Volume Articles

Commentary: "Rapid Report - Treatment of Hemophilia Patients

Tonio Schoenfelder* and Hans-Holger Bleß

IGES Institut GmbH, Friedrichstraße 180, D-10117 Berlin, Germany

Mini-review on "A novel one-step purification of mouse factor IX"

Sumita Choudhury, William E. Plautz, Cosette Zacarias and Rinku Majumder*

Department of Biochemistry & Molecular Biology, LSU Health Science Center, 1901 Perdido Street, MEB-7114, New Orleans, LA-70112

Neurofibromatosis type 1-associated brain tumors

Emily Cockey and Nicole J Ullrich*

Department of Neurology, Boston Children’s Hospital, Boston, MA 02115, USA

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder that predisposes patients to develop benign and malignant neoplasms, most often due to a loss of function mutation in the neurofibromatosis type 1 (NF1) gene. Neurofibromin, the protein product of NF1, regulates the inactivation of the Ras pathway, and thus acts as a tumor suppressor. Located in neurons, Schwann cells, and melanocytes, a decrease in neurofibromin predisposes patients with NF1 to tumors in both the central and peripheral nervous systems. Interestingly, brain tumors associated with NF1 often follow a more benign course than their sporadic counterparts and are often found in different locations. Thus, these tumors are often observed without tumor-directed therapy, unless clinical progression is noted, and then they are treated with surgery, chemotherapy or radiation. Current treatment trials seek to create more targeted therapies for specific tumor types associated with NF1 in order to increase efficacy and decrease treatment-related morbidity. This review will examine the most common types of brain tumors associated with NF1, including pilocytic astrocytomas, optic pathway gliomas, brainstem gliomas and glioblastomas, and will provide an overview of the clinical implications, current treatments, and ongoing clinical trials for these tumors.

Apoptosis-based therapy to treat pulmonary arterial hypertension

Yuichiro J. Suzuki¹, Yasmine F. Ibrahim^1,2 and Nataliia V. Shults^1*

¹Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington DC 20007 USA
²Department of Pharmacology, Minia University School of Medicine, Minia, Egypt

 Pulmonary arterial hypertension (PAH) is rare, but patients who are diagnosed with this disease still suffer from a lack of satisfactory treatment strategies to prolong survival. While currently approved drugs for PAH have some benefits, these vasodilators only have limited efficacy for eliminating pulmonary vascular remodeling and reducing mortality. Thus, our laboratory has been exploring the use of aggressive drugs, which are capable of causing apoptotic cell death, to treat PAH. We have so far found that three classes of anti-tumor agents, including anthracyclines, taxanes, and proteasome inhibitors, are capable of reducing pulmonary vascular thickness in rats with PAH. These drugs kill cells in remodeled pulmonary vessels without affecting the normal, healthy pulmonary vasculature, revealing that proliferating vascular cells in PAH patients are more sensitive to drug-induced apoptosis compared to the differentiated phenotype that is physiologically important for smooth muscle contraction. Since many apoptosis-inducing drugs cause cardiotoxicity in cancer patients, and because PAH patients already have a weakened heart, we focus on finding biological mechanisms that may reverse pulmonary vascular remodeling without promoting cardiotoxicity. We found two agents, dexrazoxane and pifithrin-α, that selectively inhibit cardiac muscle apoptosis without affecting the drug-induced apoptosis of the proliferating pulmonary vascular cells. Thus, we propose that the addition of apoptosis-inducing drugs and cardioprotectants to PAH therapies may be effective in treating patients and preventing right heart failure.

Gene therapy for hemoglobin disorders - a mini-review

Parul Rai¹ and Punam Malik^1,2*

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.

Podocyturia as a biomarker of early kidney damage in fabry nephropathy

Hernán Trimarchi*

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

DDHD domain-containing lipases: Targets for the treatment of rare diseases

Pradeep Kumar Yadav^1,2 and Ram Rajasekharan^1,2*

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.

Differential stress response mechanisms in right and left ventricles

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.

Biomarkers for Huntington's disease: A brief overview

Annie Killoran^1* 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.

Rationally combining anti-VEGF therapy with radiation in NF2 schwannoma

Na Zhang^1,2, Xing Gao^1,3 Yingchao Zhao^1,4, Meenal Datta^1,5, Pinan Liu⁶ and Lei Xu^1*

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.

Commentary: "Dynamin 1 isoform roles in a mouse model of severe childhood epileptic encephalopathy"

Narayan Subramanian¹, Wayne N. Frankel^1,2*

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

Gayet -Wernicke encephalopathy in non alcoholic patients: A serious complication

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.

Fabry disease: Prototype of Lysosomal Storage Disorder with systemic involvement

Irene San-Román-Monserrat^1*, 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