First use of gene therapy to treat growth hormone resistant dwarfism in a mouse model.

The only treatment tested for growth hormone receptor (GHR) defective Laron Syndrome (LS) is injections of recombinant insulin-like-growth factor 1 (rhIGF1). The response is suboptimal and associated with progressive obesity. In this study, we treated 4-5-week-old Laron dwarf mice (GHR-/-) with an adeno-associated virus expressing murine GHR (AAV-GHR) injection at a dose of 4 × 1010 vector genome per mouse. Serum growth hormone (GH) levels decreased, and GH-responsive IGF1, IGF binding protein 3 (IGFBP3) and acid labile subunit (ALS) increased. There was a significant but limited increase in body weight and length, similar to the response to rhIGF1 treatment in LS patients. All the major organs increased in weight except the brain. Our study is the first to use gene therapy to treat GH-receptor deficiency. We propose that gene therapy with AAV-GHR may eventually be useful for the treatment of human LS.

Modification of a Constitutive to Glucose-Responsive Liver-Specific Promoter Resulted in Increased Efficacy of Adeno-Associated Virus Serotype 8-Insulin Gene Therapy of Diabetic Mice.

We have previously used a hepatotropic adeno-associated viral (AAV) vector with a modified human insulin gene to treat diabetic mice. The HLP (hybrid liver-specific promoter) used was constitutively active and non-responsive to glucose. In this study, we examined the effects of addition of glucose responsive elements (R3G) and incorporation of a 3' albumin enhancer (3'iALB) on insulin expression. In comparison with the original promoter, glucose responsiveness was only observed in the modified promoters in vitro with a 36 h lag time before the peak expression. A 50% decrease in the number of viral particles at 5 × 109 vector genome (vg)/mouse was required by AAV8-R3GHLP-hINSco to reduce the blood sugar level to near normoglycemia when compared to the original AAV8-HLP-hINSco that needed 1 × 1010 vg/mouse. The further inclusion of an 860 base-pairs 3'iALB enhancer component in the 3' untranslated region increased the in vitro gene expression significantly but this increase was not observed when the packaged virus was systemically injected in vivo. The addition of R3G to the HLP promoter in the AAV8-human insulin vector increased the insulin expression and secretion, thereby lowering the required dosage for basal insulin treatment. This in turn reduces the risk of liver toxicity and cost of vector production.

Correction of Murine Diabetic Hyperglycaemia With A Single Systemic Administration of An AAV2/8 Vector Containing A Novel Codon Optimized Human Insulin Gene.

We report the correction of hyperglycemia of STZ induced diabetic mice using one intravenous systemic administration of a single stranded serotype 8 pseudotyped adeno-associated virus (ssAAV2/8) vector encoding the human proinsulin gene under a constitutive liver specific promoter. In vivo dose titration experiments were carried out and we identified an optimal range that achieved maintenance of euglycaemia or a mild diabetic condition for at least 9 months and ongoing to beyond 1 year for some animals, accompanied by human C-peptide secretion and weight gain. Further DNA codon optimization of the insulin gene construct resulted in approximately 3-10 times more human C-peptide secreted in the blood of codon optimized treated animals thereby reducing the number of vector particles required to achieve the same extent of reduction in blood glucose levels as the non-codon optimized vector. The constitutive secretion of insulin achieved with a single administration of the vector could be of therapeutic value for some diabetic patients.

Effects of malnutrition on economic productivity in China as estimated by PROFILES.

OBJECTIVE: To calculate the effects of malnutrition on economic productivity in China. METHODS: PROFILES was used to quantify the function consequences of malnutrition in term of protein energy malnutrition, iron deficiency and iodine deficiency. RESULTS: Productivity gained due to improved iodine nutrition. The reduction in the TGR in 1992 to 2001 increased the net present value of further economic productivity by yen 142 billion. Reduction of the TGR rate to 5% over next 10 years would result in future productivity gains with value of yen 40 billion. Productivity gain due to reductions in child stunting would result in future economic productivity gains with the value of yen 101 billion. Reducing stunting further over the next 10 years would gain yen 20 billion. Productivity gain due to reduction of iron deficiency anemia reduced by 30% over the next 10 years would gain worth yen 107 billion and if childhood anemia reduced by 30% over next 10 years would gain yen 348 billion. CONCLUSION: These interventions have huge economic payoff. That is likely to exceed their costs many times over.

Effects of malnutrition on child survival in China as estimated by PROFILES.

OBJECTIVE: To estimate the benefits of reductions in underweight and Vitamin A deficiency for child survival in China that might be expected as a result of lowering the prevalence of these conditions. METHODS: Profiles, a process of nutrition policy analysis was used to quantify the functional consequences of malnutrition in terms of child survival. RESULTS: Underweight: The actual reduction in underweight between 1992 and 2001 (from 15.7% to the current 10.1%) resulted in saving of 176,000 child lives. As estimated, without improvements, 612,000 children will die due to underweight between 2001 and 2010, 281,000 (46%) of them living in western provinces. Reducing underweight prevalence from 10.1% to 8% could overall save 62,000 lives. The reduction of underweight prevalence in the west alone might save 56,000 lives. Vitamin A in China as a whole, vitamin A deficiency accounts, as estimated, for 7.5% of deaths of children 6-59 months old, representing 206,000 deaths over the past ten years. Halving the prevalence over the period would save 49,000 child lives. The higher prevalence and higher mortality rates in western provinces mean that even with only 28% of the Chinese population, over half of child deaths there are related to vitamin A.

[Epidemiological survey of chronic vascular complications of type 2 diabetic in-patients in four municipalities].

OBJECTIVE: To provide an epidemiological description and risk factors of chronic vascular complications of type 2 diabetic in-patients in four municipalities including Beijing, Shanghai, Tianjin, and Chongqing. METHODS: Data of the study came from 3,469 Type 2 diabetic in-patients from 1991 to 2000 in 10 medical centers of Beijing, Shanghai, Tianjin, and Chongqing. A variety of parameters of in-patients were evaluated retrospectively to know the prevalence and risk factors of chronic vascular complications in the study patients. RESULTS: Overall, the detailed prevalence of chronic vascular complications is listed as follows: diabetic retinopathy 31.5%, diabetic nephropathy 39.7%, diabetic neuropathy 51.1%, hypertension 41.8%, coronary heart disease (CHD) 25.1%, cerebral vascular disease (CVD) 17.3%, vessel complication of lower limbs 9.3%. Multivariate logistic regression analysis shows that diabetes family history, duration of diabetes (> 5 years), and systolic blood pressure (> 125 mmHg) are the risk factors for diabetic retinopathy; duration of diabetes (> 5 years), systolic blood pressure (> 125 mmHg), LDL-C (> 3.12 mmol/L), and triglyceride (> 1.70 mmol/L) are the risk factors for diabetic nephropathy; age (> 45 years), duration of diabetes (> 5 years), HbA1C (> 7.0%), systolic blood pressure (> 125 mmHg), and LDL-C (> 3.12 mmol/L), are the risk factors for CHD; age (> 45 years), duration of diabetes (> 5 years), systolic blood pressure (> 125 mmHg), and triglyceride (> 1.70 mmol/L) are the risk factors for CVD. CONCLUSION: In order to improve patients' outcome, multiple metabolic controls in type 2 diabetic patients are urgently needed, which include decreasing glycemia, reducing hypertension and improving lipid levels.