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Biomedical subjects

David G Nathan

Publications and source records attributed to David G Nathan.

At least 19 recordsLinked to original sources
PubMed2006

Ribosomal protein S24 gene is mutated in Diamond-Blackfan anemia.

Diamond-Blackfan anemia (DBA) is a rare congenital red-cell aplasia characterized by anemia, bone-marrow erythroblastopenia, and congenital anomalies and is associated with heterozygous mutations in the ribosomal protein (RP) S19 gene (RPS19) in approximately 25% of probands. We report identification of de novo nonsense and splice-site mutations in another RP, RPS24 (encoded by RPS24 [10q22-q23]) in approximately 2% of RPS19 mutation-negative probands. This finding strongly suggests that DBA is a disorder of ribosome synthesis and that mutations in other RP or associated genes that lead to disrupted ribosomal biogenesis and/or function may also cause DBA.

Alternative Splicing↗
PubMed2005

New developments in iron chelators.

PURPOSE OF REVIEW: For three decades, deferoxamine has been the only approved iron chelator. This drug has an extremely short-half life and is not orally absorbed; thus, a search has been ongoing for alternative chelators with less onerous delivery. Recently, several oral iron chelators and variations of deferoxamine to prolong the half-life have been developed. These and the methods of monitoring iron overload are the subjects of this review. RECENT FINDINGS: New chelators, combinations of chelators and regimens for known chelators and their safety and efficacy are being studied in important preclinical and clinical trials. SUMMARY: The care and clinical outcomes of patients with thalassemia and other iron-overload disorders may be markedly improved by recent discoveries and novel approaches to chelation therapy.

Heart Diseases↗
PubMed2005

The several Cs of translational clinical research.

Perhaps because I am a veteran of the "good old days" (they were really quite bad), young physicians who hope to become clinical investigators often ask me how they might establish their careers. Many are more than a little worried about their futures and often have trouble envisioning a career path that is financially secure for themselves and their families. The grumbling of clinical investigators a few years their senior enhances their angst. So I try to encourage these young physicians because I know the great intellectual (if not monetary) rewards of the field and because I know that the future of medicine absolutely depends on clinical investigators. The following is what I try to say to them.

Biomedical Research↗
PubMed2005

Thalassemia: the continued challenge.

This overview describes the history of transfusion therapy and consequent iron overload in thalassemia. It emphasizes the importance of measurement of hepatic iron and reviews the history of chelation therapy. It briefly describes the discoveries of the genetic basis of thalassemia and the application of that knowledge in prenatal diagnosis. The review goes on to emphasize pharmaceutical efforts to induce fetal hemoglobin synthesis in thalassemic red cells and ends with a discussion of oral iron chelators, stem cell transplant, and the status of gene therapy.

Administration, Oral↗
PubMed2004

RNA and protein evidence for haplo-insufficiency in Diamond-Blackfan anaemia patients with RPS19 mutations.

The genetic basis of Diamond-Blackfan anaemia (DBA), a congenital erythroid hypoplasia that shows marked clinical heterogeneity, remains obscure. However, the fact that nearly one-quarter of patients harbour a variety of mutations in RPS19, a ribosomal protein gene, provides an opportunity to examine whether haplo-insufficiency of RPS19 protein can be demonstrated in certain cases. To that end, we identified 19 of 81 DBA index cases, both familial and sporadic, with RPS19 mutations. We found 14 distinct insertions, deletions, missense, nonsense and splice site mutations in the 19 probands, and studied mutations in 10 patients at the RNA level and in three patients at the protein level. Characterization of the mutations in 10 probands, including six with novel insertions, nonsense and splice site mutations, showed that the abnormal transcript was detectable in nine cases. The RPS19 mRNA and protein in CD34+ bone marrow cells identified haplo-insufficiency in three cases predicted to have one functional allele. Our data support the notion that, in addition to rare DBA patients with the deletion of one allele, the disease in certain other RPS19 mutant patients is because of RPS19 protein haplo-insufficiency.

Anemia, Diamond-Blackfan↗
PubMed2003

Effectiveness and safety of ICL670 in iron-loaded patients with thalassaemia: a randomised, double-blind, placebo-controlled, dose-escalation trial.

BACKGROUND: Transfusional iron overload is a potentially fatal complication of the treatment of thalassaemia. We aimed to investigate short-term efficacy, pharmacokinetic/pharma- codynamic (PK/PD) relations, and safety of ICL670, a novel, tridentate, orally active iron chelator. METHODS: We enrolled 24 patients and divided them into three cohorts consisting of a minimum of seven individuals. Patients were admitted to a metabolic unit and consumed a diet with a defined content of iron. Two patients in each cohort were randomly allocated placebo. Five or more patients received one daily dose of ICL670 at 10, 20, or 40 mg x kg(-1) x day(-1), from day 1 to 12. Net iron excretion (NIE) was measured between days 1 and 12. Primary objectives included assessment of safety and tolerability (measured by adverse events and clinical laboratory monitoring), pharmacokinetics (measured as drug and drug-iron complex), and cumulative net iron excretion (measured by faecal and urine output minus food input). Analysis was for efficacy. FINDINGS: ICL670 was absorbed promptly and was detectable in the blood for 24 h. Exposure (area under the curve of plasma concentration) to ICL670 at pharmacokinetic steady state was proportional to dose. All three doses resulted in positive NIE. The NIE achieved at 20mg x kg(-1) day(-1) would prevent net iron accumulation in most patients transfused with 12-15 mL packed red-blood-cells kg(-1) month(-1), equivalent to 0.3-0.5 mg iron kg(-1) x day(-1). A linear relation (PK/PD) was recorded between exposure to ICL670 and total iron excretion, by contrast with placebo (r2=0.54, p<0.0001). Skin rashes were noted in four patients treated at 20 and 40 mg x kg(-1) x day(-1), and one patient also developed grade 2 transaminitis. INTERPRETATION: ICL670 given once daily at 20 mg/kg seems to be an effective orally active iron chelator and is reasonably well tolerated. Long-term studies are now necessary to establish the practical contribution of this drug.

Adolescent↗
PubMed2003

Clinical research: a tale of two studies.

Threats to the status of clinical research have been well documented in the past three decades, and the National Institutes of Health and the Congress have done much to alleviate them. But the relationships of academic investigators and pharmaceutical companies remain a treacherous area. This vital nexus, on which so much progress depends, must be carefully maintained. In this paper I present two examples of academic/pharmaceutical company collaborations, both in search of a similar drug. The cases illustrate both some important hazards and accomplishments of clinical research.

Benzoates↗
PubMed2002

A novel diagnostic screen for defects in the Fanconi anemia pathway.

Fanconi anemia (FA) is an autosomal recessive chromosomal instability syndrome characterized by congenital abnormalities, progressive bone marrow failure, and cancer predisposition. Although patients with FA are candidates for bone marrow transplantation or gene therapy, their phenotypic heterogeneity can delay or obscure diagnosis. The current diagnostic test for FA consists of cytogenetic quantitation of chromosomal breakage in response to diepoxybutane (DEB) or mitomycin C (MMC). Recent studies have elucidated a biochemical pathway for Fanconi anemia that culminates in the monoubiquitination of the FANCD2 protein. In the current study, we develop a new rapid diagnostic and subtyping FA assay amenable for screening broad populations at risk of FA. Primary lymphocytes were assayed for FANCD2 monoubiquitination by immunoblot. The absence of the monoubiquitinated FANCD2 isoform correlated with the diagnosis of FA by DEB testing in 11 known patients with FA, 37 patients referred for possible FA, and 29 healthy control subjects. Monoubiquitination of FANCD2 was normal in other bone marrow failure syndromes and chromosomal breakage syndromes. A combination of retroviral gene transfer and FANCD2 immunoblotting provides a rapid subtyping assay for patients newly diagnosed with FA. These new FA screening assays would allow efficient testing of broad populations at risk.

Blotting, Western↗