Senolytic therapy in mild Alzheimer’s disease shows safety in phase I trial

In a recent study published in Nature Medicine, researchers conducted the phase 1 trial of orally-administered senolytic therapy comprising quercetin (Q) and dasatinib (D) for symptomatic and early-stage Alzheimer's disease (AD) patients.

Cellular senescence, a hallmark of aging, contributes to AD pathogenesis through stress responses like mitochondrial dysfunction, deoxyribonucleic acid (DNA) damage, and proteotoxic stress. Despite the development of disease-modifying agents, these therapies have limited clinical results, highlighting the need for new drug targets.

About the study

In the present senolytic therapy to modulate the progression of AD (SToMP-AD), researchers investigated the central nervous system (CNS) penetrance, feasibility, efficacy, and safety of senolytic treatment for AD patients.

The rTg(tauP301L)4510 transgenic murine model of tau protein pathogenesis was used to assess D (100 mg) and Q (1000 mg) penetrance in the central nervous system as well as secondary outcomes such as feasibility and safety, senolytic compound target engagement, and alterations in the cerebrospinal fluid (CSF) and serological markers of cognition, AD, cognition, functional status, and neuroimaging.

The researchers included five individuals aged 65 and older with symptomatic early-stage Alzheimer’s disease in a single-center pilot trial evaluating a 12-week regimen with intermittent senolytic treatment. The study included 11 visits during which the candidates underwent physical screening, including blood collection, assessment of anthropomorphic measures, vital signs, neurological and physical evaluation, co-medication reviews, medical histories, and cognitive assessments [Montreal Cognitive Assessment (MoCA), electrocardiogram (ECG), and clinical dementia rating (CDR)].

After eligibility confirmation, two baseline assessments were performed. The initial baseline visit comprised blood collection and lumbar punctures, whereas the subsequent visit comprised evaluations of functional status, cognition, and a magnetic resonance imaging (MRI) scan of the brain.

The study protocol included confirmation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-negative reverse transcription-polymerase chain reaction (RT-PCR) results within three days of drug administration, with coronavirus disease 2019 (COVID-19) screening conducted throughout the study period.

The first drug was administered within ten days of final baseline assessments. The medications were administered in six repetitive 14-day cycles. Every cycle commenced with two days of drug administration, and a gap of 13-15 days. The procedures performed at the second baseline visit were repeated three to 10 days after final drug administration.

AD was diagnosed using the National Institute on Aging-Alzheimer's Association (NIA-AA) criteria and CDR scores. D and Q concentrations were quantified using high-performance liquid chromatography (HPLC) and tandem mass spectrometry (MS). ADRD biomarkers such as amyloid-beta (Aβ)-40, 42, phosphorylated and total tau protein, and neurofilament light (NFL) were measured in the cerebrospinal fluid.

Results

Initially, 21 individuals were screened telephonically, of whom eight were not eligible. The remaining 13 underwent physical screening, among whom seven did not satisfy the inclusion criteria, and one individual withdrew. As a result, the study population comprised five individuals, among whom the median age was 76 years; 40% were women, 80% were white of non-Hispanic ethnicity, and 20% were Hispanic. The participants were treated between March 6, 2020, and April 19, 2021.

The individuals showed increased Q and D levels in serum and cerebrospinal fluid, with D levels detected in four individuals (80%) and Q not detected. Senolytic therapy was well-tolerated, with no early discontinuation. Secondary cognitive and neuroimaging endpoints did not significantly differ from baseline to post-treatment, supporting a favorable safety profile.

Cerebrospinal fluid levels of interleukin-6 (IL-6) and glial fibrillary acidic protein (GFAP) increased with trending decreases in senescence-associated chemokines and cytokines and a trend toward higher Aβ42 levels. Drug D penetrated the central nervous system, with outcomes supporting tolerability, safety, and feasibility for AD patients.

Twice-weekly treatments lowered cortical neurofibrillary tangle accumulation by 35%, which correlated with decreased atrophy in the brain cortex and the restoration of aberrant blood flow in the cerebrum. Post-treatment, drug D was detectable in sera of all participants and ranged between 13 and 74 nanograms per mL. In the cerebrospinal fluid, post-treatment D drug levels were marginally higher than the quantification limit of 0.2 nanograms per mL among four participants, with undetectable levels among samples of the fifth individual.

Post-treatment, drug D was undetectable in the cerebrospinal fluid and serum except for one serum sample (1.9 nanograms per mL). At baseline, in serum, three individuals had undetectable Q levels, while the remaining two showed Q concentrations ranging between 1.1 and 1.7 ng/mL. After treatment, drug Q could be detected in sera of all participants, ranging between 3.3 and 26 ng/mL. In the cerebrospinal fluid, Q was undetectable pre- or post-therapy across individuals.

Serological levels of IL-10, 17, 21, 23, 31, vascular endothelial growth factor (VEGF), macrophage inflammatory protein (MIP)-1α, β, and monocyte chemoattractant protein 2 (MCP-2) decreased, while chitinase-3-like protein 1 (CHI3L1 or YKL40) levels were elevated post-treatment. In the cerebrospinal fluid, thymus- and activation-regulated chemokine (TARC), interferon-inducible T-lymphocyte alpha chemoattractant (I-TAC), eotaxin-1, 2, and MIP-1α levels were reduced, while IL-6 levels were elevated. Six adverse events were reported, of which none were serious, and all were resolved within 16 days.

Conclusion

Overall, the study findings provided results of the first open-label, phase 1, proof-of-concept trial of senolytic treatment for individuals with AD and indicated the potential of therapy-associated alterations in AD pathology and cellular senescence markers.

Written by

Pooja Toshniwal Paharia

Dr. based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.