Gamma-secretase allosteric modulation as preventive therapy in Alzheimer’s Disease

Informations projet

GALOMOD

N° de convention de subvention: 101158122

DOI

10.3030/101158122

Projet clôturé

Date de signature de la CE 29 Août 2024

Date de début 1 Septembre 2024

Date de fin 28 Février 2026

Financé au titre de

• European Research Council (ERC)

Coût total

Aucune donnée

Contribution de l’UE

€ 150 000,00

Coordonné par

VIB VZW
Belgium

Periodic Reporting for period 1 - GALOMOD (Gamma-secretase allosteric modulation as preventive therapy in Alzheimer’s Disease)

Période du rapport: 2024-09-01 au 2026-02-28

Résumé du contexte et des objectifs généraux du projet

Alzheimer’s disease (AD) is characterized by the early accumulation of amyloid beta (Aβ) plaques, followed by the formation of tau aggregates and progressive neurodegeneration, ultimately manifesting as dementia. Recent developments in anti Aβ antibody therapies have marked a breakthrough in disease management. However, these treatments remain costly, require intravenous administration, and provide only limited clinical benefit. There is therefore a pressing need for safe, affordable therapies, which would ideally be small molecules that can be administered orally over extended periods.

Targeting γ secretase, the enzyme responsible for Aβ production, has long been considered a promising therapeutic strategy, but its development has proven challenging. Novel γ secretase allosteric modulators (GAMs) operate via a fundamentally different mechanism: they selectively increase the production of shorter, non toxic Aβ species while reducing the generation of longer, aggregation prone Aβ peptides that drive neurodegeneration. Despite their potential, these next generation GAMs still lack sufficient evidence regarding their safety and efficacy in preventing AD.

The current ERC Proof of Concept project, GALOMOD, aims to generate comprehensive in vitro and in vivo data on the efficacy, specificity, and safety of a newly developed GAM compound. Specifically, the project will:
1. Acquire and benchmark the novel GAM against existing academic and industrial γ secretase–targeting compounds.
2. Evaluate its ability to promote the production of shorter Aβ species in cultured human neurons, and assess its effects on other γ secretase substrates to determine specificity.
3. Test the compound’s efficacy in modulating γ secretase activity in neurons derived from familial AD patients.
4. Assess its therapeutic potential in an in vivo mouse model of AD.
5. Conduct a market analysis of GAMs as preventive or maintenance therapies for AD.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

1. The novel GAM was evaluated alongside five comparator compounds. All tested compounds promoted the production of shorter Aβ peptides in human induced pluripotent stem cell (iPSC)–derived neurons, albeit to varying degrees.
2. In addition to APP, γ secretase processes numerous other substrates, and indiscriminate inhibition of γ secretase is associated with adverse effects. Therefore, the selectivity of the novel GAM was assessed by examining its impact on a panel of representative non APP γ secretase substrates.
3. The concentration range required to achieve the desired Aβ peptide profile was established in human iPSC-derived neurons, without inducing the broad substrate inhibition characteristic of classical γ secretase inhibitors.
4. The GAM shifted the Aβ profile in the intended direction in both heterozygous and homozygous familial Alzheimer’s disease (FAD) PSEN mutant human iPSC-derived neurons, although with reduced potency compared to wild-type neurons.
5. Consistent effects on Aβ modulation were observed in primary cortical neurons derived from multiple mouse knock-in models expressing humanized APP or PSEN FAD mutations.
6. In a mouse model expressing humanized mutant APP, early administration of the GAM resulted in a favorable shift in the Aβ profile in both brain and plasma. This was accompanied by a strong reduction in amyloid plaque formation and gliosis in the brain, without evidence of overt toxicity.
7. When administered after the onset of plaque deposition in the same mouse model, the GAM partially restored the Aβ profile in brain and plasma, and led to a partial reduction in both plaque number and plaque burden compared to untreated controls.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

1. Testing our novel GAM compared to other gamma secretase allosteric stabilisers of various academic or industrial origin provided valuable information on the position of the novel GAM relative to other compounds in the field.
2. Targeted γ secretase substrate analysis was completed and provided a concentration range with favorable Aβ profile, while leaving other substrates largely unaffected. Additional unbiased mass spectrometry based analyses are ongoing and will further strengthen this part of the data package.
3. Shifting the Aβ profile of FAD PSEN mutant iPSC-derived neurons using γ secretase allosteric modulators is directly relevant to our proposed familial Alzheimer’s disease prevention concept, because the short-to-long Aβ ratio has been linked to age at onset in familial Alzheimer’s disease.
These results provide the basis for future in vivo or translational work in familial Alzheimer’s disease mutation carriers.
4. Our in vivo experiments show that our tested GAM primarily prevents or slows the formation and growth of new plaques, rather than clearing established plaques. This is highly consistent with the preventive therapeutic concept of the ERC PoC project.