Gene/Protein Disease Symptom Drug Enzyme Compound
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Haematuria is common among persons with haemophilia (PWH), but its long-term effects on the kidney and renal function are not well defined. In addition, infection with human immunodeficiency virus (HIV) or hepatitis C, or exposure to nephrotoxic agents as therapy for these infections may place PWH at increased risk for renal disease. To examine factors associated with chronic renal disease (CRD) and acute renal disease (ARD) in PWH, we analysed data collected from the medical records of 3422 males with haemophilia living in six US states from 1993 to 1998. Renal disease cases were ascertained from among 2075 persons who were hospitalized at least once over the 6-year period. Of these, 60 (2.9%) were diagnosed during one or more hospitalizations with either ARD (29/60) or CRD (31/60). In multivariate analyses, we examined associations between renal disease and demographic and clinical factors including age, race, haemophilia type and severity, hypertension, diabetes, history of recent renal bleeds, presence of an inhibitor, and infection with hepatitis C or HIV. HIV infection and hypertension were strongly associated with both ARD and CRD. PWH who had ARD were also more likely to have an inhibitor than those without this diagnosis. PWH who had CRD were more likely to be older and non-white and to have had a recent admission for a kidney bleed than those without diagnosed CRD. In summary, we found that HIV infection and haemophilia-related factors including inhibitors and kidney bleeds were associated with renal disease in a cohort of males with haemophilia.
Haemophilia 2003 Nov
PMID:Renal disease among males with haemophilia. 1475 Sep 36

The year 2002 marked the 20th anniversary of the first successful product of modern biotechnology, the regulatory approval of recombinant insulin for biopharmaceutical applications. Insulin is also the first crystalline protein to be approved for therapeutic use. Over the past two decades, almost 150 biopharmaceuticals have gained marketing authorisation; however, insulin remains the only crystalline protein on the market. Significant research and development efforts have focused on the engineering of protein molecules, efficacy testing, model development, and protein production and characterisation. These advances have dramatically boosted the therapeutic applications of proteins, which now include treatments against acute conditions, such as cancer, cardiovascular disease and viral disease, and chronic conditions, such as diabetes, growth hormone deficiency, haemophilia, arthritis, psoriasis and Crohn's disease. Despite these successes, many challenges normally associated with biopharmaceuticals, such as poor stability and limited delivery options, remain. Protein crystals have shown significant benefits in the delivery of biopharmaceuticals to achieve high concentration, low viscosity formulation and controlled release protein delivery. This review will discuss challenges related to the broader utilisation of protein crystals in biopharmaceutical applications, as well as recent advances and valuable new directions that protein crystallisation-based technologies present.
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PMID:Protein crystals for the delivery of biopharmaceuticals. 1500 25

Physical activity is a key component of a healthy lifestyle. Exercise and physical activity have been shown to help maintain a healthy body weight, reduce stress, increase self-esteem and feelings of wellbeing, control blood pressure, and prevent heart disease and diabetes. Children with haemophilia may feel restricted from competing in sports through parental concern or pain and difficulty in moving, or they may rebel against such restrictions, thus leaving themselves open to serious injury. Several groups have attempted to classify sports activities with regard to the level of risk involved; however, these are not consistent. It is important to match the child's abilities with the sport in which they want to take part, and suggest alternatives if this is not possible. Prevention of injury should not depend solely on use of factor concentrates.
Haemophilia 2004 Oct
PMID:Risks and benefits of sports and fitness activities for people with haemophilia. 1547 91

Nine patients with chronic extensor mechanism disruption were treated with an extended medial gastrocnemius rotational flap reconstruction of the extensor mechanism. Seven patients previously had total knee arthroplasty and two patients had chronic infection of nonreplaced, native knees. Four patients previously had failed Achilles' tendon allograft reconstruction after total knee arthroplasty and two were complicated by infection. Infected arthroplasty patients had a staged procedure with placement of an antibiotic spacer after debridement and extended medial gastrocnemius rotational flap, followed by total knee arthroplasty replant 8 weeks later. The four infected arthroplasty patients had medical comorbidities that included a patient with HIV and hemophilia, and two with diabetes mellitus. Another patient with rheumatoid arthritis was severely malnourished as a result of dumping syndrome. Of the four patients treated by this two-stage procedure, one died in the early postoperative period from chronic medical issues after the second stage and another patient elected to have above-knee amputation after the first stage because of severe reflex sympathetic dystrophy. The final group of seven patients was studied at a mean followup of 21 months (range, 7-31 months), the average extensor lag was 13.5 degrees (range, 0-50 degrees ), and the average range of motion was 2 degrees to 93 degrees . The two patients with nonreplaced, native knees had extensor lags of 30 degrees and 10 degrees . All patients were able to regain sufficient extensor mechanism strength to return to independent ambulation, and all infections resolved after treatment. Two patients were able to ascend stairs foot over foot without support. In addition to the patient who had amputation, the other complication involved a wound breakdown that required a free flap at 13 months in a patient who had a failed Achilles' tendon allograft reconstruction after takedown of a knee fusion. Medial gastrocnemius flap reconstruction can provide successful salvage of a failed extensor mechanism allograft or an alternative to allograft reconstruction in patients with poor soft tissue coverage, previous infection, or a compromised immune system.
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PMID:Extended medial gastrocnemius rotational flap for treatment of chronic knee extensor mechanism deficiency in patients with and without total knee arthroplasty. 1553 42

Gene therapy is defined as the introduction of genetic material in a patient's cells with resulting therapeutic benefit. It is a promising new biomedical discipline that could potentially lead to new treatments for hereditary diseases, cardiovascular and neurologic disorders, cancer, diabetes and even infectious diseases. The introduction of genetic material into somatic cells requires gene delivery vectors. Since viruses have developed efficient means to introduce their own genetic material into cells they can be readily adapted as viral vectors for gene therapy. Preclinical studies in animal models have shown that therapeutic effects can be achieved after gene therapy for genetic, acquired and complex disorders. Furthermore, therapeutic effects have been obtained in several phase I/II gene therapy clinical trials for hemophilia, severe combined immune deficiency (SCID) and cancer. Gene transfer technology has improved significantly over the past few years and has led to the development of vectors which have fewer side-effects without compromising their efficacy, at least partly due the development of cell-type specific targetable vectors. Nevertheless, the success of gene therapy is still very much depending upon the continuous development of improved vector technologies which would hopefully and ultimately cure diseases which are refractory to current treatment paradigms.
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PMID:[Recent developments in gene therapy]. 1555 1

There have been conflicting reports in the literature about the protective effect of hemophilia on the occurrence of ischemic heart disease (IHD). Circulatory disease has been reported as the second most common cause of death in persons with hemophilia in the United States. In addition to diabetes and hypertension, high levels of FVIII, as may occur during factor concentrate infusions, may increase IHD risk in this population. To estimate the prevalence of heart disease and examine factors associated with IHD and other heart diseases among persons with hemophilia, we analyzed data collected from the medical records of 3,422 males with hemophilia living in six U.S. states from 1993 to 1998. Heart disease cases were ascertained from among 2,075 persons who were hospitalized at least once during the 6-year period. Of these, 48 were diagnosed with IHD and 106, with other types of heart disease. The age-specific prevalence of IHD ranged from 0.05% in those under 30 years to 15.2% in those 60 years or older. Hospital discharge rates in males with hemophilia with IHD and other types of heart disease were lower compared to rates in age-matched U.S. males. In our cohort, as in the general population, IHD was independently associated with age, hypertension, diabetes, and hyperlipidemia. Other heart diseases were associated with HIV infection, hypertension, hemophilia B, and diabetes. In summary, persons with hemophilia have unique risk factors such as infusion of factor concentrates and infection with HIV that may predispose them to heart disease as their life expectancy increases.
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PMID:Prevalence and risk factors for heart disease among males with hemophilia. 1584 61

In the majority of potential applications gene therapy will require an effective transfer of a transgene in vivo resulting in high-level and long-term transgene expression, all in the absence of significant toxicity or inflammatory responses. The most efficient vehicles for delivery of foreign genes to the target tissues are modified adenoviruses. Adenoviral vectors of the first generation, despite the high infection efficacy, have an essential drawback: they induce strong immune response, which leads to short term expression of the transgene, and limits their usefulness in clinical trials. In contrast, helper-dependent adenoviral vectors (HdAd) lacking all viral coding sequences display only minimal immunogenicity and negligible side-effects, allowing for long-term transgene expression. Thus, HdAd vehicles have become the carrier of choice for adenoviral vector-mediated experimental gene therapy, effectively used in animal models for delivery of transgenes into the liver, skeletal muscle, myocardium or brain. Strong and long-lasting expression of therapeutic genes has allowed for successful treatment of dyslipidemias, muscular dystrophy, obesity, hemophilia, and diabetes. Additionally, the large cloning capacity of HdAd, up to 37 kb, facilitates the use of physiologically regulated, endogenous promoters, instead of artificial viral promoter sequences. This enables also generation of the single vectors expressing multiple genes, which can be potentially useful for treatment of polygenic diseases. In this review we characterize the basic features of HdAd vectors and describe some of their experimental and potential clinical applications.
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PMID:Helper-dependent adenoviral vectors in experimental gene therapy. 1608 8

We describe a series of twelve patients with a psoas abscess seen in a three-year period in a university hospital and a large teaching hospital in the Netherlands. In our series, five of the 12 patients had a primary psoas abscess. The predisposing conditions were intravenous drug use, diabetes mellitus, prostate carcinoma and haematoma in the psoas muscle in a patient with haemophilia A. Seven of the 12 patients had a secondary psoas abscess. Five cases were due to vertebral osteomyelitis including two cases of tuberculosis. In the other two cases it was due to colitis and urinary tract infection. It is remarkable that in our series there was only one patient with a psoas abscess secondary to a disease of the digestive tract, while this is the most common cause of a secondary psoas abscess in the literature. There were two cases of tuberculosis which is an emerging disease again.
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PMID:Psoas abscess: report of a series and review of the literature. 1630 64

Prophylaxis with von Willebrand factor (VWF)-containing concentrates is considered to be a potential approach for patients with von Willebrand disease (VWD) and severe bleeding tendency. We report the case of a 57-year-old man with type 3 VWD and a history of recurrent melaena. Bleeding frequency and severity had progressively increased and the patient showed chronic anaemia and persistent haemoglobin in the stools. Endoscopic examinations revealed multiple vascular mucosal abnormalities (MVA) of the stomach and large bowel. Photocoagulation of some actively bleeding lesions and octreotide did not significantly affect his clinical conditions: six red cell transfusions and >400 000 IU of intermediate-purity factor VIII (FVIII) concentrate (Haemate P) on-demand were needed during 2002. Prophylaxis with Haemate P 40 IU kg(-1) (102 IU kg(-1) VWF:RCo) thrice weekly was associated with improvement of his mean haemoglobin levels, cessation of clear-cut melaena and red cell transfusions and reduction of total Haemate P requirements (-20% over 2003-04). Prophylaxis with Haemate P is still ongoing without any adverse event over a 30-month period. Clinical course and pharmacokinetic evaluations led to administer Haemate P each 72-96 h. Possible vascular complications were excluded by a careful clinical follow up, as the patient suffered from arterial hypertension and diabetes mellitus; thrombophilic abnormalities were previously excluded and no signs of abnormal coagulation activation or FVIII:C levels >150% were detected thereafter. Long-term prophylaxis with Haemate P has been shown to be safe, effective (also in terms of quality of life) and cost saving in this patient with severe gastrointestinal bleeding due to MVA and VWD.
Haemophilia 2006 Jan
PMID:Long-term prophylaxis with intermediate-purity factor VIII concentrate (Haemate P) in a patient with type 3 von Willebrand disease and recurrent gastrointestinal bleeding. 1640 82

There is now conclusive evidence that gene therapy can lead to real clinical benefit. Initial enthusiasm has been muted by set-backs related to viral vectors including retroviral oncogenesis and adenoviral inflammatory response. Plasmid-mediated muscle-targeted gene transfer offers the potential of a cost-effective pharmaceutical grade therapy delivered by simple intramuscular injection without the need for anaesthetic, cell culture, transplantation or immunosuppression. This approach is particularly appropriate for long-term circulating therapeutic protein replacement currently requiring repeated injection therapy. Wide-ranging clinical applications include haemophilia, chronic anaemia, growth hormone deficiency and diabetes. Inadequate transgene expression, unregulated protein delivery and immune response have been major limiting factors. Recent innovations including in situ electroporation enabling sustained systemic protein delivery within the therapeutic range are reviewed. Pharmacological and physiological approaches to regulation are discussed in addition to the role of innate and humoral immunity. Translation of advances in all of these areas to clinical success will enable muscle-targeted gene therapy to capitalise on its inherent strengths and realise its long-standing promise.
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PMID:Plasmid-mediated muscle-targeted gene therapy for circulating therapeutic protein replacement: a tale of the tortoise and the hare? 1647 48


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