Biology subjects

Tecedor, L.

Publications and source records attributed to Tecedor, L..

5 recordsLinked to original sources

bioRxiv2026

Computational modeling and preclinical validation support targeting somatic instability for Huntington's disease treatment

Huntingtons disease (HD) is caused by an expanded CAG trinucleotide repeat within the huntingtin (HTT) gene. Genetic modifiers of disease onset and progression in HD implicate somatic instability (SI) of the expanded CAG repeat as a key pathogenic driver, with MSH3 emerging as a leading therapeutic target. Reducing SI, particularly in the most affected neuronal cell type, medium spiny neurons (MSNs) of the striatum, is thus a rational therapeutic strategy for HD. To inform the development of an SI-targeted therapy, we generated a computational model simulating SI in MSNs to infer therapeutic effects on MSN survival resulting from an intervention that reduces SI. The model takes advantage of HD patient data to predict therapeutic benefit across a range of inherited CAG lengths and ages of intervention, considering the degree of target engagement regionally and per cell. To target SI experimentally, we designed an artificial microRNA to lower MSH3 mRNA (miMSH3) after delivery with AAV-DB-3, a previously described MSN-targeting AAV capsid variant. AAV-DB-3.miMSH3 achieved from 48 to 94% MSH3 mRNA reduction in MSNs of nonhuman primates (NHPs), which, when modeled, would reduce the composite Unified Huntington Disease Rating Scale change over baseline from 50 to over 120% as well as delay motor symptom onset by many years. AAV-DB-3.miMSH3 also showed robust target engagement in vivo with up to 46% reduction in SI in HdhQ111 mice. The integration of preclinical experimental data and the computational model support the translational potential of AAV-DB-3.miMSH3 as a disease-modifying therapy applicable for HD patients with a broad range of inherited repeat lengths. One Sentence SummaryPredictive modeling to guide therapeutic targeting of disease modifiers in Huntingtons disease.

neuroscience↗

bioRxiv2024

Optimized AAV capsids for diseases of the basal ganglia show robust potency and distribution in adult nonhuman primates

Huntingtons disease and other disorders of the basal ganglia create challenges for biomolecule-based medicines given the poor accessibility of these deep brain structures following intracerebral or intravascular delivery. Additionally, for adeno-associated viruses (AAVs) intravascular delivery exposes peripheral tissues to the vast majority of the therapy, increasing the risk of immune responses and the quantity and associated cost of goods required for therapeutically relevant brain penetration levels. Here, we found that low dose, low volume delivery of unbiased AAV libraries into a focused brain region allowed recovery of novel capsids capable of broad access to key deep brain and cortical structures relevant for human therapies at doses orders of magnitude lower than used in current clinical trials. One such capsid, AAV-DB-3, provided transduction of up to 45% of medium spiny neurons in the adult NHP striatum, along with substantial transduction of relevant deep layer neurons in the cortex. Notably, AAV-DB-3 behaved similarly in mice as in NHPs and also potently transduced human neurons derived from induced pluripotent stem cells. Thus, AAV-DB-3 provides a unique AAV for network level brain gene therapies that translates up and down the evolutionary scale for preclinical studies and eventual clinical use.

neuroscience↗

bioRxiv2023

APOE2 gene therapy reduces amyloid deposition, and improves markers of neuroinflammation and neurodegeneration in a mouse model of Alzheimer disease

Epidemiological studies show that individuals who carry the relatively uncommon APOE {varepsilon}2 allele rarely develop Alzheimer disease, and if they do they have a later age of onset, milder clinical course, and less severe neuropathological findings than others with Alzheimer disease. The contrast is especially stark in comparison to the phenotype associated with the major genetic risk factor for Alzheimer disease, APOE {varepsilon}4, which has an age of onset several decades earlier, as well as a more aggressive clinical course and notably more severe neuropathological findings, especially in terms of the amount of amyloid deposition. Even one APOE {varepsilon}2 allele improves phenotype, but it is uncertain if that is due to the replacement of a more toxic allele by APOE {varepsilon}2, or if APOE {varepsilon}2 has a protective, neuro-modulatory effect. Here, we demonstrate that brain exposure to APOE2 via a gene therapy approach which bathes the entire cortical mantle in the gene product after transduction of the ependyma, rapidly ameliorates established A{beta} plaque deposition, neurodegenerative synaptic loss, and, remarkably, reduces microglial activation in an APP/PS1 mouse model despite continued expression of human APOE4. This result suggests a promising protective effect of exogenous APOE2, revealing a cell non-autonomous effect of the protein on microglial activation. We also show that plaque associated microglia in the brain of patients who inherit APOE2 similarly have less microglial reactivity to plaques. These data raise the potential that an APOE2 therapeutic could be effective in Alzheimer disease even in individuals born with the risk {varepsilon}4 allele. One Sentence SummaryIntroduction of ApoE2 using an AAV that transduces the ependymal cells of the ventricle causes a reduction in amyloid load and plaque associated synapse loss, and reduces neuroinflammation by modulating microglial responsiveness to plaques.

neuroscience↗

bioRxiv2021

Neuronal genetic rescue normalizes brain network dynamics in a lysosomal storage disorder despite persistent storage accumulation

Although neurologic symptoms occur in two-thirds of lysosomal storage disorders (LSDs), for most we do not understand the mechanisms underlying brain dysfunction. A major unanswered question is if the pathogenic hallmark of LSDs, storage accumulation, induces functional defects directly or is a disease bystander. Also, for most LSDs we do not know the impact of loss-of-function in individual cell types. Understanding these critical questions are essential to therapy development. Here, we determined the impact of genetic rescue in distinct cell types on neural circuit dysfunction in CLN3 disease, the most common pediatric dementia and a representative LSD. We restored Cln3 expression via AAV-mediated gene delivery and conditional genetic rescue in a CLN3 mouse model. Surprisingly, we found that low-level rescue of Cln3 expression in neurons alone normalized clinically-relevant electrophysiologic markers of network dysfunction, despite the presence of substantial residual histopathology, in contrast to restoring expression in astrocytes. Thus, loss of Cln3 function in neurons, not storage accumulation, underlies neurologic dysfunction in CLN3 disease, implying that storage clearance may be an inappropriate target for therapy development and an ineffectual biomarker.

neuroscience↗

bioRxiv2020

Regulated control of gene therapies with a drug induced switch

To date, gene therapies for human application rely on engineered promoters that cannot be finely controlled. Here, we report a universal switch element that allows precise control for gene silencing or gene replacement after exposure to a small molecule. Importantly, these small molecule inducers are in human use, are orally bioavailable when given to animals or humans, and can reach both peripheral tissues and the brain. Moreover, the switch system (Xon) does not require the co-expression of any regulatory proteins. Using Xon, translation of desired elements for gene knockdown or gene replacement occurs after a single oral dose, and expression levels can be controlled by drug dose or in waves with repeat drug intake. This universal switch can provide temporal control of gene editing machinery and gene addition cassettes that can be adapted to cell biology applications and animal studies. Additionally, due to the oral bioavailability and safety of the drugs employed, the Xon switch provides an unprecedented opportunity to refine gene therapies for more appropriate human application.

molecular biology↗