scholarly journals Intrastriatal Administration of AAV5-miHTT in Non-Human Primates and Rats Is Well Tolerated and Results in miHTT Transgene Expression in Key Areas of Huntington Disease Pathology

2021 ◽  
Vol 11 (2) ◽  
pp. 129
Author(s):  
Elisabeth A. Spronck ◽  
Astrid Vallès ◽  
Margit H. Lampen ◽  
Paula S. Montenegro-Miranda ◽  
Sonay Keskin ◽  
...  
Keyword(s):  
Huntington Disease ◽  
Genetic Disorder ◽  
Sprague Dawley ◽  
Convection Enhanced Delivery ◽  
Virus Serotype ◽  
Mutant Huntingtin Protein ◽  
Serotype 5 ◽  
Magnetic Resonance Imaging Mri ◽  
The Brain ◽  
Intrastriatal Administration

Huntington disease (HD) is a fatal, neurodegenerative genetic disorder with aggregation of mutant Huntingtin protein (mutHTT) in the brain as a key pathological mechanism. There are currently no disease modifying therapies for HD; however, HTT-lowering therapies hold promise. Recombinant adeno-associated virus serotype 5 expressing a microRNA that targets HTT mRNA (AAV5-miHTT) is in development for the treatment of HD with promising results in rodent and minipig HD models. To support a clinical trial, toxicity studies were performed in non-human primates (NHP, Macaca fascicularis) and Sprague-Dawley rats to evaluate the safety of AAV5-miHTT, the neurosurgical administration procedure, vector delivery and expression of the miHTT transgene during a 6-month observation period. For accurate delivery of AAV5-miHTT to the striatum, real-time magnetic resonance imaging (MRI) with convection-enhanced delivery (CED) was used in NHP. Catheters were successfully implanted in 24 NHP, without neurological symptoms, and resulted in tracer signal in the target areas. Widespread vector DNA and miHTT transgene distribution in the brain was found, particularly in areas associated with HD pathology. Intrastriatal administration of AAV5-miHTT was well tolerated with no clinically relevant changes in either species. These studies demonstrate the excellent safety profile of AAV5-miHTT, the reproducibility and tolerability of intrastriatal administration, and the delivery of AAV5-miHTT to the brain, which support the transition of AAV5-miHTT into clinical studies.

EXTH-31. BRAIN DISTRIBUTION, CLEARANCE AND TOXICITY EVALUATION OF SMALL-MOLECULE INHIBITORS FOLLOWING CONVECTION-ENHANCED DELIVERY TO THE BRAINSTEM

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi170-vi170
Author(s):  
Erica Power ◽  
Juhee Oh ◽  
Jonghoon Choi ◽  
William Elmquist ◽  
David Daniels
Keyword(s):  
Small Molecule ◽  
Drug Concentration ◽  
Small Molecule Inhibitors ◽  
Efflux Pump ◽  
Sprague Dawley ◽  
Convection Enhanced Delivery ◽  
Efflux Pump Inhibitor ◽  
Delivery Technique ◽  
The Brain

Abstract BACKGROUND Diffuse midline gliomas (DMGs) harboring the H3K27M mutation are highly aggressive, fatal brainstem tumors that primarily occur in children. The blood-brain barrier (BBB) prevents numerous drugs from reaching CNS tumors, like DMG, at cytotoxic concentrations. Convection-enhanced delivery (CED) has emerged as a drug delivery technique that bypasses the BBB through a direct interstitial infusion under a pressure gradient. However, drug distribution and clearance from the brain following CED is poorly understood and has been cited as a potential reason for the lack of efficacy observed in prior clinical trials. OBJECTIVE The objective of this study was to understand how two small molecule inhibitors (alisertib, ponatinib) that inhibit cell growth and proliferation in DMG cells in vitro distribute and clear from the brain following CED to the brainstem. METHODS Sprague-dawley rats underwent a single 60mL CED infusion of drug to the brainstem (200mM alisertib, 10mM ponatinib) and were sacrificed 0.083, 1, 2, 4, 8 and 24 hours following the completion of the infusion. Brains were dissected and drug concentration was determined via HPLC analysis. RESULTS No rats showed any clinical or neurological signs of toxicity post-infusion. Both drugs showed significant differences in drug concentration based on anatomical brain region where higher concentrations were observed in the pons and cerebellum compared to the cortex. Drug half-life in the brain was ~0.5 hours for alisertib and ~1 hour for ponatinib, but this was not significantly increased following co-administration of elacridar, a BBB efflux pump inhibitor. CONCLUSIONS These results suggest that elimination of drugs from the brain in a complex, multifactorial mechanism that warrants further preclinical investigation prior to the initiation of a clinical trial.

scholarly journals PDTM-30. UNDERSTANDING THE EFFECTS OF MOLECULAR SIZE ON VOLUME OF DISTRIBUTION IN CONVECTION-ENHANCED DELIVERY

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi193-vi194
Author(s):  
Erica Power ◽  
Julian Rechberger ◽  
Liang Zhang ◽  
David Daniels
Keyword(s):  
Molecular Weight ◽  
Single Injection ◽  
Fluorescent Microscopy ◽  
Molecular Size ◽  
Volume Of Distribution ◽  
Sprague Dawley ◽  
Convection Enhanced Delivery ◽  
Microscopy Imaging ◽  
Delivery Technique ◽  
The Brain

Abstract BACKGROUND Diffuse midline gliomas harboring the H3K27M mutation, previously known as diffuse intrinsic pontine gliomas (DIPG), are rare and aggressive pediatric brain tumors. Over 100 clinical trials with different chemotherapeutics have failed to show any therapeutic benefit. One reason for failure is likely due to poor delivery of these agents to the brainstem. Convection-enhanced delivery (CED) is an emerging delivery technique used to directly inject the agent of interest into the brainstem under pressure. While there is evidence that this may be an effective delivery method, little work has been done to understand the optimal physical properties of these drugs. We sought characterize volume of distribution in the brain based on molecular size of the agent delivered via CED. METHODS Sprague- Dawley rats underwent a single injection of FITC-dextran (3,000 Da, 10,000 Da, 20,000 Da, 70,000 Da, 150,000 Da) via CED into the pons. Post-injection, animals were sacrificed and their brains harvested. Fluorescent microscopy imaging was used to calculate the volume of distribution of the FITC-dextran throughout the brain. RESULTS The volume of distribution (Vd) decreased exponentially according to a two-phase delay (r2= 0.94) as the molecular size of the FITC-dextran increased. The highest mean Vd (107.87mm3) was at a molecular weight of 3,000 Da, and lowest mean Vd (26.48 mm3) was at a molecular weight of 150,000 Da. ANOVA analysis was statistically significant (p= 0.0017). CONCLUSIONS As the molecular size of the FITC-dextran increased, the volume of distribution within the brain following a single injection via CED into the pons decreased. A better understanding of how drugs distribute by convection will allow us to optimize treatment regimens for DIPG tumors.

Ultrasound-assisted convection-enhanced delivery to the brain in vivo with a novel transducer cannula assembly

2012 ◽  
Vol 117 (6) ◽  
pp. 1128-1140 ◽  
Author(s):  
George K. Lewis ◽  
Zachary R. Schulz ◽  
Susan C. Pannullo ◽  
Teresa L. Southard ◽  
William L. Olbricht
Keyword(s):  
Continuous Wave ◽  
Sprague Dawley ◽  
Convection Enhanced Delivery ◽  
Rodent Brain ◽  
Sprague Dawley Rats ◽  
Ultrasound Assisted ◽  
Group 2 ◽  
The Brain ◽  
Group 1

Object In convection-enhanced delivery (CED), drugs are infused locally into tissue through a cannula inserted into the brain parenchyma to enhance drug penetration over diffusion strategies. The purpose of this study was to demonstrate the feasibility of ultrasound-assisted CED (UCED) in the rodent brain in vivo using a novel, low-profile transducer cannula assembly (TCA) and portable, pocket-sized ultrasound system. Methods Forty Sprague-Dawley rats (350–450 g) were divided into 2 equal groups (Groups 1 and 2). Each group was divided again into 4 subgroups (n = 5 in each). The caudate of each rodent brain was infused with 0.25 wt% Evans blue dye (EBD) in phosphate-buffered saline at 2 different infusion rates of 0.25 μl/minute (Group 1), and 0.5 μl/minute (Group 2). The infusion rates were increased slowly over 10 minutes from 0.05 to 0.25 μl/minute (Group 1) and from 0.1 to 0.5 μl/minute (Group 2). The final flow rate was maintained for 20 minutes. Rodents in the 4 control subgroups were infused using the TCA without ultrasound and without and with microbubbles added to the infusate (CED and CED + MB, respectively). Rodents in the 4 UCED subgroups were infused without and with microbubbles added to the infusate (UCED and UCED + MB) using the TCA with continuous-wave 1.34-MHz low-intensity ultrasound at a total acoustic power of 0.11 ± 0.005 W and peak spatial intensity at the cannula tip of 49.7 mW/cm2. An additional 4 Sprague-Dawley rats (350–450 g) received UCED at 4 different and higher ultrasound intensities at the cannula tip ranging from 62.0 to 155.0 mW/cm2 for 30 minutes. The 3D infusion distribution was reconstructed using MATLAB analysis. Tissue damage and morphological changes to the brain were assessed using H & E. Results The application of ultrasound during infusion (UCED and UCED + MB) improved the volumetric distribution of EBD in the brain by a factor of 2.24 to 3.25 when there were no microbubbles in the infusate and by a factor of 1.16 to 1.70 when microbubbles were added to the infusate (p < 0.001). On gross and histological examination, no damage to the brain tissue was found for any acoustic exposure applied to the brain. Conclusions The TCA and ultrasound device show promise to improve the distribution of infused compounds during CED. The results suggest further studies are required to optimize infusion and acoustic parameters for small compounds and for larger molecular weight compounds that are representative of promising antitumor agents. In addition, safe levels of ultrasound exposure in chronic experiments must be determined for practical clinical evaluation of UCED. Extension of these experiments to larger animal models is warranted to demonstrate efficacy of this technique.

scholarly journals Joubert’s syndrome: a case report

2020 ◽  
Vol 7 (10) ◽  
pp. 2068
Author(s):  
Kapil S. Bainade ◽  
Veeranna A. Kotrashetti ◽  
Vijay B. Sonawane ◽  
Amit Vatakar ◽  
Shuchi R. Bhatarkar
Keyword(s):  
Genetic Disorder ◽  
Signs And Symptoms ◽  
Joubert Syndrome ◽  
Molar Tooth ◽  
Breathing Patterns ◽  
Molar Tooth Sign ◽  
Specific Finding ◽  
Abnormal Breathing ◽  
Magnetic Resonance Imaging Mri ◽  
The Brain

Joubert syndrome is an autosomal recessive genetic disorder that affects the area of the brain that controls balance and coordination. This syndrome is difficult to diagnose clinically because of its variable phenotype.  Signs and symptoms commonly include hypotonia abnormal breathing patterns; abnormal eye movements; ataxia; distinctive facial features; and intellectual disability. Various other abnormalities may also be present. This condition is characterized by a specific finding on an magnetic resonance imaging (MRI) called a "molar tooth sign" in which the cerebellar vermis of the brain is absent or underdeveloped and the brain stem is abnormal. The exact diagnosis is often not made for several years after birth.We present a case of Joubert syndrome in a thirteen year old male with developmental delay, ataxia, mild hypotonia, nystagmus and molar tooth sign on MRI. Awareness of the characteristic clinical and radiological findings in Joubert syndrome will help in early diagnosis, appropriate counselling and proper rehabilitation.

scholarly journals A Review on Structure Based Therapeutic Approach for Huntington Disease

2021 ◽  
Vol 12 (1) ◽  
pp. 536-543
Author(s):  
Om Prakash Goshain ◽  
Satish Kumar Sharma
Keyword(s):  
Er Stress ◽  
Huntington Disease ◽  
Structural Changes ◽  
Dynamic Simulations ◽  
Association Pattern ◽  
The Social ◽  
Mutant Huntingtin Protein ◽  
Protein Response ◽  
Novel Drug ◽  
The Brain

Huntington disease (HD) is a fatal and progressive neurodegenerative disease that has affected the social and personal life of patients. The disease causes the most disturbing symptoms of chorea, which is characterized by uncontrolled body movements. HD patients are being treated by providing drugs that maintain neurotransmission balance and relieve chorea symptoms. HD has been associated with mutant Huntingtin protein (mHtt) with more than thirty-six polyQ stretches at N terminal of 34 kDaHtt protein. mHtt protein undergoes misfolding, which leads to accumulation of toxic mHtt aggregates in the brain. The phenomenon of protein aggregation initiates a cascade of events, eventually leading to endoplasmic reticulum (ER) stress and misregulated unfolding protein response (UPR). Different molecular targets have been identified from ER stress and UPR pathways for finding potential molecules that can treat HD. Overall, the mechanism causes structural transitions in mHtt, which can be controlled at the subatomic and molecular level by molecular dynamic simulations (MDS). The MDS strategies help to observe structural changes in the mHtt protein and association pattern between the protein and novel drug compounds. Hence, this study explains the journey of HD research to computational strategies and the scope of structural drug designing in psychologically disturbing Huntington’s disease.

Permeability of the microcirculation in area postrema of rat

1988 ◽  
Vol 46 ◽  
pp. 348-349
Author(s):  
Shams M. Ghoneim ◽  
Frank M. Faraci ◽  
Gary L. Baumbach
Keyword(s):  
Brain Stem ◽  
Area Postrema ◽  
Upper Body ◽  
Sprague Dawley ◽  
Sodium Cacodylate ◽  
Acute Hypertension ◽  
Sprague Dawley Rats ◽  
Ultrastructural Characteristics ◽  
The Brain ◽  
Adjacent Brain

The area postrema is a circumventricular organ in the brain stem and is one of the regions in the brain that lacks a fully functional blood-brain barrier. Recently, we found that disruption of the microcirculation during acute hypertension is greater in area postrema than in the adjacent brain stem. In contrast, hyperosmolar disruption of the microcirculation is greater in brain stem. The objective of this study was to compare ultrastructural characteristics of the microcirculation in area postrema and adjacent brain stem.We studied 5 Sprague-Dawley rats. Horseradish peroxidase was injected intravenously and allowed to circulate for 1, 5 or 15 minutes. Following perfusion of the upper body with 2.25% glutaraldehyde in 0.1 M sodium cacodylate, the brain stem was removed, embedded in agar, and chopped into 50-70 μm sections with a TC-Sorvall tissue chopper. Sections of brain stem were incubated for 1 hour in a solution of 3,3' diaminobenzidine tetrahydrochloride (0.05%) in 0.05M Tris buffer with 1% H2O2.

Role of Cardiac MRI in Detecting Familial Hypertrophic Cardiomyopathy: Review

2016 ◽  
Vol 1 (1) ◽  
pp. 4
Author(s):  
Marymol Koshy ◽  
Bushra Johari ◽  
Mohd Farhan Hamdan ◽  
Mohammad Hanafiah
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Magnetic Resonance ◽  
Genetic Disorder ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Non Invasive ◽  
Wide Range ◽  
Proper Diagnosis ◽  
Magnetic Resonance Imaging Mri ◽  
Potential Use

Hypertrophic cardiomyopathy (HCM) is a global disease affecting people of various ethnic origins and both genders. HCM is a genetic disorder with a wide range of symptoms, including the catastrophic presentation of sudden cardiac death. Proper diagnosis and treatment of this disorder can relieve symptoms and prolong life. Non-invasive imaging is essential in diagnosing HCM. We present a review to deliberate the potential use of cardiac magnetic resonance (CMR) imaging in HCM assessment and also identify the risk factors entailed with risk stratification of HCM based on Magnetic Resonance Imaging (MRI).

Management of Glioblastoma Multiforme by Phytochemicals: Applications of Nanoparticle Based Targeted Drug Delivery System

2020 ◽  
Vol 21 ◽  
Author(s):  
Sayed Md Mumtaz ◽  
Gautam Bhardwaj ◽  
Shikha Goswami ◽  
Rajiv Kumar Tonk ◽  
Ramesh K. Goyal ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Glioblastoma Multiforme ◽  
Drug Delivery System ◽  
Delivery System ◽  
Genetic Disorder ◽  
Drug Regimen ◽  
Brain Regions ◽  
Radio Therapy ◽  
Novel Drug ◽  
The Brain

: The Glioblastoma Multiforme (GBM; grade IV astrocytoma) exhort tumor of star-shaped glial cell in the brain. It is a fast-growing tumor that spreads to nearby brain regions specifically to cerebral hemispheres in frontal and temporal lobes. The etiology of GBM is unknown, but major risk factors are genetic disorder like neurofibromatosis and schwanomatosis which develop the tumor in the nervous system. The management of GBM with chemo-radio therapy leads to resistance and current drug regimen like Temozolomide (TMZ) is less efficacious. The reasons behind failure of drugs are due to DNA alkylation in cell cycle by enzyme DNA guanidase and mitochondrial dysfunction. Naturally occurring bio-active compounds from plants known as phytochemicals, serve as vital sources for anti-cancer drugs. Some typical examples include taxol analogs, vinca alkaloids such as vincristine, vinblastine, podophyllotoxin analogs, camptothecin, curcumin, aloe emodin, quercetin, berberine e.t.c. These phytochemicals often act via regulating molecular pathways which are implicated in growth and progression of cancers. However the challenges posed by the presence of BBB/BBTB to restrict passage of these phytochemicals, culminates in their low bioavailability and relative toxicity. In this review we integrated nanotech as novel drug delivery system to deliver phytochemicals from traditional medicine to the specific site within the brain for the management of GBM.

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