotic effects that suppresses microglial activation and reduces oxidative stress.
Because there is evidence of glutamate toxicity and abnormal neuronal firing occurring in other cerebellar diseases, treat with Riluzole, a glutamate modulator shown to reduce neuroinflammation and neurodegeneration (but probably only as a symptomatic therapy).
Treat with N-acetylcysteine, an antioxidant that reduces reactive oxygen species and indirectly reduces inflammation.
Treat with PPAR agonists such as Pioglitazone (PPARγ) and bezafibrate (PPARα/δ) which are broadly anti-inflammatory and improve mitochondrial function.
Treat with NAD+ boosters such as nicotinamide riboside (e.g., Niagen) to improve mitochondrial health and possibly reduce neuroinflammation.
Supplement patients with Omega-3 fatty acids, which are anti-inflammatory lipid mediators and modulate microglial activation.
Treat with cannabinoids such as cannabidiol or mixed THC/CBD, which have been shown to reduce neuroinflammation in multiple models.
Treat with purinergic receptor antagonists such as P2X7 blockers, because P2X7 is upregulated in activated microglia, and inhibition reduces IL-1β release.
Treat with CSF1R inhibitors such as PLX3397 to suppress activated microglia that contribute to neurotoxicity.
Enhance microglial phagocytosis and resolution with TREM2 agonists to promote neuroprotective microglial phenotypes.
Treat with colony stimulating factors (e.g., GM-CSF modulation) to balance microglial activation and repair processes.
Place patients on a ketogenic diet (or more potent ketone esters) to reduce oxidative stress and inflammation via metabolic reprogramming.
Treat with mitochondrial antioxidants such as MitoQ or SkQ1 to reduce mitochondrial ROS, which drive inflammatory signaling.
Use bone marrow transplants or hematopoietic stem cell transplants which have been shown to have benefit in immune correction and may have downstream effects that reduce neuroinflammation.
Target reactive astrocytes to inhibit or reprogram A1 neurotoxic astrocytes which are a damaging subtype of astrocytes that appear in response to inflammation and microglial activation.
Induce immune tolerance with tolerogenic vaccines or microbiome modulation to train/reprogram the immune system to tolerate certain antigens and reduce chronic activation.

Correct Mitochondrial Dysfunction

The ATM protein is as much a mitochondrial caretaker as it is a DNA-damage kinase. When ATM is missing or inactive, mitochondria leak electrons and over-produce ROS, accumulate because mitophagy stalls, remain hyper-fused, blocking quality segregation, and fail to launch new, healthy organelles under stress.Together, these defects create a feed-forward loop of oxidative stress, energy failure, and inflammation that likely underpins much of the neurodegeneration and metabolic fragility seen in A-T.

Examples

Treat patients with metabolic therapies like Dojolvi (heptanoate C7), a fatty acid under clinical investigation for A-T that may enhance mitochondrial signaling and function.
Use other drugs that address mitochondrial dysfunction by targeting oxidative phosphorylation or mitochondrial biogenesis.
Boost NAD⁺ levels (with precursors like nicotinamide riboside or NMN, or by using PARP inhibitors to restore metabolic balance and energy production).
Activate the mitochondrial unfolded protein response to improve mitochondrial proteostasis and resilience under cellular stress.
Enhance mitophagy using agents like rapamycin or AMPK activators to clear dysfunctional mitochondria.
Enhance mitochondrial resilience using mitochondrial transfer or novel activators of PGC-1α.
Because iron homeostasis is disrupted in A-T, use iron chelators to reduce labile iron pools and oxidative damage that are harmful to mitochondria.
Treat with N-Acetyl-L-Leucine, an amino acid.
Inhibit the long isoform of Tfap2c by blocking a motif so that WWOX can enter the nucleus even in the absence of ATM and improve the cellular response to oxidative stress.

Reduce Cellular Senescence

A growing body of evidence suggests that excessive cellular senescence contributes significantly to the progression of A-T. Without functional ATM protein, many cells enter a senescent state, where they stop dividing but continue releasing pro-inflammatory and tissue-damaging signals. These senescent cells accumulate over time, particularly in the brain, lungs, and immune system.

Examples

Address Mechanical Stress Problems

Emerging research suggests that cells lacking functional ATM protein are unusually sensitive to mechanical stress, forces and tension within tissues that arise from movement, growth, or changes in the cellular environment. The inability to respond properly to these physical stresses can lead to DNA damage, nuclear envelope rupture, and inflammatory signaling, particularly in tissues like the brain and lungs that experience constant mechanical strain. By targeting the pathways that sense or buffer mechanical stress, or by reinforcing cellular structures such as the nuclear membrane or cytoskeleton, it may be possible to reduce tissue damage, inflammation, and cell loss in A-T.

Examples

Address mechanical stress in cells due to stretching, compression, shear, or tension with drugs that support microtubules (like low-dose taxol), or Rho/ROCK pathway modulators that modulate actin contractility (and have been shown to protect neurons under stress), or by boosting lamin A/C function (a key protein in the nucleus that helps buffer mechanical strain), or by treating with molecules that promote cytoskeletal resilience or mechano-transduction stability (e.g., YAP/TAZ pathway modulators).

Modulate Brain Activity/Circuitry

While A-T is caused by the loss of the ATM protein, many of the symptoms that most impact quality of life, such as poor coordination, slurred speech, and involuntary movements, stem from disrupted communication within the brain’s motor control circuits, particularly in the cerebellum. As neurons degenerate or become dysregulated, the balance of excitation and inhibition in these circuits is altered, leading to abnormal signaling and impaired motor function. Modulating brain circuitry – either by dampening overactive pathways, enhancing compensatory ones, or rebalancing neurotransmission – offers a way to improve neurological symptoms without needing to correct the underlying genetic defect. This approach could provide meaningful functional gains for individuals with A-T.

Examples

Correct abnormal brain circuitry (through drugs that adjust activity in specific neuron subtypes).
Use neuromodulation techniques (deep brain stimulation, trans-cranial stimulation, focused ultrasound, or other methods). For example, using deep brain stimulation to target non-traditional nodes in motor circuits – such as cerebellar output pathways, the zona incerta, or pedunculopontine nucleus – rather than targeting more typical areas (e.g., the globus pallidus internus or ventral intermediate nucleus of the thalamus) could potentially address the ataxia experienced by all A-T patients instead of only the dystonia experienced by a small subset of A-T patients.
Develop a prosthetic or substitute cerebellum for A-T patients by recording cerebellar inputs and outputs continuously in healthy people on a massive scale using non-invasive, non-genetic techniques with broad spatial and temporal coverage, and then applying machine learning to decode the complex interactions among mossy fibers, climbing fibers, Purkinje cells, and deep cerebellar nuclei, while addressing challenges posed by non-linear circuit dynamics and synaptic plasticity.

Replace Neurons or Promote Survival with Growth Factors

The loss of the ATM protein leads to progressive neurodegeneration, particularly in the cerebellum, where critical neurons like Purkinje cells gradually die off. Because these neurons are essential for coordinating movement, strategies that promote their survival or replace them are compelling. Delivering neurotrophic factors, molecules that support neuron health and resilience, may slow or prevent neuronal death, while emerging cell-based therapies may replace lost neurons and restore circuit function. Together, these approaches offer a potential path to preserve or even regain motor control in individuals with A-T, addressing the neurodegenerative effects of the disease directly.

Examples

Address Immune, Lung and Cancer Issues

Beyond impacting the nervous system, A-T also causes serious problems in the immune system, lungs, and cancer susceptibility, which are all rooted in the loss of ATM’s role in DNA repair and cellular regulation. Many individuals with A-T experience recurrent infections due to weakened immunity, chronic lung disease from inflammation and impaired repair, and a sharply elevated risk of cancer due to genomic instability. Addressing these systemic issues – by strengthening immune function, protecting and repairing lung tissue, and reducing cancer risk through targeted surveillance or therapies – can significantly improve quality of life and survival for people with A-T, making them essential components of a comprehensive treatment strategy.

Examples

Improve immune function (immunoglobulin replacement, hematopoietic stem cell transplantation).
Modify cancer treatment protocols (to develop safer, more effective regimens tailored to ATM-deficient cells).
Enhance pulmonary care (innovative physiotherapy, anti-infectives, and respiratory support approaches).
Address gastrointestinal and nutritional deficits (e.g., proactive G-tube placement and tailored nutrition plans)
Explore microbiome modulation (use of prebiotics, probiotics, or microbial consortia to support immune and gut health)

Symptom Management, Vaccines and Mental Health

While efforts to develop disease-modifying treatments for A-T continue, managing day-to-day symptoms remains essential for improving the quality of life for those living with the condition. Supportive care can help individuals maintain function and independence, helping them live fuller, more supported lives.

Examples

Address tremors and other peripheral nervous system symptoms (using drugs or devices to manage motor symptoms and improve function).
Use speech, occupational, and physical therapies (integrated, proactive rehab strategies tailored to A-T progression).
Give intravenous immunoglobulin treatment, a sterile solution of concentrated antibodies (immunoglobulin G or IgG) extracted from pooled human plasma donated by thousands of healthy individuals, to provide passive immunity by supplying antibodies that A-T patients cannot produce in sufficient quantities.
Treat with prophylactic antibiotics.
Maintain pulmonary hygiene and airway clearance.
Provide nutritional support, including feeding tubes for severe swallowing issues.
Vaccinate with the influenza vaccine, pneumococcal vaccines (both PCV13 and PPSV23) and COVID-19 vaccines.
Offer mental health support (counseling and psychiatric care for patients and families dealing with stress, depression, and anxiety).

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Therapeutic Strategies For Ataxia-Telangiectasia

Replace, Correct or Compensate for the Loss of the ATM Gene

Reduce Neuroinflammation

Correct Mitochondrial Dysfunction

Reduce Cellular Senescence

Address Mechanical Stress Problems

Modulate Brain Activity/Circuitry

Replace Neurons or Promote Survival with Growth Factors

Address Immune, Lung and Cancer Issues

Symptom Management, Vaccines and Mental Health

Empowering Scientists and Clinicians

Research Grant Program

Patient Data for Researchers

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