Great expectations: virus-mediated gene therapy in neurological disorders

2020 ◽  
Vol 91 (8) ◽  
pp. 849-860 ◽  
Author(s):  
Didu Kariyawasam ◽  
Ian E Alexander ◽  
Manju Kurian ◽  
Michelle Anne Farrar
Keyword(s):  
Gene Therapy ◽  
Health System ◽  
Neurological Disorders ◽  
Muscular Atrophy ◽  
Neurological Diseases ◽  
Quality Care ◽  
Great Expectations ◽  
Ongoing Research ◽  
Regulatory Policies ◽  
Effective Delivery

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.

scholarly journals Intranasal Delivery of Nanoformulations: A Potential Way of Treatment for Neurological Disorders

Molecules ◽  
2020 ◽  
Vol 25 (8) ◽  
pp. 1929 ◽  
Author(s):  
Salman Ul Islam ◽  
Adeeb Shehzad ◽  
Muhammad Bilal Ahmed ◽  
Young Sup Lee
Keyword(s):  
Drug Delivery ◽  
Neurological Disorders ◽  
Neurological Diseases ◽  
Nasal Delivery ◽  
Intranasal Route ◽  
Drug Molecules ◽  
Surface Enhanced ◽  
Effective Delivery ◽  
The Central Nervous System ◽  
The Brain

Although the global prevalence of neurological disorders such as Parkinson’s disease, Alzheimer’s disease, glioblastoma, epilepsy, and multiple sclerosis is steadily increasing, effective delivery of drug molecules in therapeutic quantities to the central nervous system (CNS) is still lacking. The blood brain barrier (BBB) is the major obstacle for the entry of drugs into the brain, as it comprises a tight layer of endothelial cells surrounded by astrocyte foot processes that limit drugs’ entry. In recent times, intranasal drug delivery has emerged as a reliable method to bypass the BBB and treat neurological diseases. The intranasal route for drug delivery to the brain with both solution and particulate formulations has been demonstrated repeatedly in preclinical models, including in human trials. The key features determining the efficacy of drug delivery via the intranasal route include delivery to the olfactory area of the nares, a longer retention time at the nasal mucosal surface, enhanced penetration of the drugs through the nasal epithelia, and reduced drug metabolism in the nasal cavity. This review describes important neurological disorders, challenges in drug delivery to the disordered CNS, and new nasal delivery techniques designed to overcome these challenges and facilitate more efficient and targeted drug delivery. The potential for treatment possibilities with intranasal transfer of drugs will increase with the development of more effective formulations and delivery devices.

scholarly journals Retromer Combinatorials for Gene-Therapy Across a Spectrum of Neurological Diseases

2020 ◽  
Author(s):  
Yasir H. Qureshi ◽  
Vivek M. Patel ◽  
Suvarnambiga Kannan ◽  
Samuel D Waksal ◽  
Gregory A. Petsko ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Neurological Disorders ◽  
Viral Vectors ◽  
Neurological Diseases ◽  
Neuroblastoma Cell ◽  
Biological Pathway ◽  
Endosomal Trafficking ◽  
Limited Effect ◽  
And Function ◽  
Neuroblastoma Cell Lines

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.

Microbiota-Immune System Interactions in Human Neurological Disorders

2020 ◽  
Vol 19 (7) ◽  
pp. 509-526
Author(s):  
Qin Huang ◽  
Fang Yu ◽  
Di Liao ◽  
Jian Xia
Keyword(s):  
Immune System ◽  
Gut Microbiota ◽  
Neurological Disorders ◽  
Brain Function ◽  
Neurological Diseases ◽  
Host Immune System ◽  
Gut Dysbiosis ◽  
Characteristic Features ◽  
Novel Therapeutic Strategies

: Recent studies implicate microbiota-brain communication as an essential factor for physiology and pathophysiology in brain function and neurodevelopment. One of the pivotal mechanisms about gut to brain communication is through the regulation and interaction of gut microbiota on the host immune system. In this review, we will discuss the role of microbiota-immune systeminteractions in human neurological disorders. The characteristic features in the development of neurological diseases include gut dysbiosis, the disturbed intestinal/Blood-Brain Barrier (BBB) permeability, the activated inflammatory response, and the changed microbial metabolites. Neurological disorders contribute to gut dysbiosis and some relevant metabolites in a top-down way. In turn, the activated immune system induced by the change of gut microbiota may deteriorate the development of neurological diseases through the disturbed gut/BBB barrier in a down-top way. Understanding the characterization and identification of microbiome-immune- brain signaling pathways will help us to yield novel therapeutic strategies by targeting the gut microbiome in neurological disease.

scholarly journals Cerebrospinal Fluid Parameters in Antisense Oligonucleotide-Treated Adult 5q-Spinal Muscular Atrophy Patients

2021 ◽  
Vol 11 (3) ◽  
pp. 296
Author(s):  
Lars Hendrik Müschen ◽  
Alma Osmanovic ◽  
Camilla Binz ◽  
Konstantin F. Jendretzky ◽  
Gresa Ranxha ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Spinal Muscular Atrophy ◽  
Total Protein ◽  
Antisense Oligonucleotide ◽  
Muscular Atrophy ◽  
Neurological Diseases ◽  
Clinical Signs ◽  
Central Nervous System Disease ◽  
Oligoclonal Bands ◽  
System Disease

Approval of nusinersen, an intrathecally administered antisense oligonucleotide, for the treatment of 5q-spinal muscular atrophy (SMA) marked the beginning of a new therapeutic era in neurological diseases. Changes in routine cerebrospinal fluid (CSF) parameters under nusinersen have only recently been described in adult SMA patients. We aimed to explore these findings in a real-world setting and to identify clinical and procedure-associated features that might impact CSF parameters. Routinely collected CSF parameters (leukocyte count, lactate, total protein, CSF/serum albumin quotient (QAlbumin), oligoclonal bands) of 28 adult SMA patients were examined for up to 22 months of nusinersen treatment. Total protein and QAlbumin values significantly increased in the first 10 months, independent of the administration procedure. By month 14, no further increases were detected. Two patients developed transient pleocytosis. In two cases, positive oligoclonal bands were found in the beginning and in four patients throughout the whole observation period. No clinical signs of inflammatory central nervous system disease were apparent. Our data confirm elevated CSF total protein and QAlbumin during nusinersen treatment. These alterations may be caused by both repeated lumbar punctures and the interval between procedures rather than by the medication itself. Generally, there were no severe alterations of CSF routine parameters. These results further underline the safety of nusinersen therapy.

scholarly journals Industry update for May 2019

2019 ◽  
Vol 10 (9) ◽  
pp. 555-561
Author(s):  
Louise Rosenmayr-Templeton
Keyword(s):  
Gene Therapy ◽  
Cost Effectiveness ◽  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Clinical Results ◽  
The Other ◽  
Press Releases ◽  
The Us ◽  
True Meaning ◽  
Genetic Medicine

This industry update features a round-up of pharmaceutical news in May 2019 based on press releases and websites. The month was characterized by the achievement of significant milestones in gene therapy. The biggest of these was the US FDA’s approval of Zolgensma®. This medicine sums up the promise and price of genetic medicine. On one hand the clinical results show Zolgensma can dramatically improve the prognosis for infants with spinal muscular atrophy after just one administration, while on the other, it has been priced at around US$2.1 million. With more such therapies likely to reach the market, the debate on Zolgensma goes beyond cost, to overall affordability, the true meaning of cost–effectiveness and how to reward companies for effective, innovative medicines.

scholarly journals The atlas of RNase H antisense oligonucleotide distribution and activity in the CNS of rodents and non-human primates following central administration

2020 ◽  
Author(s):  
Paymaan Jafar-nejad ◽  
Berit Powers ◽  
Armand Soriano ◽  
Hien Zhao ◽  
Daniel A Norris ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Muscular Atrophy ◽  
Neurological Diseases ◽  
Cell Types ◽  
Rnase H ◽  
Central Administration ◽  
Spinal Motor Neurons ◽  
New Class ◽  
Wide Range ◽  
Therapeutic Development

Abstract Antisense oligonucleotides (ASOs) have emerged as a new class of drugs to treat a wide range of diseases, including neurological indications. Spinraza, an ASO that modulates splicing of SMN2 RNA, has shown profound disease modifying effects in Spinal Muscular Atrophy (SMA) patients, energizing efforts to develop ASOs for other neurological diseases. While SMA specifically affects spinal motor neurons, other neurological diseases affect different central nervous system (CNS) regions, neuronal and non-neuronal cells. Therefore, it is important to characterize ASO distribution and activity in all major CNS structures and cell types to have a better understanding of which neurological diseases are amenable to ASO therapy. Here we present for the first time the atlas of ASO distribution and activity in the CNS of mice, rats, and non-human primates (NHP), species commonly used in preclinical therapeutic development. Following central administration of an ASO to rodents, we observe widespread distribution and target RNA reduction throughout the CNS in neurons, oligodendrocytes, astrocytes and microglia. This is also the case in NHP, despite a larger CNS volume and more complex neuroarchitecture. Our results demonstrate that ASO drugs are well suited for treating a wide range of neurological diseases for which no effective treatments are available.

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