Mark J C Nuijten1,2* and Jan Vis3

1A2M (Ars Accessus Medica), 1546 LG Amsterdam, The Netherlands
2H4V, 1546 LG Amsterdam, The Netherlands
3Talanton, Amsterdam, The Netherlands
4RSM, Erasmus University, Rotterdam, The Netherlands

 Rational: Many pharmaceutical companies, especially biotechnology companies, are now commercializing innovative so-called expensive medicinal products, e.g. biologicals, and especially orphan drugs, with an incremental cost-effectiveness ratio (ICER), which will probably exceed threshold values that are commonly regarded as acceptable for reimbursement.

Objective: The goal of this paper is to propose an additional methodology to evaluate and valuate innovative drugs from a broader perspective by applying concepts from business valuation, when the ICER exceeds the threshold.

Methods: Medical innovation relies on the market mechanisms in the finance market of biotechnology including the incentives of the various stakeholders, especially the capital providers, who demand a required return on investment. The justification of the orphan drug price can be based on the Discounted Cash Flow method, which is based on the expected free cash flows and the required cost of capital, and can be used to validate the price of the new drug from a narrow investor’s perspective.

Conclusion: We propose an alternative policy approach for the evaluation of ultra-innovative drugs from a broader perspective by bridging concepts from health economics and the economics of business (economic) valuation. This approach may justify a drug price, especially when ICER exceeds the threshold.

DOI: 10.29245/2572-9411/2017/1.1056 View / Download Pdf

Karolis Jonavicius1*, Kestutis Salcius2, Raimundas Meskauskas3, Nomeda Valeviciene4, Virgilijus Tarutis2 and Vytautas Sirvydis2

1Faculty of Medicine, Vilnius University, Vilnius, Lithuania
2Department of Cardiovascular Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
3National Center of Pathology, Affiliate of Vilnius University Hospital Santariskiu Clinics
4Department of Radiology, Nuclear medicine and Physics of Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania

DOI: 10.29245/2572-9411/2016/3.1063 View / Download Pdf

Kim A Lennox and Mark A Behlke*

Integrated DNA Technologies, Inc., Coralville, IA, 52241, USA

DOI: 10.29245/2572-9411/2016/3.1066 View / Download Pdf

Daniel H. Elbrecht, Christopher J. Long and James J. Hickman*

NanoScience Technology Center, University of Central Florida, Orlando, Florida, 32826, USA

 Transepithelial/endothelial electrical resistance (TEER) is a valuable method for assaying in vitro barrier tissue integrity, and is becoming an important measurement for body-on-a-chip barrier tissue devices due to its usefulness and non-invasive nature. The measurement concept is relatively straightforward, with TEER measurements performed by applying an AC electrical signal across electrodes placed on both sides of a cellular monolayer and measuring voltage and current to calculate the electrical resistance of the barrier. However, details of the setup, measurement circuit, and applied electrical signal must be properly designed for accurate measurements. Several main factors contribute to errors and variability in the measurement of TEER values, and while many of these factors can be reasonably controlled with little effort in Transwell®-type culture conditions, these factors can become major issues in body-on-a-chip devices without proper design. This mini-review outlines several important aspects of TEER measurements, including the basic theory, commercial systems used to perform measurements, major factors that contribute to measurement errors, and the application of TEER measurements to current body-on-a-chip barrier tissue devices, with the aim of providing guidance for the design of novel body-on-a-chip systems.

DOI: 10.29245/2572-9411/2016/3.1026 View / Download Pdf

Brian Godman1,2,3*, Isabel Frost4, Richard Harrington5 and Finlayson AE6

1Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86, Stockholm, Sweden
2Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom
3Liverpool Health Economics Centre, University of Liverpool, Chatham Street, Liverpool, UK L69 7ZH
4Department of Zoology, University of Oxford, Oxford, OX1 3PS, United Kingdom
5Nuffield Department of Population Health, British Heart Foundation Centre on Population Approaches for NCD Prevention, University of Oxford, Oxford, United Kingdom
6Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom

 There are considerable differences in how patients respond to treatments due to a number of factors calling for personalised approaches to care, which is happening. However, the early promise of personalised medicine has not always translated into improved care for patients. Payers have concerns that current tests can be costly, requests for funding specific tests have subsequently been reversed as more information becomes available, and there is currently fragmentation in the funding of diagnostic tests. Payers also have concerns that pharmaceutical companies are exploiting the situation by seeking orphan status for their new targeted medicines driving up requested prices. It is also not clear who should fund biomarkers that accompany new expensive medicines. This is changing as the cost of tests come down, and payers develop new models to optimise the managed entry of new medicines as well as evaluate potential prices for new medicines for orphan diseases. There are also developments with ‘big data’ offering new understanding of disease complexity to enhance pipeline productivity and diagnosis as well as ongoing developments with drug resistance testing and research into the role of microbiomes to improve future health. Current challenges and concerns are being addressed. This will continue to improve patient care.

DOI: 10.29245/2572-9411/2016/3.1067 View / Download Pdf

Ralf-Dieter Hilgers1*, FranzKönig2, Geert Molenberghs3 and Stephen Senn4

1Department of Medical Statistics, RWTH Universit Aachen, Pauwelstr 30, D? 52074 Aachen, Germany
2Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
3I?BioStat, Universiteit Hasselt, B?3590 Diepenbeek, Belgium
4Competence Centre for Methodology and Statistics, Luxembourg Institute of Health, L?1445 Strassen, Luxembourg

 The mostly unmet need as well as the pressure to show efficacy of new therapies to treat rare diseases contrasts with the limited possibility to use traditional statistical methods to design and analyse clinical trials in this setting. Within this paper, we will refer to the current state of design and analysis methods, as well as practical conditions to be considered when conducting a clinical trial for rare diseases. We will embed the research of the IDeAl project within this setting and give some first recommendations to improve the methodology for clinical trials in rare diseases.

DOI: 10.29245/2572-9411/2016/3.1054 View / Download Pdf

Louise F. Øbro1, Katja V. Pedersen2, Søren K. Lildal1, Susanne S. Osther1, Helene U. Jung1, Kim H. Andreassen1 and Palle J. S. Osther1,*

1Department of Urology, Urological Research Center, Lillebaelt Hospital, University of Southern Denmark, Fredericia, Denmark
2Department of Clinical Genetics, Lillebaelt Hospital, University of Southern Denmark, Vejle, Denmark

 Cystinuria is a rare genetic disorder caused by mutations in the genes that encode the two subunits of amino acid transport, resulting in failure of absorption of filtered dibasic amino acids including cystine in the proximal tubules. Despite new knowledge of the molecular basis of cystinuria, it continues to be one of the most challenging stone diseases. There is no curative treatment of cystinuria, and patients will have life-long risk of stone formation, repeated surgery, impaired renal function and quality of life. Management of cystinuria requires a multi-modal approach in dedicated centres to improve treatment outcome and patient compliance. Recent developments in cystine crystal growth inhibitors may hold promise for more effective stone prevention in the future.

DOI: 10.29245/2572-9411/2016/3.1047 View / Download Pdf

Justin M. Bradley, Nick E. Le Brun and Geoffrey R. Moore*

Centre for Molecular and Structural Biochemistry, School of Chemistry, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK

DOI: 10.29245/2572-9411/2016/3.1061 View / Download Pdf

Philippa C. Fowler#, Dwayne J. Byrne# and Niamh C. O’Sullivan*

UCD School of Biomolecular and Biomedical Sciences, UCD Conway Institute, University College Dublin, Dublin 4, Ireland

 Hereditary spastic paraplegias (HSPs) are a group of inherited neurodegenerative conditions characterised by retrograde degeneration of the longest motor neurons in the corticospinal tract, resulting in muscle weakness and spasticity of the lower limbs. To date more than 70 genetic loci have been associated with HSP, however the majority of cases are caused by mutations that encode proteins responsible for generating and maintaining tubular endoplasmic reticulum (ER) structure. These ER-shaping proteins are vital for the long-term survival of axons, however the mechanisms by which mutations in these proteins give rise to HSP remain poorly understood. To begin to address this we have characterized in vivo loss of function models of two very rare forms of HSP caused by loss of the ER-shaping proteins ARL6IP1 (SPG61) and RTN2 (SPG12). These models display progressive locomotor defects, disrupted organisation of the tubular ER and length-dependant defects in the axonal mitochondrial network. Here we compare our findings with those associated with more common forms HSP including: Spastin, Atlastin-1 and REEP 1 which together account for over half of all cases of autosomal dominant HSP. Furthermore, we discuss recent observations in other HSP models which are directly implicated in mitochondrial function and localization. Overall, we highlight the common features of our rare models of HSP and other models of disease which could indicate shared mechanisms underpinning neurodegeneration in these disorders.

DOI: 10.29245/2572-9411/2016/3.1051 View / Download Pdf

W.C. Aw, N. A. Youngson and J. W. O. Ballard*

School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, Australia

 Mitochondria are an important regulator of organismal fitness and the key energy converting organelle. The flow of energy in eukaryotes involves the conversion of macronutrients to form substrates that drive mitochondrial respiration. Changing the relative ratio of dietary macronutrients can influence metabolic flexibility and alter the production of mitochondrial metabolites, such as reactive oxygen species (ROS), which can influence mitochondrial functions and affect the organismal health. In this review, we describe the differences in mitochondrial output due to dietary macronutrient composition in individuals with Complex I mutations. Non-synonymous mutations in mitochondrial Complex I subunits are a common cause of early-onset mitochondrial diseases. We discuss the possibility of manipulating macronutrient ratios as a treatment for some cases of mild mitochondrial dysfunction.

DOI: 10.29245/2572-9411/2016/3.1043 View / Download Pdf

Sith Siramolpiwat1,2, Susana Seijo3*

1Chulabhorn International College of Medicine, Thammasat University, Pathumthani, 12120, Thailand
2Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Thammasat University, Pathumthani, 12120, Thailand
3CTO, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA

Idiopathic non-cirrhotic portal hypertension (INCPH) is a rare disorder consisting of intrahepatic portal hypertension in the absence of other identifiable intrinsic liver diseases and/or splanchnic vein thrombosis. The exact pathophysiology of INCPH is yet to be determined. This disorder is linked with several conditions such as immunological disorders, chronic infections, prothrombotic disorders, genetic predisposition and/or toxins. There is no specific positive diagnostic test. The diagnosis of INCPH is based on a high index of suspicion, a set of clinical criteria and exclusion of other causes of portal hypertension. Liver biopsy is mandatory to firmly rule out cirrhosis or other causes of liver diseases. The patency of splanchnic venous system should be also demonstrated. Most patients present with signs or symptoms of portal hypertension (i.e. gastro-esophageal varices, variceal bleeding), which should receive the same management strategy as per the current accepted guidelines in cirrhosis. The prevalence of portal vein thrombosis in INCPH ranges from 13-46%. Although liver function is usually preserved and prognosis is generally good, some patients may develop liver-related complications that would eventually require liver transplantation and/or that would overshadow long-term prognosis. 

DOI: 10.29245/2572-9411/2016/3.1038 View / Download Pdf

Stanley T. Crooke*, Wen Shen and Xue-hai Liang

Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA

 Human RNase H1 cleaves RNA only when the RNA is present in a DNA-RNA heteroduplex. Previous efforts to create RNase H1 knockout mice resulted in embryonic lethality1, but demonstrated that RNase H1 is required for mitochondrial function. We constructed viable constitutive hepatocyte liver specific RNase H1 knock out mice by coupling the Cre recombinase to an albumin promoter as albumin is not expressed till late in gestation. We also constructed hepatocyte specific tamoxifen inducible hepatocyte knockout mice.

Our studies demonstrate that mammalian RNase H1 is required for transcription of mitochondrial ribosomal DNA and removal of R Loops. The absence of RNase H1 leads to mitochondrial dysfunction and hepatocyte apoptosis and liver dysfunction. Subsequently, a clone of hepatocytes that lost the Cre-recombinase and thereby regained RNase H1 expression emerged, supporting the analysis of events leading to liver regeneration. RNase H1 is confirmed to be responsible for the pharmacological effects of DNA-like antisense drugs as well.

DOI: 10.29245/2572-9411/2016/3.1053 View / Download Pdf

Yuichiro Sakamoto*

Department of Emergency and Critical Care Medicine Faculty of Medicine, Saga University, Saga, Japan

DOI: 10.29245/2572-9411/2016/3.1039 View / Download Pdf

Christian Apsey and Brenda L. Bohnsack*

Kellogg Eye Center and Department of Ophthalmology and Vision Sciences, University of Michigan, Ann Arbor, Michigan 48105, USA

 Primary infantile-onset glaucoma is a rare, potentially blinding disease that is due to malformation of the trabecular meshwork and aqueous outflow tracts (goniotrabeculodysgenesis). While goniotrabeculodysgenesis is typically an isolated finding, there are reports of primary infantile-onset glaucoma in the setting of collagen disorders, specifically Stickler syndrome and osteogenesis imperfecta.

In Stickler syndrome, defects in type II or type XI collagen are commonly associated with craniofacial anomalies, hearing loss, hypermobile joints, and vitreoretinal abnormalities. Osteogenesis imperfecta is caused by disruption in type I collagen synthesis and is characterized by frequent bone fractures. Both type I and type II collagens are major structural proteins in the trabecular meshwork of the eye and both of these collagen disorders show higher incidences of adult-onset glaucoma. Herein we review the association between primary infantile-onset glaucoma and collagen disorders, which gives insight into the development of the trabecular meshwork and the aqueous outflow tracts of the eye.

DOI: 10.29245/2572-9411/2016/3.1049 View / Download Pdf

Mehdi B Hamaneh and Yi-Kuo Yu*

National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA

 In recent years several methods have been proposed to assign pairwise mechanism-based similarity scores to human diseases. Despite their differences in approach and performance, these methods work in a somewhat similar manner: first a set of biomolecules (genes, proteins, chemicals, etc.) is associated with each disease, and then a measure is defined to calculate the similarity between the sets assigned to a pair of diseases. Since the similarity score between two diseases is defined based on the underlying molecular processes, a high score may hint at a shared cause, and therefore a similar treatment, for both diseases. This is of great practical importance especially when a rare or newly-discovered disease, for which limited information is available, is found to be related to a disease with a known treatment. Thus, in this mini-review we briefly discuss the recently developed methods for computing mechanism-based disease-disease similarities.

DOI: 10.29245/2572-9411/2016/3.1044 View / Download Pdf

Narayan Subramanian1, Wayne N. Frankel1,2*

1Institute for Genomic Medicine, Columbia University Medical Center, New York, NY 10032, USA
2Department of Genetics & Development, Columbia University Medical Center, New York, NY 10032, USA

DOI: 10.29245/2572-9411/2016/2.1041 View / Download Pdf

Irene San-Román-Monserrat1*, Juan-Ramón Gimeno-Blanes2, María Elena Rodríguez-González-Herrero3, Andrea Sodi4, Alessandro Mecocci5, Marisol Alegría-Fernández6, David López –Cuenca7 and Beatriz Rodríguez-González- Herrero8

1Department of Internal Medicine, Hospital General Universitario Reina Sofía, Murcia, Spain
2Department of Cardiology, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain
3Department of Ophthalmology, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain
4Department of Ophthalmology, Careggi Teaching Hospital, Firenze, Italy
5Department of Informatics and Mathematical Sciences, Siena University, Siena, Italy
6Hospital Universitario Virgen de la Arrixaca, Murcia, Spain
7Hospital Universitario Virgen de la Arrixaca, Murcia, Spain
8ENT Consultant, Hospital Comarcal del Noroeste, Caravaca, Murcia, Spain

DOI: 10.29245/2572-9411/2016/2.1040 View / Download Pdf

Ammouri W*, Harmouche H, Alaoui M, Tazi ZM, Maamar MM and Adnaoui M

Internal Medicine Department, CHU Ibn Sina, University of Medicine Rabat, Morocco

 Gayet-Wernicke encephalopathy is an acute, reversible neuropsychiatric emergency due to thiamine defciency. Chronic alcoholism is recognized as the most common cause of Wernicke’s encephalopathy, but other causes, including fasting/starvation and malnutrition, have been documented within the scientific literature. These causes may not be readily recognized by healthcare professionals and may lead to Wernicke’s encephalopathy being overlooked as a diagnosis when a nonalcoholic patient presents with classic signs and symptoms of the disorder.

The diagnosis of the disease is clinical and magnetic resonance imaging confirms the diagnosis by the presence of hypersignals most frequently in the periaqueductal level of thalami and mammilary bodies. Urgent and adequate thiamine replacement is necessary to avoid death or progression to Korsakoff syndrome with largely irreversible brain damage. Wernicke Korsakoff syndrome refers to a condition where features of Wernicke encephalopathy are mixed with those of Korsakoff syndrome. Although thiamine is the cornerstone of treatment of Wernicke encephalopathy, there are no universally accepted guidelines with regard to its optimal dose, mode of administration, frequency of administration or duration of treatment. We present recommendations for the clinical management of Gayet-Wernicke encephalopathy based on literature review.

DOI: 10.29245/2572-9411/2016/2.1037 View / Download Pdf

Na Zhang1,2, Xing Gao1,3 Yingchao Zhao1,4, Meenal Datta1,5, Pinan Liu6 and Lei Xu1*

1Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114.
2Department of Otolaryngology Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing China, 100730.
3Department of Oral and Maxillofacial Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
4Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430023, China.
5Department of Chemical and Biological Engineering, Tufts University, Medford, MA 02155, USA.
6Neural Reconstructional Department, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China, 100050.

 Neurofibromatosis type 2 is characterized by bilateral vestibular schwannomas, which are benign tumors that originate from the nerve sheath and damage the nerve as they grow, causing neurological dysfunction such as hearing loss. Current standard radiation therapy can further augment hearing loss by inducing local damage to mature nerve tissue. Treatment with bevacizumab, a Vascular Endothelial Growth Factor (VEGF)-specific antibody, is associated with tumor control and hearing improvement in NF2 patients; however, its effect is not durable and its mechanism of action on improving nerve function is unknown. Anti-VEGF treatment can normalize the tumor vasculature, improving vessel perfusion and delivery of oxygen. It is known that oxygen is a potent radiosensitizer; therefore, combining anti-VEGF treatment with radiation therapy can achieve better tumor control and allow for the use of lower radiation doses, thus minimizing treatment-related neurological toxicity.

DOI: 10.29245/2572-9411/2016/2.1042 View / Download Pdf

Annie Killoran1* and Kevin Biglan2

1Department of Neurology, University of Iowa, IA, USA
2Department of Neurology, University of Rochester, New York, USA

 Huntington’s disease (HD) causes progressive neurological deterioration that leads to death. It is inherited in an autosomal dominant fashion, and individuals with a positive family history can be tested for the presence of the HD mutation prior to the development of the overt features that subjectively define disease onset. An objective biomarker denoting this time point would improve onset accuracy, and ideally be sufficiently sensitive to monitor progression leading up to this juncture. Once manifestations arise, patients are treated symptomatically. There are no disease-modifying treatments available for HD, but many are in development. A major goal is to develop a therapy that will delay the onset of the disease or to potentially even prevent the disease from occurring altogether. However, how does one assess the efficacy of these experimental therapeutics in individuals who carry the HD gene mutation, but are clinically-unaffected? Sensitive and reliable outcome measures are required for preventative clinical trials. Candidate biomarkers include subtle, but quantifiable abnormalities detected on clinical exam, findings on brain imaging, and levels of pathologically-relevant molecules collected in bodily fluids.

DOI: 10.29245/2572-9411/2016/2.1029 View / Download Pdf

Makhosazane Zungu-Edmondson and Yuichiro J. Suzuki*

Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC 20057

 Right ventricular (RV) failure is the major cause of death among patients with pulmonary hypertension. However, differences between the RV and left ventricle (LV) of the adult heart have not been defined, despite myocytes from these two ventricles originate from different progenitor cells. The lack of such knowledge interferes with developing therapeutic strategies to protect the RV. The goal of this study was to identify possible differences between stress responses in the RV and LV free walls of adult rats. We found that levels of angiogenesis and autophagy/mitophagy proteins are higher in the LV than in the RV. Thus, the LV may be more resistant to stress-induced damage. To test this, isolated rat hearts were subjected to biventricular working heart perfusion and ischemia/reperfusion (I/R) injury. However, I/R was found to cause apoptosis in both LV and RV to a similar extent. One mechanism of cardiac apoptosis involves downregulation of GATA4 transcription factor that controls gene transcription of anti-apoptotic Bcl-xL. Interestingly, only in the RV, I/R caused downregulation of GATA4 and Bcl-xL, suggesting that mechanisms of apoptosis may be different between the two ventricles. Levels of tropomyosin and troponin T were also found to be decreased in response to I/R only in the RV, but not in the LV. Downregulation of the GATA4/Bcl-xL axis and the reduction of tropomyosin and troponin T are RV-specific events that occur in response to stress. This information may be useful for designing RV-specific therapeutic strategies to treat RV failure in pulmonary hypertension patients.

DOI: 10.29245/2572-9411/2016/2.1033 View / Download Pdf

Pradeep Kumar Yadav1,2 and Ram Rajasekharan1,2*

1Lipidomic Centre, Department of Lipid Science, CSIR-Central Food Technological Research Institute (CFTRI), Mysore 570020, Karnataka, India
2Academy of Scientific & Innovative Research, CSIR-CFTRI, Mysore, India

 The DDHD domain-containing lipases belong to the intracellular phospholipase A1 (iPLA1) family. Phospholipases have been implicated in the regulation of lipid metabolism, intracellular membrane trafficking, and signaling. In addition, phospholipases have been linked to the development of rare and neurodegenerative diseases. The rare and neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease have been focused on phospholipase A2. But there is a scarcity of literature on the role of PLA1 in rare and neurodegenerative diseases. Recently, in humans, mutation in DDHD1 and DDHD2 (iPLA1 members) has been identified as a cause of specific types of hereditary spastic paraplegia (HSP) termed as SPG28 and SPG54, respectively. Ddl1 (DDHD domain-containing lipase 1), a yeast homolog of human DDHD1/2, hydrolyzes cardiolipin (CL), phosphatidylethanolamine, and phosphatidylglycerol. Ddl1 has an important role in the mitochondrial phospholipids remodeling. Defects in phospholipids remodeling and mitochondrial functions have been implicated in the development of the Barth syndrome, HSPs, and other neurodegenerative disorders. Mutations in DDHD1 and DDHD2 produce DDL1-defective yeast strain like phenotypes (mitochondrial dysfunction and defects in lipid metabolism).

Therefore, the DDL1-defective yeast could be a good model system to understand hereditary spastic paraplegia.

DOI: 10.29245/2572-9411/2016/2.1032 View / Download Pdf

Hernán Trimarchi*

Nephrology Service, Hospital Británico de Buenos Aires, Buenos Aires, Argentina

DOI: 10.29245/2572-9411/2016/2.1030 View / Download Pdf

Parul Rai1 and Punam Malik1,2*

1Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
2Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA

 Gene therapy by either gene insertion or editing is an exciting curative therapeutic option for monogenic hemoglobin disorders like sickle cell disease and β-thalassemia. The safety and efficacy of gene transfer techniques has markedly improved with the use of lentivirus vectors. The clinical translation of this technology has met with good success, although key limitations include number of engraftable transduced hematopoietic stem cells and adequate transgene expression that results in complete correction of β0 thalassemia major. This highlights the need to identify and address factors that might be contributing to the in-vivo survival of the transduced hematopoietic stem cells or find means to improve expression from current vectors. In this review, we briefly discuss the gene therapy strategies specific to hemoglobinopathies, the success of the preclinical models and the current status of gene therapy clinical trials.

DOI: 10.29245/2572-9411/2016/2.1028 View / Download Pdf