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At least 19 recordsLinked to original sources
PubMed2026

Exploring Genetic Therapies Targeting Amyotrophic Lateral Sclerosis in Animal Models: A Systematic Review and Meta-Analysis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare, neurodegenerative disease, for which there is currently no known cure. ALS primarily affects motor neurons, with rapid deterioration, meaning symptoms develop quickly, from problems with speech and muscle weakness to breathing issues and paralysis. This systematic review aimed to explore the preclinical efficacy of various genetic therapies used to target ALS using in&#xa0;vivo rodent models. METHODS: In vivo studies of genetic therapies targeting ALS and its symptoms published between January 2015 and December 2025 were included in this review. The following databases were used: Web of Science, Scopus and PubMed. The primary outcome investigated was the total number of motor neurons, with secondary outcomes of rodent survival and muscle function by observing rotarod performance also being analysed. The SYRCLE tool was used to assess risk of bias in included studies. RESULTS: Of the 451 studies identified by searching the databases, 53 studies were found to be eligible for this systematic review. The articles were divided into subcategories depending on the gene target of each therapy. Meta-analysis of outcomes within appropriate studies showed significant improvements for the majority of selected outcomes (p&#x2009;<&#x2009;0.05), favouring genetic therapy intervention. CONCLUSIONS: Results suggest that genetic therapies in rodent models targeting ALS are effective. However, due to a high risk of bias in preclinical studies, further high-quality studies are warranted to support this conclusion and onward translation into the clinic.

Animals↗
PubMed1979

Response of variant hereditary angioedema phenotypes to danazol therapy. Genetic implications.

Hereditary angioedema (HAE), an auto-somal dominant disorder characterized by attacks of episodic edema is associated with decreased functional levels of the C1 esterase inhibitor. Approximately 85% of patients have lowered antigen levels of a normal inhibitor protein. 15% of patients have normal or elevated antigenic levels of functionless protein. We have examined the response to danazol therapy of patients with the variant HAE phenotypes possessing the abnormal protein in an effort to determine if these patients possess a normal structural C1 inhibitor allele. Four patients with a variant HAE phenotype were treated successfully with danazol. In two patients, distinguished by the presence of a functionless, albumin-bound, C1 inhibitor (phenotype 2), phenotypic analysis of the danazol response by bidirectional immunoelectrophoresis revealed the appearance of the normal C1 inhibitor gene product during danazol therapy. This relatively cathodal C1 inhibitor peak appears in conjunction with the development of nearly normal functional activity. All of the functional C1 inhibitory activity which appeared in the phenotype 2 treatment serum was associated with the electrophoretically normal inhibitor. This normal protein could be separated from the functionless inhibitor protein by immunoadsorption and molecular sieve chromatography. Danazol therapy of the two patients with an electrophoretically normal, functionless C1 inhibitor (phenotype 3) also resulted in a clinical remission associated with development of a significant increment in functional serum C1 inhibitory activity and C1 inhibitor protein. These findings demonstrate that these two HAE phenotypic variants are heterozygous for the normal serum C1 inhibitor, a finding which was not apparent before phenotypic analysis of this serum during danazol therapy. These data provide strong evidence for a basic similarity between the common form of HAE and its phenotypic variants. They also suggest that a structural gene lesion may result in the abnormalities of serum C1 inhibitor function and disease expression in all three of these HAE phenotypes.

Angioedema↗
PubMed2024

AAV gene therapy for hereditary spastic paraplegia type 50: a phase 1 trial in a single patient.

There are more than 10,000 individual rare diseases and most are without therapy. Personalized genetic therapy represents one promising approach for their treatment. We present a road map for individualized treatment of an ultra-rare disease by establishing a gene replacement therapy developed for a single patient with hereditary spastic paraplegia type 50 (SPG50). Through a multicenter collaboration, an adeno-associated virus-based gene therapy product carrying the AP4M1 gene was created and successfully administered intrathecally to a 4-year-old patient within 3 years of diagnosis as part of a single-patient phase 1 trial. Primary endpoints were safety and tolerability, and secondary endpoints evaluated efficacy. At 12 months after dosing, the therapy was well tolerated. No serious adverse events were observed, with minor events, including transient neutropenia and Clostridioides difficile gastroenteritis, experienced but resolved. Preliminary efficacy measures suggest a stabilization of the disease course. Longer follow-up is needed to confirm the safety and provide additional insights on the efficacy of the therapy. Overall, this report supports the safety of gene therapy for SPG50 and provides insights into precision therapy development for rare diseases. Clinical trial registration: NCT06069687 .

Humans↗
PubMed1992

Correction of purine nucleoside phosphorylase deficiency by retroviral-mediated gene transfer in mouse S49 T cell lymphoma: a model for gene therapy of T cell immunodeficiency.

To determine the effectiveness of retroviral-mediated purine nucleoside phosphorylase (PNP) gene transfer and expression for metabolic correction of PNP deficiency, we used as a gene transfer target the NSU-1 subline of murine S49 T lymphoma cells, an in vitro genetic model of PNP deficiency. NSU-1 cells were transduced with recombinant retroviruses that express either the murine or human PNP coding sequences under transcriptional regulation of the Moloney murine leukemia virus (Mo-MLV) long terminal repeat (LTR), resulting in expression of substantial levels of PNP activity. Untransduced or control virus-transduced NSU-1 cells were extremely sensitive to deoxyguanosine, a PNP substrate that is toxic for lymphoid cells. However, PNP-virus transduction of NSU-1 cells metabolically corrected the sensitivity of these cells to deoxyguanosine, resulting in near wild-type levels of growth inhibition. These results demonstrate that retroviral-mediated PNP gene transfer and expression corrects the metabolic defect observed in PNP-deficient murine lymphoid cells, suggesting that PNP gene transfer and expression in human lymphoid cells might similarly correct substrate-mediated toxicity and provide an effective genetic therapy.

Animals↗
PubMed1992

Retroviral-mediated gene therapy--safety considerations and preclinical studies.

Retroviral mediated gene transfer (1) is now a clinical reality, with several protocols being conducted. The features that have made these vectors appropriate for the first clinical studies in humans are (i) they are derived from well characterized murine retroviruses (ii) many foreign genes have been expressed in many different cell types, and transduction efficiency can be very high (iii) helper or wild type virus free vectors can be obtained in good titer and (iv) the number of sites of proviral integration is limited although the site of integration in the genome is random. Most of the work described has been conducted in the laboratories of our collaborators, notably Drs. W. French Anderson, R. Michael Blaese, Steven A. Rosenberg, and Arthur W. Nienhuis at the National Institutes of Health, Bethesda, MD, and Dr. Malcolm K. Brenner at St. Jude's Hospital in Memphis, as well as work conducted at Genetic Therapy, Inc. But it is very important to appreciate that retroviral vectors themselves were developed from the pioneering work of researchers in a large number of laboratories in the early and mid 80's.

Animals↗
PubMed2026

From scissors to editors: how the evolution of precision is redefining therapeutic genome editing.

Since its introduction as a genome-editing tool, CRISPR-based technology has undergone rapid refinement, with precision emerging as a central focus of development. Early CRISPR-Cas9 systems demonstrated unprecedented ease and efficiency in targeting specific DNA sequences, but concerns over off-target effects and variable editing outcomes limited their broader application. This review outlines the progression of CRISPR from its discovery in prokaryotes to its application as a versatile tool in precision medicine, where it supports targeted therapies for genetic disorders in various ways. Although technical challenges, including off-target editing and delivery inefficiencies, persist alongside ethical considerations of accessibility and long-term consequences, CRISPR's ongoing refinements and innovations reflect a clear trajectory toward greater specificity, safety, and predictability, positioning CRISPR as an increasingly precise platform for both fundamental research and therapeutic use.

Gene Editing↗
PubMed1991

Retrovirus-mediated gene expression in mammalian cells.

Significant advances have been made in precisely defining the elements in the Moloney murine leukemia virus genome responsible for tissue-restricted expression. This knowledge should lead to improved expression vectors for gene transfer in mammalian cells. In the past year, retrovirus-mediated gene expression in a diverse range of cell types has been reported. These cells have been used to study gene transfer relevant to a range of inherited diseases.

Animals↗
PubMed1991

Adenovirus vectors for gene expression.

Adenoviruses possess a combination of features that make them highly suitable as vectors for expression of heterologous genes. Non-conditional and non-defective adeno-vectors have been constructed to obtain high level expression of a number of foreign genes and some of them have been shown in animal models to exhibit excellent promise as vaccine candidates.

Adenoviridae↗
PubMed2025

The role of iPSC research for insight into inherited arrhythmia conditions.

Human induced pluripotent stem cells (iPSCs) have emerged as a transformative platform for modeling inherited cardiac arrhythmia syndromes and uncovering human-specific disease mechanisms. However, the promise of iPSC-derived cardiomyocytes lies beyond the recapitulation of arrhythmogenic phenotypes and channelopathies. In this review, we explore recent works which have enabled mechanistic interrogation and therapeutic insight for inherited arrhythmia syndromes, beyond the capabilities of traditional animal models. Such studies have leveraged iPSCs to elucidate the role of splice variants, transcriptional regulation, and mitochondrial stress in arrhythmogenesis. Further, iPSC systems have proven important for reclassifying variants of uncertain significance and in modeling idiopathic arrhythmias where genotype-phenotype links are elusive. Advances in directed differentiation now permit chamber-specific cardiac cell generation, allowing for atrial and ventricular disease modeling and revealing critical cell-cell interactions. iPSCs also serve as high-fidelity precursor platforms for drug testing, offering predictive insight into mutation-specific responses to pharmacologic and genetic therapies. Though limitations in maturation and scalability persist, ongoing efforts for integration with tissue engineering, multi-cellular models, and computational frameworks are evolving to improve model reliability. iPSC-based systems now occupy a critical role in arrhythmia research, bridging basic discovery with translational applications, thereby contributing to personalizing care and advancing therapeutics in inherited and idiopathic arrhythmic syndromes.

Humans↗
PubMed2025

Blood phenylalanine lowering partially reverses white matter changes in a mouse model of phenylketonuria.

Phenylketonuria (PKU) is a genetic defect caused by lack of the liver enzyme phenylalanine hydroxylase (PAH). This deficiency results in elevated blood phenylalanine (Phe) levels and neurotoxicity, which is manifested by reduced brain size, lower neurotransmitter levels, and reduced myelination. The goal of this study was to investigate brain myelination defects and their reversibility upon blood Phe lowering by analyzing the corpus callosum (CC) of adult Pahenu2 (PAH-deficient) mice. MRI and immunostaining demonstrated a significant reduction in CC volume in Pahenu2 mice. Treatment with an adeno-associated vector (AAV) encoding mouse PAH for 3.5 months improved but did not completely normalize CC volume. Total cholesterol, a major component of myelin, was unchanged in the CC of Pahenu2 mouse, while some sterol intermediates were significantly reduced by treatment. Single-nuclei transcriptomics showed an upregulation of oxidative stress-related pathways and increased expression of transthyretin, ApoE, Cst3, and Cd81 in CC in Pahenu2 mice. Normalization of blood Phe restored gene expression to levels comparable to those of heterozygous mice and was associated with the generation of differentiated myelin-producing oligodendrocyte subtypes and neuroprotective astrocytes. In summary, Pahenu2 mice showed white matter abnormalities and changes in transcriptome and sterol profiles, which were partially corrected by the normalization of blood Phe.

Animals↗
PubMed2012

MRI roadmap-guided transendocardial delivery of exon-skipping recombinant adeno-associated virus restores dystrophin expression in a canine model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) cardiomyopathy patients currently have no therapeutic options. We evaluated catheter-based transendocardial delivery of a recombinant adeno-associated virus (rAAV) expressing a small nuclear U7 RNA (U7smOPT) complementary to specific cis-acting splicing signals. Eliminating specific exons restores the open reading frame resulting in translation of truncated dystrophin protein. To test this approach in a clinically relevant DMD model, golden retriever muscular dystrophy (GRMD) dogs received serotype 6 rAAV-U7smOPT via the intracoronary or transendocardial route. Transendocardial injections were administered with an injection-tipped catheter and fluoroscopic guidance using X-ray fused with magnetic resonance imaging (XFM) roadmaps. Three months after treatment, tissues were analyzed for DNA, RNA, dystrophin protein, and histology. Whereas intracoronary delivery did not result in effective transduction, transendocardial injections, XFM guidance, enabled 30&#xb1;10 non-overlapping injections per animal. Vector DNA was detectable in all samples tested and ranged from <1 to >3000 vector genome copies per cell. RNA analysis, western blot analysis, and immunohistology demonstrated extensive expression of skipped RNA and dystrophin protein in the treated myocardium. Left ventricular function remained unchanged over a 3-month follow-up. These results demonstrated that effective transendocardial delivery of rAAV-U7smOPT was achieved using XFM. This approach restores an open reading frame for dystrophin in affected dogs and has potential clinical utility.

Animals↗
PubMed2014

Gene transfer of arginine kinase to skeletal muscle using adeno-associated virus.

In this study, we tested the feasibility of non-invasively measuring phosphoarginine (PArg) after gene delivery of arginine kinase (AK) using an adeno-associated virus (AAV) to murine hindlimbs. This was achieved by evaluating the time course, regional distribution and metabolic flux of PArg using (31)phosphorus magnetic resonance spectroscopy ((31)P-MRS). AK gene was injected into the gastrocnemius of the left hindlimb of C57Bl10 mice (age 5 weeks, male) using self-complementary AAV, type 2/8 with desmin promoter. Non-localized (31)P-MRS data were acquired over 9 months after injection using 11.1-T and 17.6-T Bruker Avance spectrometers. In addition, (31)P two-dimensional chemical shift imaging and saturation transfer experiments were performed to examine the spatial distribution and metabolic flux of PArg, respectively. PArg was evident in each injected mouse hindlimb after gene delivery, increased until 28 weeks, and remained elevated for at least 9 months (P<0.05). Furthermore, PArg was primarily localized to the injected posterior hindimb region and the metabolite was in exchange with ATP. Overall, the results show the viability of AAV gene transfer of AK gene to skeletal muscle, and provide support of PArg as a reporter that can be used to non-invasively monitor the transduction of genes for therapeutic interventions.

Animals↗
PubMed2016

Characterization of a novel adeno-associated viral vector with preferential oligodendrocyte tropism.

No adeno-associated virus (AAV) capsid has been described in the literature to exhibit a primary oligodendrocyte tropism when a constitutive promoter drives gene expression, which is a significant barrier for efficient in vivo oligodendrocyte gene transfer. The vast majority of AAV vectors, such as AAV1, 2, 5, 6, 8 or 9, exhibit a dominant neuronal tropism in the central nervous system. However, a novel AAV capsid (Olig001) generated using capsid shuffling and directed evolution was recovered after rat intravenous delivery and subsequent capsid clone rescue, which exhibited a >95% tropism for striatal oligodendrocytes after rat intracranial infusion where a constitutive promoter drove gene expression. Olig001 contains a chimeric mixture of AAV1, 2, 6, 8 and 9, but unlike these parental serotypes after intravenous administration Olig001 has very low affinity for peripheral organs, especially the liver. Furthermore, in mixed glial cell cultures, Olig001 exhibits a 9-fold greater binding when compared with AAV8. This novel oligodendrocyte-preferring AAV vector exhibits characteristics that are a marked departure from previously described AAV serotypes.

Animals↗