Gene therapy: an alternative to treat Alzheimer’s disease

Doshi, Vanshika; Joshi, Garima; Sharma, Sanjay; Choudhary, Deepak

doi:10.1007/s00210-023-02873-z

Cited by 2 publications

(5 citation statements)

References 76 publications

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“…Gene transfer of APOE ε2 could be a promising treatment, but, to date, the result has not been wholly satisfying [ 195 ]. Currently, for APOE4 homozygotes patients, a phase I/II clinical trial is ongoing (NCT03634007).…”

Section: Gene Therapymentioning

confidence: 99%

“…More specifically, in order to perform promising gene therapy for AD, it is important to identify specific molecules that are targetable. For example, the nerve growth factor (NGF) is a neurotrophic factor crucial for developing and maintaining hippocampal functions [ 195 ]. For its essential role in memory function, it has been proposed and tried to deliver the NGF gene with some promising results [ 195 , 196 ].…”

Section: Gene Therapymentioning

confidence: 99%

“…For example, the nerve growth factor (NGF) is a neurotrophic factor crucial for developing and maintaining hippocampal functions [ 195 ]. For its essential role in memory function, it has been proposed and tried to deliver the NGF gene with some promising results [ 195 , 196 ]. In 2003, Tuszynski et al, performed a phase 1 trial of ex vivo NGF gene delivery in eight mild AD patients, implanting autologous fibroblasts genetically modified to express human NGF into the forebrain.…”

Section: Gene Therapymentioning

confidence: 99%

“…BDNF is a nervous system growth factor that regulates neuronal function in key memory circuits of the brain, reducing cell loss, stimulating cell function, and building new connections between brain cells in animal models. Also, experimental trials in animal models have demonstrated that delivery of the BDNF gene improved memory functions [ 195 , 199 ]. However, the attempts at BDNF-related therapy in animal models have shown that its injection did not correlate with spare neurons nor with levels of amyloid or amyloid plaques [ 195 ].…”

Section: Gene Therapymentioning

confidence: 99%

“…Also, experimental trials in animal models have demonstrated that delivery of the BDNF gene improved memory functions [ 195 , 199 ]. However, the attempts at BDNF-related therapy in animal models have shown that its injection did not correlate with spare neurons nor with levels of amyloid or amyloid plaques [ 195 ]. A phase I first-in-human clinical trial is currently ongoing (NCT05040217), to test whether a BDNF administered into the brain continuously by gene therapy can slow or prevent cell loss in the brains of people affected by MCI and AD.…”

Section: Gene Therapymentioning

confidence: 99%

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Novel Therapeutic Strategies in Alzheimer’s Disease: Pitfalls and Challenges of Anti-Amyloid Therapies and Beyond

Tondo,

De Marchi,

Bonardi

et al. 2024

JCM

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Alzheimer’s disease (AD) causes a significant challenge to global healthcare systems, with limited effective treatments available. This review examines the landscape of novel therapeutic strategies for AD, focusing on the shortcomings of traditional therapies against amyloid-beta (Aβ) and exploring emerging alternatives. Despite decades of research emphasizing the role of Aβ accumulation in AD pathogenesis, clinical trials targeting Aβ have obtained disappointing results, highlighting the complexity of AD pathophysiology and the need for investigating other therapeutic approaches. In this manuscript, we first discuss the challenges associated with anti-Aβ therapies, including limited efficacy and potential adverse effects, underscoring the necessity of exploring alternative mechanisms and targets. Thereafter, we review promising non-Aβ-based strategies, such as tau-targeted therapies, neuroinflammation modulation, and gene and stem cell therapy. These approaches offer new avenues for AD treatment by addressing additional pathological hallmarks and downstream effects beyond Aβ deposition.

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Section: Gene Therapymentioning

confidence: 99%

Section: Gene Therapymentioning

confidence: 99%

Section: Gene Therapymentioning

confidence: 99%

Section: Gene Therapymentioning

confidence: 99%

Section: Gene Therapymentioning

confidence: 99%

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Novel Therapeutic Strategies in Alzheimer’s Disease: Pitfalls and Challenges of Anti-Amyloid Therapies and Beyond

Tondo,

De Marchi,

Bonardi

et al. 2024

JCM

View full text Add to dashboard Cite

show abstract

Haploinsufficiency and Alzheimer’s Disease: The Possible Pathogenic and Protective Genetic Factors

Bagyinszky,

2024

IJMS

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Alzheimer’s disease (AD) is a complex neurodegenerative disorder influenced by various genetic factors. In addition to the well-established amyloid precursor protein (APP), Presenilin-1 (PSEN1), Presenilin-2 (PSEN2), and apolipoprotein E (APOE), several other genes such as Sortilin-related receptor 1 (SORL1), Phospholipid-transporting ATPase ABCA7 (ABCA7), Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), Phosphatidylinositol-binding clathrin assembly protein (PICALM), and clusterin (CLU) were implicated. These genes contribute to neurodegeneration through both gain-of-function and loss-of-function mechanisms. While it was traditionally thought that heterozygosity in autosomal recessive mutations does not lead to disease, haploinsufficiency was linked to several conditions, including cancer, autism, and intellectual disabilities, indicating that a single functional gene copy may be insufficient for normal cellular functions. In AD, the haploinsufficiency of genes such as ABCA7 and SORL1 may play significant yet under-explored roles. Paradoxically, heterozygous knockouts of PSEN1 or PSEN2 can impair synaptic plasticity and alter the expression of genes involved in oxidative phosphorylation and cell adhesion. Animal studies examining haploinsufficient AD risk genes, such as vacuolar protein sorting-associated protein 35 (VPS35), sirtuin-3 (SIRT3), and PICALM, have shown that their knockout can exacerbate neurodegenerative processes by promoting amyloid production, accumulation, and inflammation. Conversely, haploinsufficiency in APOE, beta-secretase 1 (BACE1), and transmembrane protein 59 (TMEM59) was reported to confer neuroprotection by potentially slowing amyloid deposition and reducing microglial activation. Given its implications for other neurodegenerative diseases, the role of haploinsufficiency in AD requires further exploration. Modeling the mechanisms of gene knockout and monitoring their expression patterns is a promising approach to uncover AD-related pathways. However, challenges such as identifying susceptible genes, gene–environment interactions, phenotypic variability, and biomarker analysis must be addressed. Enhancing model systems through humanized animal or cell models, utilizing advanced research technologies, and integrating multi-omics data will be crucial for understanding disease pathways and developing new therapeutic strategies.

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Gene therapy: an alternative to treat Alzheimer’s disease

Cited by 2 publications

References 76 publications

Novel Therapeutic Strategies in Alzheimer’s Disease: Pitfalls and Challenges of Anti-Amyloid Therapies and Beyond

Novel Therapeutic Strategies in Alzheimer’s Disease: Pitfalls and Challenges of Anti-Amyloid Therapies and Beyond

Haploinsufficiency and Alzheimer’s Disease: The Possible Pathogenic and Protective Genetic Factors

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