scholarly journals Gene therapy with oligonucleotides for neurological diseases

2012 ◽  
Vol 52 (11) ◽  
pp. 1213-1213
Author(s):  
Takanori Yokota
2020 ◽  
Author(s):  
Yasir H. Qureshi ◽  
Vivek M. Patel ◽  
Suvarnambiga Kannan ◽  
Samuel D Waksal ◽  
Gregory A. Petsko ◽  
...  

ABSTRACTEndosomal trafficking is a biological pathway implicated in Alzheimer’s and Parkinson’s disease, and a growing number of other neurological disorders. For this category of diseases, the endosome’s trafficking complex retromer has emerged as a validated therapeutic target. Retromer’s core is a heterotrimeric complex composed of the scaffold protein VPS35 to which VPS26 and VPS29 bind. Unless it is deficient, increasing expression of VPS35 by viral vectors has a limited effect on other trimeric members and on retromer’s overall function. Here we set out to address these constraints and, based on prior insight, hypothesized that co-expressing VPS35 and VPS26 would synergistically interact and elevate retromer’s trimeric expression and function. Neurons, however, are distinct in expressing two VPS26 paralogs, VPS26a and VPS26b, and so to test the hypothesis we generated three novel AAV9 vectors harboring the VPS35, or VPS26a, or VPS26b transgene. First, we optimized their expression in neuroblastoma cell lines, then, in a comprehensive series of neuronal culture experiments, we expressed VPS35, VPS26a, and VPS26b individually and in all possible combinations. Confirming our hypothesis, expressing individual proteins failed to affect the trimer, while VPS35 and VPS26 combinatorials synergized the trimer’s expression. In addition, we illustrate functional synergy by showing that only VPS35 and VPS26 combinatorials significantly increase levels of Sorl1, a key retromer-receptor deficient in Alzheimer’s disease. Collectively, and together with other recent observations, these results suggest a precision-medicine logic when applying retromer gene therapy to a host of neurological disorders, depending on each disorder’s specific retromer-related molecular and anatomical phenotype.


2020 ◽  
Vol 91 (8) ◽  
pp. 849-860 ◽  
Author(s):  
Didu Kariyawasam ◽  
Ian E Alexander ◽  
Manju Kurian ◽  
Michelle Anne Farrar

Gene therapy (GT) has tremendous potential for the treatment of neurological disorders to transform patient care. The successful application of virus-mediated GT to treat spinal muscular atrophy is a significant milestone, serving to accelerate similar progress in a spectrum of neurological conditions, with more than 50 clinical trials currently underway, across neurodevelopmental, neurodegenerative, muscular dystrophy, epilepsy, chronic pain and neoplastic diseases. This review provides an overview of the key features of virus-mediated GT, paradigms of delivery and dosing, potential risks and highlights ongoing research to optimise safe and effective delivery of vectors into the nervous system. Examples of the application of GT in various neurological diseases alongside clinical development challenges will be presented. As the development and translation of GTs gain pace, success can only ultimately be realised for patients following implementation in the health system. The challenges and controversies of daunting costs, ethics, early diagnosis and health system readiness will require innovative pricing schemes, regulatory policies, education and organisation of a skilled workforce to deliver of high-quality care in clinical practice as we prepare for advanced therapeutics in neurology.


Author(s):  
William Bowers ◽  
Suresh de Silva ◽  
Howard Federoff

Neoplasia ◽  
1999 ◽  
Vol 1 (5) ◽  
pp. 402-416 ◽  
Author(s):  
Andreas Jacobs ◽  
Xandra O. Breakefield ◽  
Cornel Fraefel

2021 ◽  
Vol 4 (10) ◽  
pp. e202101040
Author(s):  
Cristin D Davidson ◽  
Alana L Gibson ◽  
Tansy Gu ◽  
Laura L Baxter ◽  
Benjamin E Deverman ◽  
...  

Niemann–Pick C1 disease (NPC1) is a rare, fatal neurodegenerative disease caused by mutations in NPC1, which encodes the lysosomal cholesterol transport protein NPC1. Disease pathology involves lysosomal accumulation of cholesterol and lipids, leading to neurological and visceral complications. Targeting the central nervous system (CNS) from systemic circulation complicates treatment of neurological diseases with gene transfer techniques. Selected and engineered capsids, for example, adeno-associated virus (AAV)-PHP.B facilitate peripheral-to-CNS transfer and hence greater CNS transduction than parental predecessors. We report that systemic delivery to Npc1m1N/m1N mice using an AAV-PHP.B vector ubiquitously expressing NPC1 led to greater disease amelioration than an otherwise identical AAV9 vector. In addition, viral copy number and biodistribution of GFP-expressing reporters showed that AAV-PHP.B achieved more efficient, albeit variable, CNS transduction than AAV9 in Npc1m1N/m1N mice. This variability was associated with segregation of two alleles of the putative AAV-PHP.B receptor Ly6a in Npc1m1N/m1N mice. Our data suggest that robust improvements in NPC1 disease phenotypes occur even with modest CNS transduction and that improved neurotrophic capsids have the potential for superior NPC1 AAV gene therapy vectors.


Author(s):  
Lisa M. Stanek ◽  
Lamya S. Shihabuddin ◽  
Seng H. Cheng

2020 ◽  
Vol 20 (3) ◽  
pp. 164-173
Author(s):  
Saleha Rehman ◽  
Bushra Nabi ◽  
Faheem Hyder Pottoo ◽  
Sanjula Baboota ◽  
Javed Ali

: The neuropsychiatric illnesses have been enigmatic, with no effective treatment to date. The complexity and heterogeneity of psychiatric disorders are daunting for the development of novel treatment modalities. The conventional treatment approaches are less effective and are associated with several side effects, thus creating the need for the development of more innovative strategies. Since psychiatric disorders are known to exhibit genetic linkage, gene therapy has created an interest among the researchers worldwide. The delivery of nucleic acids is a complex process requiring the transport of genetic material across various intracellular and extracellular barriers to reach the target cells eliciting the transfection process. Therefore, the identification or development of the delivery system for nucleic acid delivery still remains the challenge. Viral vectors are quite effective but are associated with toxicity and side effects. With the rapid advancement in the field of nanotechnology, nanosized materials were identified to be the perfect candidate for nonviral vectors in gene delivery. The biggest advantage of nanoparticles is that their surface can be engineered in many possible ways to deliver the drugs directly to the target site. Although gene therapy has already been established as an innovative treatment modality for several neurological diseases, its use in psychiatry still warrants more investigations for its translation into clinical use. The present manuscript discusses the prospects of gene therapy in psychiatric disorders, their benefits, and pitfalls. The review embarks upon the importance of nanoparticle-based gene therapy for effective management of psychiatric disorders.


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