scholarly journals Design and Validation of a Multi-Point Injection Technology for MR-Guided Convection Enhanced Delivery in the Brain

2021 ◽  
Vol 3 ◽  
Author(s):  
Kayla Prezelski ◽  
Megan Keiser ◽  
Joel M. Stein ◽  
Timothy H. Lucas ◽  
Beverly Davidson ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Viral Vectors ◽  
Low Flow ◽  
Limiting Factor ◽  
Volume Distribution ◽  
Convection Enhanced Delivery ◽  
Flow Rates ◽  
Point Injection ◽  
Subcortical Regions ◽  
Injection Technology

Convection enhanced delivery (CED) allows direct intracranial administration of neuro-therapeutics. Success of CED relies on specific targeting and broad volume distributions (VD). However, to prevent off-target delivery and tissue damage, CED is typically conducted with small cannulas and at low flow rates, which critically limit the maximum achievable VD. Furthermore, in applications such as gene therapy requiring injections of large fluid volumes into broad subcortical regions, low flow rates translate into long infusion times and multiple surgical trajectories. The cannula design is a major limiting factor in achieving broad VD, while minimizing infusion time and backflow. Here we present and validate a novel multi-point cannula specifically designed to optimize distribution and delivery time in MR-guided intracranial CED of gene-based therapeutics. First, we evaluated the compatibility of our cannula with MRI and common viral vectors for gene therapy. Then, we conducted CED tests in agarose brain phantoms and benchmarked the results against single-needle delivery. 3T MRI in brain phantoms revealed minimal susceptibility-induced artifacts, comparable to the device dimensions. Benchtop CED of adeno-associated virus demonstrated no viral loss or inactivation. CED in agarose brain phantoms at 3, 6, and 9 μL/min showed >3x increase in volume distribution and 60% time reduction compared to single-needle delivery. This study confirms the validity of a multi-point delivery approach for improving infusate distribution at clinically-compatible timescales and supports the feasibility of our novel cannula design for advancing safety and efficacy of MR-guided CED to the central nervous system.

scholarly journals Design and validation of a multi-point injection technology for MR-guided convection enhanced delivery in the brain

2021 ◽  
Author(s):  
Kayla Prezelski ◽  
Megan Keiser ◽  
Joel M. Stein ◽  
Timothy H. Lucas ◽  
Beverly Davidson ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Viral Vectors ◽  
Low Flow ◽  
Limiting Factor ◽  
Volume Distribution ◽  
Convection Enhanced Delivery ◽  
Flow Rates ◽  
Point Injection ◽  
Subcortical Regions ◽  
Injection Technology

Convection enhanced delivery (CED) allows direct intracranial administration of neuro-therapeutics. Success of CED relies on specific targeting and broad volume distributions (VD). However, to prevent off-target delivery and tissue damage, CED is typically conducted with small cannulas and at low flow rates, which critically limit the maximum achievable VD. Furthermore, in applications such as gene therapy requiring injections of large fluid volumes into broad subcortical regions, low flow rates translate into long infusion times and multiple surgical trajectories. The cannula design is a major limiting factor in achieving broad VD, while minimizing infusion time and backflow. Here we present and validate a novel multi-point cannula specifically designed to optimize distribution and delivery time in MR-guided intracranial CED of gene-based therapeutics. First, we evaluated the compatibility of our cannula with MRI and common viral vectors for gene therapy. Then, we conducted CED tests in agarose brain phantoms and benchmarked the results against single-needle delivery. 3T MRI in brain phantoms revealed minimal susceptibility-induced artifacts, comparable to the device dimensions. Benchtop CED of adeno-associated virus demonstrated no viral loss or inactivation. CED in agarose brain phantoms at 3, 6, and 9 microL/min showed >3x increase in volume distribution and 60% time reduction compared to single-needle delivery. This study confirms the validity of a multi-point delivery approach for improving infusate distribution at clinically-compatible timescales and supports the feasibility of our novel cannula design for advancing safety and efficacy of MR-guided CED to the central nervous system.

Non-Viral Vectors for Gene Delivery

2018 ◽  
Vol 9 (1) ◽  
pp. 4-11 ◽  
Author(s):  
Aparna Bansal ◽  
Himanshu
Keyword(s):  
Gene Therapy ◽  
Viral Vectors ◽  
Transfection Efficiency ◽  
Gene Transfection ◽  
Expression System ◽  
Target Cells ◽  
Specific Expression ◽  
Naked Dna

Introduction: Gene therapy has emerged out as a promising therapeutic pave for the treatment of genetic and acquired diseases. Gene transfection into target cells using naked DNA is a simple and safe approach which has been further improved by combining vectors or gene carriers. Both viral and non-viral approaches have achieved a milestone to establish this technique, but non-viral approaches have attained a significant attention because of their favourable properties like less immunotoxicity and biosafety, easy to produce with versatile surface modifications, etc. Literature is rich in evidences which revealed that undoubtedly, non–viral vectors have acquired a unique place in gene therapy but still there are number of challenges which are to be overcome to increase their effectiveness and prove them ideal gene vectors. Conclusion: To date, tissue specific expression, long lasting gene expression system, enhanced gene transfection efficiency has been achieved with improvement in delivery methods using non-viral vectors. This review mainly summarizes the various physical and chemical methods for gene transfer in vitro and in vivo.

scholarly journals Gene therapy via canalostomy approach preserves auditory and vestibular functions in a mouse model of Jervell and Lange-Nielsen syndrome type 2

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xuewen Wu ◽  
Li Zhang ◽  
Yihui Li ◽  
Wenjuan Zhang ◽  
Jianjun Wang ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Mouse Model ◽  
Inner Ear ◽  
Viral Vectors ◽  
Survival Rates ◽  
Semicircular Canals ◽  
Dependent Manner ◽  
Syndrome Type ◽  
Dose Dependent

AbstractMutations in voltage-gated potassium channel KCNE1 cause Jervell and Lange-Nielsen syndrome type 2 (JLNS2), resulting in congenital deafness and vestibular dysfunction. We conducted gene therapy by injecting viral vectors using the canalostomy approach in Kcne1−/− mice to treat both the hearing and vestibular symptoms. Results showed early treatment prevented collapse of the Reissner’s membrane and vestibular wall, retained the normal size of the semicircular canals, and prevented the degeneration of inner ear cells. In a dose-dependent manner, the treatment preserved auditory (16 out of 20 mice) and vestibular (20/20) functions in mice treated with the high-dosage for at least five months. In the low-dosage group, a subgroup of mice (13/20) showed improvements only in the vestibular functions. Results supported that highly efficient transduction is one of the key factors for achieving the efficacy and maintaining the long-term therapeutic effect. Secondary outcomes of treatment included improved birth and litter survival rates. Our results demonstrated that gene therapy via the canalostomy approach, which has been considered to be one of the more feasible delivery methods for human inner ear gene therapy, preserved auditory and vestibular functions in a dose-dependent manner in a mouse model of JLNS2.

scholarly journals How Far Are Non-Viral Vectors to Come of Age and Reach Clinical Translation in Gene Therapy?

2021 ◽  
Vol 22 (14) ◽  
pp. 7545
Author(s):  
Myriam Sainz-Ramos ◽  
Idoia Gallego ◽  
Ilia Villate-Beitia ◽  
Jon Zarate ◽  
Iván Maldonado ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Clinical Practice ◽  
Gene Delivery ◽  
Viral Vectors ◽  
Viral Vector ◽  
Clinical Success ◽  
Genetic Material ◽  
Viral Gene ◽  
Promising Alternative ◽  
Vector Systems

Efficient delivery of genetic material into cells is a critical process to translate gene therapy into clinical practice. In this sense, the increased knowledge acquired during past years in the molecular biology and nanotechnology fields has contributed to the development of different kinds of non-viral vector systems as a promising alternative to virus-based gene delivery counterparts. Consequently, the development of non-viral vectors has gained attention, and nowadays, gene delivery mediated by these systems is considered as the cornerstone of modern gene therapy due to relevant advantages such as low toxicity, poor immunogenicity and high packing capacity. However, despite these relevant advantages, non-viral vectors have been poorly translated into clinical success. This review addresses some critical issues that need to be considered for clinical practice application of non-viral vectors in mainstream medicine, such as efficiency, biocompatibility, long-lasting effect, route of administration, design of experimental condition or commercialization process. In addition, potential strategies for overcoming main hurdles are also addressed. Overall, this review aims to raise awareness among the scientific community and help researchers gain knowledge in the design of safe and efficient non-viral gene delivery systems for clinical applications to progress in the gene therapy field.

scholarly journals Future Prospects of Gene Therapy for Friedreich’s Ataxia

2021 ◽  
Vol 22 (4) ◽  
pp. 1815 ◽  
Author(s):  
Gabriel Ocana-Santero ◽  
Javier Díaz-Nido ◽  
Saúl Herranz-Martín
Keyword(s):  
Gene Therapy ◽  
Viral Vectors ◽  
Autosomal Recessive ◽  
State Of The Art ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
First Intron ◽  
Progressive Neurodegeneration ◽  
Feasible Solutions ◽  
Neurogenetic Disease

Friedreich’s ataxia is an autosomal recessive neurogenetic disease that is mainly associated with atrophy of the spinal cord and progressive neurodegeneration in the cerebellum. The disease is caused by a GAA-expansion in the first intron of the frataxin gene leading to a decreased level of frataxin protein, which results in mitochondrial dysfunction. Currently, there is no effective treatment to delay neurodegeneration in Friedreich’s ataxia. A plausible therapeutic approach is gene therapy. Indeed, Friedreich’s ataxia mouse models have been treated with viral vectors en-coding for either FXN or neurotrophins, such as brain-derived neurotrophic factor showing promising results. Thus, gene therapy is increasingly consolidating as one of the most promising therapies. However, several hurdles have to be overcome, including immunotoxicity and pheno-toxicity. We review the state of the art of gene therapy in Friedreich’s ataxia, addressing the main challenges and the most feasible solutions for them.

Assessment of the Use of Humidified Nasal Cannulas for Oxygen Therapy in Patients with Epistaxis

ORL ◽  
2021 ◽  
pp. 1-5
Author(s):  
Jingjing Liu ◽  
Tengfang Chen ◽  
Zhenggang Lv ◽  
Dezhong Wu
Keyword(s):  
Flow Rate ◽  
Oxygen Therapy ◽  
Preliminary Investigation ◽  
Nasal Cannula ◽  
Low Flow ◽  
Antiplatelet Drugs ◽  
Flow Rates ◽  
The Past ◽  
Oxygen Inhalation ◽  
Significant Difference

<b><i>Introduction:</i></b> In China, nasal cannula oxygen therapy is typically humidified. However, it is difficult to decide whether to suspend nasal cannula oxygen inhalation after the nosebleed has temporarily stopped. Therefore, we conducted a preliminary investigation on whether the use of humidified nasal cannulas in our hospital increases the incidence of epistaxis. <b><i>Methods:</i></b> We conducted a survey of 176,058 inpatients in our hospital and other city branches of our hospital over the past 3 years and obtained information concerning their use of humidified nasal cannulas for oxygen inhalation, nonhumidified nasal cannulas, anticoagulant and antiplatelet drugs, and oxygen inhalation flow rates. This information was compared with the data collected at consultation for epistaxis during these 3 years. <b><i>Results:</i></b> No significant difference was found between inpatients with humidified nasal cannulas and those without nasal cannula oxygen therapy in the incidence of consultations due to epistaxis (χ<sup>2</sup> = 1.007, <i>p</i> &#x3e; 0.05). The same trend was observed among hospitalized patients using anticoagulant and antiplatelet drugs (χ<sup>2</sup> = 2.082, <i>p</i> &#x3e; 0.05). Among the patients with an inhaled oxygen flow rate ≥5 L/min, the incidence of ear-nose-throat (ENT) consultations due to epistaxis was 0. No statistically significant difference was found between inpatients with a humidified oxygen inhalation flow rate &#x3c;5 L/min and those without nasal cannula oxygen therapy in the incidence of ENT consultations due to epistaxis (χ<sup>2</sup> = 0.838, <i>p</i> &#x3e; 0.05). A statistically significant difference was observed in the incidence of ENT consultations due to epistaxis between the low-flow nonhumidified nasal cannula and nonnasal cannula oxygen inhalation groups (χ<sup>2</sup> = 18.428, <i>p</i> &#x3c; 0.001). The same trend was observed between the 2 groups of low-flow humidified and low-flow nonhumidified nasal cannula oxygen inhalation (χ<sup>2</sup> = 26.194, <i>p</i> &#x3c; 0.001). <b><i>Discussion/Conclusion:</i></b> Neither high-flow humidified nasal cannula oxygen inhalation nor low-flow humidified nasal cannula oxygen inhalation will increase the incidence of recurrent or serious epistaxis complications; the same trend was observed for patients who use anticoagulant and antiplatelet drugs. Humidification during low-flow nasal cannula oxygen inhalation can prevent severe and repeated epistaxis to a certain extent.

Tropism-Modified Adenoviral and Adeno-Associated Viral Vectors for Gene Therapy

2002 ◽  
Vol 2 (3) ◽  
pp. 273-293 ◽  
Author(s):  
Stuart Nicklin ◽  
Andrew Baker
Keyword(s):  
Gene Therapy ◽  
Viral Vectors
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