Israel Medical Association Journal

Treatment of vasculitides has progressed markedly over the past few decades. Recent therapeutic strategies in severe and refractory anti-neutrophil cytoplasmic antibodies-associated vasculitides include immunomodulating methods (e.g., plasma exchanges), products (such as intravenous immunoglobulins) and, more recently, new agents called biotherapies. Some of them (e.g., anti-tumor necrosis factor-alpha and anti-CD20 monoclonal antibodies) have achieved promising results and are now often used to treat severe cases.

Background: Ion Channel Innovations has developed a gene transfer product, ftMaxi-K, and has begun clinical trials to investigate the effect of increased expression of Maxi-K channels in the smooth muscle of the penis or bladder in patients with erectile dysfunction and those with overactive bladder. The primary function of K channels is to modulate Ca⁺⁺ influx through Ca-channels (i.e., L-type, voltage-dependent). The amount of Ca⁺⁺ that enters the cell through these channels is a major determinant of the free intracellular calcium levels inside the smooth muscle cell, which in turn determines the degree of smooth muscle cell contraction. Increased Maxi-K channel activity is associated with smooth muscle cell relaxation, resulting in, for example, penile erection and detrussor muscle relaxation. A phase I clinical trial that used dMaxi-K has been completed and a similar trial to assess safety of the transfer for overactive bladder is about to begin.

Objectives: To assess the safety and tolerability of escalating dMaxi-K doses by clinical evaluations and laboratory tests, and to measure efficacy objectives by means of the International Index of Erectile Function scale.

Methods: In the erectile dysfunction trial 11 patients with moderate to severe erectile dysfunction were given a single-dose corpus cavernosum injection of dMaxi-K, a "naked" DMA plasmid carrying the human cDNA encoding for the gene for the a, or pore-forming, subunit of the human smooth muscle Maxi-K channel, hSIo. Three patients each were given 500,1000, and 5000 pg and two patients were given 7500 pg doses of ftMaxi-K and followed for 24 weeks. Patient responses were validated by partner responses.

Results: There were no serious adverse events and no dose-related adverse events attributed to gene transfer for any patient at any dose or study visit. No clinically significant changes from baseline were seen in physical evaluations (general and genitourinary), hematology, chemistry and hormone analyses, or in cardiac events evaluated by repeated electrocardiograms. Importantly, no plasmid was detected in the semen of patients at any time after the injections. Patients given the two highest doses of dMaxi-K had apparent sustained improvements in erectile function as indicated by improved IIEF-EF domain scores over the length of the study. One patient given 5000 (jg and one given 7500 [jg reported EF category improvements that were highly clinically significant and were also maintained through the 24 weeks of study.
Conclusions: Efficacy conclusions cannot be drawn from results of a phase 1 trial with no control group. However, the promising primary safety outcomes of the study and preliminary indications of effectiveness provide evidence that ftMaxi-K gene transfer is a viable approach to the treatment of erectile dysfunction and other smooth muscle diseases with targeted access

Background: Genetic hemochromatosis leads to iron overload in many tissues and may lead to liver cirrhosis and hepatocellular carcinoma. Early diagnosis and therapy are crucial. Since 80–100% of hemochromatosis patients of European origin are homozygous for a cysteine to tyrosine exchange in the HFE gene at codon 282, genetic screening might be useful. Representative population studies are needed to evaluate the phenotype of people heterozygous and homozygous for the C282Y mutation.

Objective: To determine the correlation between parameters of iron metabolism and the hemochromatosis genotype in a large population-based study.

Methods: A representative population-based survey, the Diabetomobil study, analyzed 5,083 German probands. Serum transferrin saturation and ferritin levels were determined, and the C282Y mutation of the HFE gene was analyzed by restriction fragment length polymorphism- polymerase chain reaction analysis.

Results: Nine of 373 probands with a transferrin saturation > 55% (2.4%) and none of 264 randomly selected probands with a transferrin saturation £ 55% (0%) were homozygous for the C282Y mutation. Three of the nine homozygous probands had ferritin values less than 250 µg/L. The frequency of the heterozygous genotype was 8.8%, and the percentage of heterozygous probands increased with increasing levels of transferrin saturation.

Conclusion:We propose a population screening strategy with an initial transferrin saturation test, followed by genotyping for the C282Y mutation if the transferrin saturation is above 55%, regardless of the ferritin level. Heterozygous individuals with higher transferrin saturation values may be protected against iron loss but may also be more susceptible for certain liver diseases, depending on the simultaneous prevalence of other diseases.
 

Severe combined immunodeficiencies represent a heterogeneous group of hereditary defects of the immune system that affect both T and B cells and whose etiology has only recently begun to be understood. A portion of these SCID patients bear a defect in either of the two recombination-activating genes, Rag-1 or Rag-2, while others have mutations in a newly identified gene, Artemis. Omenn syndrome is an unusual severe immunodeficiency with T cells but no B cells, and peculiar features also due to a defect in Rag-1 or Rag-2 genes. All these three forms are characterized by an impairment of the VDJ recombination, the process that insures the somatic diversification of immunoglobulin and T cell receptor-encoding genes. Recent findings have enabled us to better understand the pathophysiology of these three immunodeficiencies, which affect the V(D)J recombination process to a different extent and in different ways.