Tau-Targeted Therapeutic Strategies: Mechanistic Targets, Clinical Pipelines, and Analysis of Failures

Tau protein is encoded by the MAPT gene on chromosome 17q21.31 [12]. As a member of the MT-associated protein family, tau is primarily expressed in neurons, where it stabilises and regulates axonal MTs [37]. It is transcribed as a single pre-mRNA and processed by alternative splicing to yield six major isoforms by the presence or absence of N-terminal inserts and the number of MT-binding repeats in the C-terminus [38]. Specifically, exons 2 and 3 encode N-terminal inserts generating 0N, 1N, and 2N variants, while exon 10 inclusion produces 4 MT-binding-repeat (4R) isoforms and its exclusion generates three-repeat (3R) isoforms [39,40]. Tau’s primary physiological function is stabilising and promoting the assembly of axonal MTs [41], thereby supporting neuronal morphology, axonal transport and cytoskeletal integrity [42]. Isoform context frames epitope availability even under physiological conditions. 4R isoforms show higher MT affinity and dwell time on the lattice than 3R species, while N-terminal inserts modulate interfilament spacing and protein–protein interactions [43,44]. These intrinsic differences influence which repeat-domain epitopes are solvent-exposed and help explain region-specific vulnerability. This physiological baseline becomes clinically actionable once isoform ratios shift in disease, because epitope choice for antibodies and vaccines and splice-modulating strategies for antisense oligonucleotides (ASOs) can be aligned to the predominant isoform pool [39,45,46,47]. Besides cytoskeletal support, tau regulates cargo transport, recruits signalling molecules, and modulates translation by binding ribosomes and repressing protein synthesis, particularly in synaptic contexts where plasticity depends on local translation [48,49,50]. Studies implicated tau in the regulation of long-term memory, habituation, sleep–wake cycles, and synaptic plasticity via effects on long-term potentiation/depression (LTP/LTD) [51,52,53,54].

In addition to its MT-stabilising role, tau exhibits diverse cellular functions that extend its regulatory influence. Tau regulates motor protein dynamics by forming concentrated microdomains along axonal MTs, thereby differentially affecting kinesin and dynein mobility, enabling precise spatial control and cargo delivery [55]. Besides the cytoskeleton, tau also participates in synaptic plasticity and neuronal communication by regulating dendritic spine density and synaptic strength mechanisms. For instance, tau deficiency impairs LTP and dendritic spine density, highlighting its essential role in cognitive performance [56,57]. Furthermore, tau supports neurogenesis and neuronal maturation, as evidenced by its involvement in dendritic development and granule cell migration [58]. Tau also performs protective nuclear functions, safeguarding genomic integrity under stress conditions and preventing chromosomal instability by maintaining pericentromeric heterochromatin organisation [59,60]. In addition, tau is involved in regulating iron homeostasis and mitochondrial transport, which contributes to cellular metabolism and oxidative balance [61,62,63].

Genetic studies using tau-deficient mice have revealed the complexity of tau’s physiological roles. Although tau knockout mice develop without severe mental defects due to other tubulin compensations, tau deficiency results in hyperactivity, reduced LTP, altered fear-conditioning behaviour, disrupted sleep patterns with increased wakefulness and reduced non-rapid eye movement sleep, anxiety-related behaviour, muscle weakness, impaired peripheral glucose metabolism, and pancreatic function [64,65,66,67]. These phenotypes demonstrate that tau participates in neural and behavioural regulation physiologically.

In disease, isoform and conformer heterogeneity are amplified. AD features mixed 3R/4R filaments, whereas progressive supranuclear palsy (PSP)/corticobasal degeneration (CBD) are 4R-dominant and Pick’s disease is 3R-predominant [68]. Conformer differences map onto seeding kinetics and regional spread, such that antibodies raised to N-terminal linear epitopes may fail to bind aggregation-competent cores, whereas microtubule-binding region (MTBR)-directed epitopes remain accessible across seeds [69]. Therapeutically, isoform composition and fold-specific exposure act as gatekeepers for epitope targeting.

In AD, tau accrues several abnormal PTMs, including hyperphosphorylation, acetylation, and ubiquitination, which weaken MT-binding, mislocalize tau to dendrites and synapses, and prime NFT assembly. Given the central role of hyperphosphorylation in tau pathology, considerable effort has been directed toward targeting tau phosphorylation as a therapeutic strategy. Several approaches aim to inhibit the kinases responsible for pathological phosphorylation or enhance the activity of tau phosphatases. Suppressing pathological phosphorylation by inhibiting kinases or activating phosphatases is a major strategy. Among kinase inhibitors, GSK-3β and CDK5 remain the most explored nodes. The GSK-3β inhibitor tideglusib reduced phosphorylated tau in a mouse model but failed to deliver clinical benefit in randomised phase II AD trials, highlighting target engagement and time-window limitations [125,126]. In contrast, inhibition of Fyn/Src proteins with saracatinib (AZD0530) achieved ample brain penetration and biomarker-target engagement but did not translate into clinical efficacy, suggesting that upstream synaptic signaling modulation alone may be insufficient [127]. Similarly, p38α MAPK inhibitors, such as Neflamapimod, demonstrated encouraging biomarker changes in exploratory studies but failed to demonstrate significant cognitive benefits [128]. These findings, taken together, suggest that while distinct kinase nodes regulate tau phosphorylation, their effects are limited in distinct ways: tideglusib is limited by disease stage sensitivity, saracatinib by downstream redundancy, and p38α inhibition by incomplete mechanistic selectivity. On the phosphatase side, PP2A can be pharmacologically active. Sodium selenate increases PP2A activity and dephosphorylates tau. It also improved cognition in preclinical AD models [129].

Another strategy associated with reducing phosphorylation is to regulate tau O-glycosylation. Because O-GlcNAcylation on Ser and Thr sites antagonises phosphorylation, O-GlcNAcase (OGA) inhibitors elevate tau O-GlcNAc to dampen multisite hyperphosphorylation and fibrillization. Multiple brain-penetrant OGAs entered the clinic. Ceperognastat illustrates central target engagement and robust OGA occupancy, but failed its phase II primary endpoint in early AD [130]. ASN90 advanced toward phase II [131]; BIIB113 completed phase I but was discontinued in 2025 [132]. The emergence of LY-3372689 demonstrates Lilly’s aggressive attempts to study tau-targeted drugs, especially OGA inhibitors. This mechanism remains compelling, warranting further clinical evaluation. Overall, the mechanism remains compelling, but duration, dose and stage selection likely determine clinical trials’ success.

Another strategy is to correct the acetylation axis. Small-molecule p300 inhibitors such as salsalate reduced ac-Lys174 and total tau in vivo [133]. Conversely, site-specific acetylation within KXGS motifs is perhaps protective, underscoring site-dependence and the need for selective HDAC pathway [134]. Beyond enzymes, Selenoprotein W was shown to promote tau ubiquitination and inhibit Lys281 acetylation, thereby restoring UPS-dependent clearance [135]. Overall, the balance among kinase, phosphatase, and O-GlcNAc governs the initiation of tau expression level, while acetylation–ubiquitination crosstalk regulates its stability and clearance level. These key steps can all be used as drug design targets.

Aggregation is initiated when post-translational and environmental cues expose the β-sheet–forming hexapeptides PHF6 (VQIVYK) and PHF6* (VQIINK) in the repeat domain, creating nuclei that template cross-β assembly. Tau is further concentrated into condensates that mature into oligomers, which form protofibrils that become paired helical filaments [88]. Based on different mechanisms, inhibitors are divided into four types: phenothiazine derivatives, natural polyphenols, peptide-based inhibitors, and metal chelators. Among small-molecule inhibitors, phenothiazine derivatives have been extensively studied for their ability to prevent tau aggregation. Phenothiazines bind aggregation-prone interfaces within the repeat domain to disrupt inter-strand hydrogen bonding, thereby destabilising fibrils and slowing elongation. These compounds, particularly methylene blue and TRx0237, both intercalate at cross-β interfaces, reducing the thioflavin signal [136,137]. Despite initial preclinical success, methylene blue failed to meet primary cognitive endpoints, with post hoc monotherapy signals remaining controversial [138]. These issues may illustrate the brain exposure and endpoint sensitivity. Phenothiazines, therefore, map to the fibril-remodelling blockade tier, and future development based on optimised CNS pharmacokinetics and biomarker-mediated designs.

Natural polyphenols have been widely investigated for their anti-aggregation properties [139]. For example, epigallocatechin gallate (EGCG) and curcumin both have this effect. EGCG is a green tea catechin, engages multiple hot spots on tau fibrils to remodel mature cross-β architecture into off-pathway, non-toxic oligomers, while impeding further elongation. This intervention reduces tau propagation and lowers toxicity readouts, but shifts the ensemble rather than preventing nucleation [140]. Current research focuses on formulation strategies to enhance their delivery efficiency into the brain.

Peptide inhibitors target key aggregation-prone motifs in tau, competitively bind PHF6 and PHF6* raise the nucleation barrier and cap growing filament ends, thereby suppressing primary nucleation and early elongation [141]. Because native L-peptides are protease-sensitive and blood–brain barrier (BBB) limited, the second-generation designs use lipidation and intranasal delivery to preserve target occupancy in the CNS [142]. These peptides act upstream of fibril remodellers and are best positioned for early-stage disease.

Metal ions such as zinc and copper can accelerate tau aggregation through direct coordination to histidines and cysteines and by promoting oxidative crosslinking [143]. Therefore, chelators lower the effective cofactor activity, attenuating nucleation and off-pathway oxidative stabilisation of oligomers. Clioquinol and PBT2 reduced tau and Aβ aggregation and toxicity in models but failed to reveal consistent clinical benefit in AD, largely due to specificity and safety constraints [144,145]. Consequently, metal modulation now serves as an adjunct strategy, ideally coupled with direct aggregation blockers and redox control.

Pathogenic tau is thought to spread as extracellular assemblies that enter neurons via heparan-sulfate-dependent macropinocytosis and related pathways. Thus, immunotherapies can lower PHF and NFT accrual and propagation by blocking uptake and routing immune complexes to microglial endolysosomes via Fcγ receptors. These approaches intersect with spreading nodes by neutralizing seed-competent extracellular tau and routing immune complexes to Fcγ receptor-dependent lysosomal clearance in microglia, thereby reducing exosome-supported spreading and HSPG/LRP1-mediated neuronal uptake [146].

Active immunotherapy strategies aim to elicit an endogenous immune response against pathological tau species through vaccination. Although fewer in number compared to passive approaches, tau vaccines offer potential advantages in terms of long-term efficacy and lower treatment burden. JNJ-2056 (ACI-35030) is a liposomal phosphorylated tau vaccine that is in randomised mid-stage testing, reflecting its positioning to intercept propagation before overt tangle spread. By design, antibody output is biased toward late phospho-epitopes that track with fibril maturation, aiming for long-lived neutralisation without frequent infusions [147]. In contrast, GV1001 (tertomotide) is a telomerase peptide vaccine repurposed to AD and PSP, which has anti-inflammatory and antioxidant actions and has entered phase II studies, but its putative benefit relates to neuroprotective immunomodulation rather than direct anti-tau binding [148,149].

Passive approaches have the ability to target different stages of tau through pairing neutralisation with Fc-driven microglial clearance [150]. E2814 (etalanetug) is a humanised IgG1 against the MTBR, targeting the MTBR HVPGG motif and is bi-epitopic on 4R and mono-epitopic on 3R tau, aligning with propagating seeds [151]. In AD and primary tauopathies producing up to 75% and 50% reductions in CSF MTBR-tau243 and pTau217 over 2 years in dominantly inherited AD, with tau-PET trends to decline versus natural history [152]. It is being advanced in phase II/III trials. Some other mAbs illustrate orthogonal epitope strategies now in early clinical phases. LuAF-87908 is a humanised IgG1 antibody directed against pTau, while MK-2214 specifically targets the Ser413 phosphorylation site, a residue implicated in tau pathology [153,154]. APNmAb005 is designed to recognise high molecular weight and aggregated tau species that are thought to be particularly neurotoxic. VY-7523 binds to the C-terminal domain of tau, potentially interfering with tau-mediated intracellular interactions or aggregation [153]. Therapeutic programs target tau at different stages: antibodies against early phospho-epitopes aim to intercept initiation, while MTBR- and oligomer-selective monoclonal antibodies are designed to limit ongoing spread and to promote microglial lysosomal degradation of pathogenic tau [155]. Although more candidates have emerged for immunotherapy, clinical trials have shown that targeted intervention cannot be fully translated into clinical benefits. Poor antibody exposure in the brain parenchyma is one of the main limitations. The interstitial concentration of conventional intravenous IgG is low, making it difficult to maintain targeted occupancy at the synaptic level [156]. The clinical results of mAb semorinemab did not reach the primary efficacy endpoint of reducing the decline in the clinical dementia score (CDR-SB), nor did they reach the two secondary focus points of evaluating ADAS-Cog13 and ADCS-ADL performance [157,158]. In order to increase brain exposure, receptor-mediated transcellular transport (RMT) is a current research direction. This non-invasive strategy binds to specific receptors on the surface of endothelial cells and can transport large molecules across the BBB. Furthermore, most current anti-tau antibodies target N-terminal epitopes, such as Biogen’s gosuranemab and AbbVie’s ABBV-8E12 (which recognises an epitope near the N-terminus) [13]. These antibodies do not specifically target pathogenic tau, such as phosphorylated tau, failing to maximize therapeutic efficacy and often resulting in clinical failure [13,159]. Therefore, the development of antibodies needs to be more targeted at pathogenic tau protein. Although tau antibodies are typically formulated with IgG4 or Fc-reduced antibodies to reduce microglial hyperactivation, infusion reactions and ADA still need to be monitored to avoid suspension due to side effects like AN-1792 [160,161].

In tauopathies, hyperdynamic MTs and transport failure arise as the tau function is compromised, providing a mechanistic rationale for MT-stabilising agents (MSAs) that restore dynamics toward a healthy regime. [162]. Among the various MSAs investigated, paclitaxel demonstrated initial promise but proved unsuitable for neurotherapeutic applications due to its limitation to BBB penetration and significant peripheral toxicity [163,164]. In contrast, epothilone D has emerged as the most clinically relevant candidate, distinguished by its superior BBB permeability and favourable safety profile at therapeutically relevant doses. Preclinical validation in tau transgenic mouse models has demonstrated that epothilone D treatment produces multiple beneficial effects, including enhanced MT density, improved axonal transport dynamics, reduced tau pathology burden, and significant amelioration of cognitive deficits [165,166,167].

Although the taxane analog TPI-287 has entered Phase I/II clinical trials for AD and PSP/CBS, hypersensitivity reactions have occurred, and no significant clinical benefit has been demonstrated [168]. Among these agents, paclitaxel has poor brain penetration, epothilone D has demonstrated CNS activity but has uncertain long-term tolerability, and TPI-287 achieves brain exposure but raises concerns about peripheral toxicity [169]. These differences highlight that BBB permeability, isomer selectivity, and long-term tolerability are key differentiating factors among MSAs.

Despite these promising preclinical results, several challenges remain in translating MSAs to clinical applications. The primary concern involves the inherent non-selectivity of current agents, which bind to all tubulin-containing MTs. This broad activity profile raises concerns about potential off-target effects in peripheral tissues, particularly given that many MSAs were originally developed as anti-cancer agents with established toxicity profiles. Additionally, the long-term consequences of chronic MT stabilisation in the nervous system remain incompletely characterised. Current efforts focus on developing neuron-selective MSAs with improved safety profiles [170]. Moreover, the complementary mechanism of action suggests potential synergistic benefits when MSAs are combined with other therapeutic approaches, such as tau aggregation inhibitors or phosphorylation modulators, offering the possibility of multi-target combination therapies that address different aspects of tau pathologies.

Since cell-to-cell propagation of tau is one of the strongest predictors of clinical progression in individuals with neurodegenerative diseases, researching methods to block tau propagation is necessary [171]. The propagation cascade comprises three interconnected phases: neuronal secretion, extracellular transport, and recipient cell uptake, each presenting distinct therapeutic intervention opportunities. Mechanistically, these interventions target the exosome export and receptor-mediated uptake (HSPG/LRP1) steps that control seed availability and neuronal entry, respectively.

Pathological tau is exported from neurons via unconventional pathways that bypass the classical ER–Golgi route. Activity-dependent release at presynaptic terminals creates focal spots for seed export, and late endosome and lysosome routes regulated by soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) (e.g., VAMP8) further expand the extracellular pool. VAMP8 upregulation increases tau secretion while lowering intracellular accumulation. Thus the inhibition of nSMase2 with GW4869 suppresses exosome biogenesis and reduces extracellular seed availability, thereby lowering the input flux of propagating species [172]. Once released, tau spreads as free assemblies and within extracellular vesicles, which stabilise propagation seeds and distribute them along connected circuits. This interstitial reservoir scales with neuronal activity and glial handling, positioning vesicle biogenesis and release as tractable control points. Extracellular seeds engage specific cell-surface receptors that govern internalisation efficiency [173]. Heparan-sulfate proteoglycans (HSPGs) via sulfation-pattern-dependent binding trigger macropinocytosis, while low-density lipoprotein receptor-related protein 1 (LRP1) supports receptor-mediated endocytosis of monomeric and aggregated tau, disrupting HSPG interactions or antagonising LRP1-mediated endocytosis limits neuronal entry and downstream seeding [174]. After endocytic uptake, endolysosomal escape permits access to cytosolic tau and templated misfolding, sustaining the prion-like spread across anatomically connected regions [175,176]. Because extracellular neutralisation is a major choke point, epitope selection in tau-directed immunotherapy remains a key determinant of intercepting efficiency and routing immune complexes to clearance pathways.

Different treatments for tauopathies correspond to different steps of tau pathobiology. From a mechanistic perspective, combination therapy is most appropriate when the pharmacodynamic antagonism is limited and safety interactions are manageable [177]. One of the strategies is the combination of tau-targeting ASOs and tau immunotherapy.

ASOs directly reduce neuronal tau production, reducing the intracellular conformer supply and the subsequent extracellular propagation, while passive or active immunotherapy neutralises residual extracellular assemblies and promotes microglial clearance [146,178]. This combination addresses both the source and the vector of proliferation. In clinical applications, it is important to note that strong upstream inhibition may reduce cerebrospinal fluid antigens, thereby reducing the efficacy of standard immunotherapy. Therefore, sequential therapy administering ASO first, followed by the antibody, may be a better approach. Evaluating of efficacy should also be combined with tau-PET results, rather than relying only on fluid biomarkers [179]. Although there is no ASO with concurrent anti-tau antibody treatment to date, the antibody–oligonucleotide conjugate technology and the cross-pathology combination of lecanemab with E2814 provide a reference for future ASO and anti-tau combinations [180,181]. Modulation of the kinase axis can be mechanistically complementary to immunotherapy by reducing phosphorylation and aggregation propensity [182]. Dosage in this strategy should be carefully selected to avoid overcorrecting physiological PTMs that support MT dynamics. Aggregation modulators can be combined with antibodies to prevent new oligomer formation while simultaneously clearing existed pathogenic proteins [183]. However, rapid disaggregation may transiently elevate soluble oligomer levels and expand the pool of antibody targets, potentially leading to inflammation [184]. This again suggests that staggered dosing and tracking of soluble oligomers and localised tau protein PET should be performed in conjunction with biomarker monitoring. MT stabilisers offer a countermeasure at the distal level of phenotypic activity by restoring cytoskeletal stability and axonal transport. Their mechanistic synergy with kinase inhibitors has the potential to reduce tau dissociation and enhance MT stability, but overstabilization can inhibit dynamic instability and impair transport, particularly when combined with PTM blockers [185]. If combining MT stabilisers with kinase inhibitors is considered, CNS selectivity and safety/efficacy endpoints focused on transport should be prioritized.

Reliable biomarkers are crucial for the design and interpretation of tau-targeted trials, whether used for patient stratification or monitoring efficacy. Tau-PET imaging has revolutionized the in vivo assessment of tau pathology by enabling regional quantification and staging paralleling Braak progression. Compared to ¹⁸Fflortaucipir, ¹⁸F-MK-6240 offers enhanced cortical contrast and higher specificity [186]. In progressive supranuclear palsy and corticobasal syndrome, ¹⁸F-PI-2620 demonstrated distinct uptake patterns consistent with quadruple tau pathology, supporting its use in stratifying non-AD tauopathy [187]. These imaging modalities are now routinely included in trial inclusion criteria and serve as quantitative endpoints for longitudinal monitoring.

CSF biomarkers remain the most widely validated fluid markers. Phosphorylated tau species, particularly pTau181, pTau217 and pTau231, provide sensitive measures of abnormal phosphorylation upstream of aggregation and are strongly associated with amyloid status and cognitive status [188]. More recently, the MT-binding region fragment MTBR-tau243 has emerged as a highly specific marker of neurofibrillary tangle pathology, closely correlating with tau-PET signals and disease severity [95]. These advances enable CSF panels to simultaneously capture early phosphorylation changes and downstream aggregate burden, providing complementary readouts for treatment monitoring.

Blood biomarkers offer a more convenient alternative to large-scale screening and repeated sampling. Plasma pTau181 and pTau217 are highly predictive of amyloid PET positivity and cognitive stage transition, with pTau217 being more sensitive for earlier changes [189]. Ultrasensitive assays such as Simoa^® Tau are enabling the increasing use of blood-based testing in stratified trial workflows, starting with blood screening followed by CSF and confirmatory tau-PET testing to ensure accurate stratification [190].

While biomarker responses are encouraging, their correspondence to clinical benefit varies across programs. Regarding approaches to reduce tau production, the antisense oligonucleotide BIIB080 (IONIS-MAPTRx) dose-dependently reduced CSF total tau and p-tau levels and demonstrated exploratory reductions in tau-PET signals in a randomised phase Ib study in mild AD [191]. This clearly demonstrates proximal target engagement, but formal clinical endpoints will not be determined until results from an ongoing phase II clinical trial are available, so no claim can be made at this time about a correlation between biomarkers and clinical efficacy. Antibodies such as semorinemab and gosuranemab have demonstrated neither clinical efficacy nor consistent biomarker improvements [157,158]. In contrast, E2814 significantly reduced CSF MTBR-tau243 and pTau217 levels and stabilised tau-PET signals, but cognitive outcomes remain awaited [181]. These experiences highlight that biomarker changes do not necessarily translate into functional improvement, and that trials must match pharmacodynamic markers to the mechanisms they are intended to reflect.

Together, tau-PET, CSF phospho-tau biomarkers, and plasma assays have become indispensable for tau-targeted therapeutic development. They allow selection of patients most likely to benefit, enable monitoring of drug engagement with tau biology, and provide early readouts that can guide adaptive trial design. Incorporation of these multimodal biomarkers has already improved the interpretability of recent ASO and antibody studies, and will be critical in future precision-medicine approaches to Alzheimer’s disease and primary tauopathies.

While current tau-targeting therapies primarily focus on reducing protein levels, inhibiting aggregation, or enhancing clearance, future treatment strategies may encompass more unconventional approaches. Beyond directly lowering tau levels, modulating non-neuronal contributors has emerged as a complementary strategy. Glial cells, particularly microglia and astrocytes, influence the tau propagation and neuroinflammation, suggesting that indirect interventions on the neuroimmune environment may modify disease progression [192]. For example, mesenchymal stem cells could be transplanted to downregulate proinflammatory mediators and active microglial cells, improving the clearance of extracellular tau aggregates and neuronal dendrite growth [193].

Furthermore, targeting the conformation and subtype-specific characteristics of tau is another promising therapeutic approach. Several studies have demonstrated that tau protein forms distinct, disease-specific pathological conformations in different tauopathies like AD and PSP [68]. Thus, future drug design may shift from broadly targeting total tau proteins to developing drugs that can specifically recognise and bind to a particular pathological conformation. For example, molecules could be designed to bind to specific pathological conformations, thus preventing further aggregation of normal tau protein. The challenge with this approach lies in accurately screening and developing highly specific molecules. While current research suggests that conformation-specific nanobodies can recognise oligomeric tau, further studies are needed to determine whether they can alleviate disease progression [194].

Finally, combining tau-targeting therapies with non-pharmacological interventions to achieve synergistic effects may be a promising future direction. This includes combining conventional medications with non-invasive neurostimulation techniques, such as transcranial magnetic stimulation (TMS) or transcranial direct current stimulation (tDCS). These techniques can modulate neuronal circuit excitability, which theoretically can influence tau protein release [195]. Thus, combining pharmacological treatment with specific lifestyle interventions, such as high-intensity exercise or cognitive training, may enhance therapeutic efficacy by activating endogenous neuroprotective mechanisms [196]. This comprehensive treatment approach acknowledges the complexity of tau pathology and aims to achieve better clinical outcomes through multi-dimensional, multi-target interventions, which may represent a more effective strategy for altering the disease progression.

No new data were created or analyzed in this study.