scholarly journals Current Status of Gene Therapy Research in Polyglutamine Spinocerebellar Ataxias

2021 ◽  
Vol 22 (8) ◽  
pp. 4249
Author(s):  
Ricardo Afonso-Reis ◽  
Inês T. Afonso ◽  
Clévio Nóbrega
Keyword(s):  
Gene Therapy ◽  
Cag Repeat ◽  
Current Status ◽  
Clinical Feature ◽  
Spinocerebellar Ataxias ◽  
Coding Region ◽  
Causative Gene ◽  
Gene Therapies ◽  
Progressive Ataxia ◽  
Near Future

Polyglutamine spinocerebellar ataxias (PolyQ SCAs) are a group of 6 rare autosomal dominant diseases, which arise from an abnormal CAG repeat expansion in the coding region of their causative gene. These neurodegenerative ataxic disorders are characterized by progressive cerebellar degeneration, which translates into progressive ataxia, the main clinical feature, often accompanied by oculomotor deficits and dysarthria. Currently, PolyQ SCAs treatment is limited only to symptomatic mitigation, and no therapy is available to stop or delay the disease progression, which culminates with death. Over the last years, many promising gene therapy approaches were investigated in preclinical studies and could lead to a future treatment to stop or delay the disease development. Here, we summed up the most promising of these therapies, categorizing them in gene augmentation therapy, gene silencing strategies, and gene edition approaches. While several of the reviewed strategies are promising, there is still a gap from the preclinical results obtained and their translation to clinical studies. However, there is an increase in the number of approved gene therapies, as well as a constant development in their safety and efficacy profiles. Thus, it is expected that in a near future some of the promising strategies reviewed here could be tested in a clinical setting and if successful provide hope for SCAs patients.

scholarly journals Clinical Characteristics and Possible Drug Targets in Autosomal Dominant Spinocerebellar Ataxias

2019 ◽  
Vol 18 (4) ◽  
pp. 279-293 ◽  
Author(s):  
Laszlo Szpisjak ◽  
Denes Zadori ◽  
Peter Klivenyi ◽  
Laszlo Vecsei
Keyword(s):  
Drug Targets ◽  
Autosomal Dominant ◽  
Scientific Progress ◽  
Cag Repeat ◽  
Motor Dysfunction ◽  
Spinocerebellar Ataxias ◽  
Coding Region ◽  
Causative Gene ◽  
Gene Therapies ◽  
Repeat Expansions

Background & Objective: The autosomal dominant spinocerebellar ataxias (SCAs) belong to a large and expanding group of neurodegenerative disorders. SCAs comprise more than 40 subtypes characterized by progressive ataxia as a common feature. The most prevalent diseases among SCAs are caused by CAG repeat expansions in the coding-region of the causative gene resulting in polyglutamine (polyQ) tract formation in the encoded protein. Unfortunately, there is no approved therapy to treat cerebellar motor dysfunction in SCA patients. In recent years, several studies have been conducted to recognize the clinical and pathophysiological aspects of the polyQ SCAs more accurately. This scientific progress has provided new opportunities to develop promising gene therapies, including RNA interference and antisense oligonucleotides. Conclusion: The aim of the current work is to give a brief summary of the clinical features of SCAs and to review the cardinal points of pathomechanisms of the most common polyQ SCAs. In addition, we review the last few year’s promising gene suppression therapies of the most frequent polyQ SCAs in animal models, on the basis of which human trials may be initiated in the near future.

scholarly journals Polyglutamine Ataxias: Our Current Molecular Understanding and What the Future Holds for Antisense Therapies

Biomedicines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1499
Author(s):  
Craig S. McIntosh ◽  
Dunhui Li ◽  
Steve D. Wilton ◽  
May T. Aung-Htut
Keyword(s):  
Trinucleotide Repeat ◽  
Spinocerebellar Ataxias ◽  
Coding Region ◽  
Causative Gene ◽  
Polyglutamine Disorders ◽  
Heterogenous Group ◽  
Clinical Presentations ◽  
Progressive Ataxia ◽  
Swallowing Difficulties ◽  
The Common

Polyglutamine (polyQ) ataxias are a heterogenous group of neurological disorders all caused by an expanded CAG trinucleotide repeat located in the coding region of each unique causative gene. To date, polyQ ataxias encompass six disorders: spinocerebellar ataxia types 1, 2, 3, 6, 7, and 17 and account for a larger group of disorders simply known as polyglutamine disorders, which also includes Huntington’s disease. These diseases are typically characterised by progressive ataxia, speech and swallowing difficulties, lack of coordination and gait, and are unfortunately fatal in nature, with the exception of SCA6. All the polyQ spinocerebellar ataxias have a hallmark feature of neuronal aggregations and share many common pathogenic mechanisms, such as mitochondrial dysfunction, impaired proteasomal function, and autophagy impairment. Currently, therapeutic options are limited, with no available treatments that slow or halt disease progression. Here, we discuss the common molecular and clinical presentations of polyQ spinocerebellar ataxias. We will also discuss the promising antisense oligonucleotide therapeutics being developed as treatments for these devastating diseases. With recent advancements and therapeutic approvals of various antisense therapies, it is envisioned that some of the studies reviewed may progress into clinical trials and beyond.

scholarly journals Gene Therapy for Liver Cancers: Current Status from Basic to Clinics

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1865 ◽  
Author(s):  
Kenya Kamimura ◽  
Takeshi Yokoo ◽  
Hiroyuki Abe ◽  
Shuji Terai
Keyword(s):  
Gene Therapy ◽  
Liver Cancer ◽  
Liver Diseases ◽  
Malignant Tumors ◽  
Therapeutic Options ◽  
Endocrine Function ◽  
Current Status ◽  
Congenital Disease ◽  
Gene Therapies ◽  
Liver Cancers

The liver is a key organ for metabolism, protein synthesis, detoxification, and endocrine function, and among liver diseases, including hepatitis, cirrhosis, malignant tumors, and congenital disease, liver cancer is one of the leading causes of cancer-related deaths worldwide. Conventional therapeutic options such as embolization and chemotherapy are not effective against advanced-stage liver cancer; therefore, continuous efforts focus on the development of novel therapeutic options, including molecular targeted agents and gene therapy. In this review, we will summarize the progress toward the development of gene therapies for liver cancer, with an emphasis on recent clinical trials and preclinical studies.

Gene therapy comes of age

Science ◽  
2018 ◽  
Vol 359 (6372) ◽  
pp. eaan4672 ◽  
Author(s):  
Cynthia E. Dunbar ◽  
Katherine A. High ◽  
J. Keith Joung ◽  
Donald B. Kohn ◽  
Keiya Ozawa ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Viral Vectors ◽  
The United States ◽  
Genetically Engineered ◽  
Drug Status ◽  
Hematopoietic Stem ◽  
Gene Therapies ◽  
Engineered T Cells ◽  
Near Future

After almost 30 years of promise tempered by setbacks, gene therapies are rapidly becoming a critical component of the therapeutic armamentarium for a variety of inherited and acquired human diseases. Gene therapies for inherited immune disorders, hemophilia, eye and neurodegenerative disorders, and lymphoid cancers recently progressed to approved drug status in the United States and Europe, or are anticipated to receive approval in the near future. In this Review, we discuss milestones in the development of gene therapies, focusing on direct in vivo administration of viral vectors and adoptive transfer of genetically engineered T cells or hematopoietic stem cells. We also discuss emerging genome editing technologies that should further advance the scope and efficacy of gene therapy approaches.

scholarly journals The Ocular Gene Delivery Landscape

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1135
Author(s):  
Bhubanananda Sahu ◽  
Isha Chug ◽  
Hemant Khanna
Keyword(s):  
Gene Therapy ◽  
Genetic Diseases ◽  
Gene Therapies ◽  
Advantages And Disadvantages ◽  
Fda Approval ◽  
New Information ◽  
Efficient Delivery ◽  
Delivery Routes ◽  
History Of ◽  
Different Parts

The eye is at the forefront of developing therapies for genetic diseases. With the FDA approval of the first gene-therapy drug for a form of congenital blindness, numerous studies have been initiated to develop gene therapies for other forms of eye diseases. These examinations have revealed new information about the benefits as well as restrictions to using drug-delivery routes to the different parts of the eye. In this article, we will discuss a brief history of gene therapy and its importance to the eye and ocular delivery landscape that is currently being investigated, and provide insights into their advantages and disadvantages. Efficient delivery routes and vehicle are crucial for an effective, safe, and longer-lasting therapy.

scholarly journals Characterization of Recombinant Adeno-Associated Viruses (rAAVs) for Gene Therapy Using Orthogonal Techniques

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 586
Author(s):  
Liam Cole ◽  
Diogo Fernandes ◽  
Maryam T. Hussain ◽  
Michael Kaszuba ◽  
John Stenson ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Light Scattering ◽  
Dynamic Light Scattering ◽  
Viral Vector ◽  
Structural Characteristics ◽  
Genetic Material ◽  
Label Free ◽  
Gene Therapies ◽  
Multiple Challenges

Viruses are increasingly used as vectors for delivery of genetic material for gene therapy and vaccine applications. Recombinant adeno-associated viruses (rAAVs) are a class of viral vector that is being investigated intensively in the development of gene therapies. To develop efficient rAAV therapies produced through controlled and economical manufacturing processes, multiple challenges need to be addressed starting from viral capsid design through identification of optimal process and formulation conditions to comprehensive quality control. Addressing these challenges requires fit-for-purpose analytics for extensive characterization of rAAV samples including measurements of capsid or particle titer, percentage of full rAAV particles, particle size, aggregate formation, thermal stability, genome release, and capsid charge, all of which may impact critical quality attributes of the final product. Importantly, there is a need for rapid analytical solutions not relying on the use of dedicated reagents and costly reference standards. In this study, we evaluate the capabilities of dynamic light scattering, multiangle dynamic light scattering, and SEC–MALS for analyses of rAAV5 samples in a broad range of viral concentrations (titers) at different levels of genome loading, sample heterogeneity, and sample conditions. The study shows that DLS and MADLS® can be used to determine the size of full and empty rAAV5 (27 ± 0.3 and 33 ± 0.4 nm, respectively). A linear range for rAAV5 size and titer determination with MADLS was established to be 4.4 × 1011–8.7 × 1013 cp/mL for the nominally full rAAV5 samples and 3.4 × 1011–7 × 1013 cp/mL for the nominally empty rAAV5 samples with 3–8% and 10–37% CV for the full and empty rAAV5 samples, respectively. The structural stability and viral load release were also inferred from a combination of DLS, SEC–MALS, and DSC. The structural characteristics of the rAAV5 start to change from 40 °C onward, with increasing aggregation observed. With this study, we explored and demonstrated the applicability and value of orthogonal and complementary label-free technologies for enhanced serotype-independent characterization of key properties and stability profiles of rAAV5 samples.

scholarly journals Genetic characteristics and epidemiology of inherited retinal degeneration in Taiwan

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Ta-Ching Chen ◽  
Ding-Siang Huang ◽  
Chao-Wen Lin ◽  
Chang-Hao Yang ◽  
Chung-May Yang ◽  
...  
Keyword(s):  
Demographic Data ◽  
Genomic Medicine ◽  
Research Database ◽  
Genetic Characteristics ◽  
Common Cause ◽  
Gene Therapies ◽  
Retinal Degenerations ◽  
Near Future ◽  
Inherited Retinal Degeneration ◽  
Bietti's Crystalline Dystrophy

AbstractInherited retinal degenerations (IRDs) are a group of phenotypically and genotypically heterogeneous disorders with substantial socioeconomic impact. In this cohort study, we tried to address the genetic characteristics and epidemiology of IRDs in Taiwan. Totally, 312 families with IRDs were identified and recruited and genetic testing was performed via probe capture-based NGS targeting 212 IRD-related genes. Statistical analysis was based on the proband of each affected family. Disease-causing genotypes were identified in 178 families (57.1%). ABCA4 variants were the most common cause of disease in this cohort (27 families, 15.2%), whereas CYP4V2 variants were the most common cause for the single phenotype—Bietti’s crystalline dystrophy (12 families, 3.8%). Some variants such as ABCA4:c.1804C>T, CYP4V2:c.802-8_810delinsGC, and EYS:c6416G>A were population-specific disease-causing hotspots. Probands affected by ABCA4, RPGR, RP1L1, and CEP290 sought medical help earlier while patients affected by EYS and CYP4V2 visited our clinic at an older age. To evaluate the representativeness of our cohort in the genetic epidemiology of IRDs in Taiwan, our demographic data were compared with that of the total IRD population in Taiwan, obtained from the National Health Insurance Research Database. This is currently the largest-scale, comprehensive study investigating the genetic characteristics and epidemiology of IRD in Taiwan. These data could help patients and caregivers to adopt precision genomic medicine and novel gene therapies in near future.

scholarly journals Discussion: Producer Bargaining: Its Current Status and Distribution of Benefits

1973 ◽  
Vol 5 (1) ◽  
pp. 45-46
Author(s):  
H. M. Harris
Keyword(s):  
Present Status ◽  
Dairy Industry ◽  
Current Status ◽  
Complete Analysis ◽  
Key Aspects ◽  
Near Future

We should be indebted to Dr. Berry for his cogent observations on some key aspects of the producer bargaining issue. At the same time, however, I would be remiss in my role as discussant if I failed to point out two major shortcomings of his paper. First, the current status of producer bargaining is treated incompletely. Second, and more glaring, is the complete omission of any discussion of the distribution of benefits of agricultural bargaining.It should be mentioned that both these shortcomings could be remedied simply by changing the title of the paper. For example, if the address was entitled, “Producer Bargaining: Its Present Status in the Dairy Industry,” these two criticisms would be largely unwarranted. I must also confess that if the assigned roles of Professor Berry and myself were reversed, he would very likely be levying the same comments about my presentation. For a complete analysis of the assigned topic involves a Herculean task – but a task with which we must come to grips in the near future.

scholarly journals Current Status of Cardiovascular Gene Therapy

2007 ◽  
Vol 15 (7) ◽  
pp. 1233-1247 ◽  
Author(s):  
Tuomas T Rissanen ◽  
Seppo Ylä-Herttuala
Keyword(s):  
Gene Therapy ◽  
Current Status
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