Research News

26 NATURE MEDICINE • VOLUME 8 • NUMBER 1 • JANUARY 2002

NEWS & VIEWS

Sickle-cell gene therapyResearchers have developed a gene ther-

apy technique that reverses the symptomsof sickle-cell disease (SCD) in mice. SCD iscaused by a single point mutation in thehuman βA-globin gene that causes hemo-globin to polymerize in long fibers upondeoxygenation. This causes red blood cellsto become deformed (sickled) and adhe-sive, triggering microcirculation occlusion,anemia, and organ damage. In the 14December issue of Science, Pawliuk et al. re-port the development of a lentiviral vectorthat expresses a form of human βA-globinprotein that prevents hemaglobin polymer-ization. The vector was designed to expressthe modified form of hemoglobin specifi-cally in hematopoietic stem cells and adultred blood cells. Transplantation of trans-genic stem cells into mice resulted in long-term expression. The authors report theerythroid-specific accumulation of the anti-sickling protein in 52% of total hemoglobinand 99% of circulating red blood cells. Thetransgene was able to correct SCD pathologyin two mouse models of SCD, reducing redblood cell sickling, splenomegaly and thecharacteristic urine concentration defects.

Profiling leukemiaUsing whole-genome profiling, investi-

gators have determined that a rare type ofacute lymphoblastic leukemia (ALL). Asubset of ALL involving the mixed-lineageleukemia (MLL) gene at chro-mosome segment 11q23 typi-cally occurs in infants and isassociated with early relapseafter chemotherapy. In theJanuary issue of Nature Genetics,Armstrong et al. show that MLLpatients have a characteristicgene-expression profile that canbe separated from conventionalALL and acute myelogenous leukemias.The authors compared gene-expressionprofiles of leukemic cells from 20 patientswith conventional childhood ALL and 17patients carrying the MLL gene transloca-tion. Approximately 1,000 genes werefound to be underexpressed in MLL cells,many of which have a function in early B-cell development. In addition, there were

Vaccine for malaria menaceResults of a study from The Gambia pro-

vide evidence of a vaccine that could preventmalaria. Plasmodium falciparum-inducedmalaria remains a major cause of diseaseand death in many parts of the tropics, es-pecially in sub-Saharan Africa. The devel-opment of an effective vaccine is a majorhealth priority for these countries. In the 8December issue of The Lancet, Bojang et al.report the results of a randomized trial as-sessing the effectiveness of the pre-erythro-cytic malaria vaccine RTS,S/AS02 againstnatural P. falciparum infection in semi-im-mune adult men in The Gambia. In thistrial, 306 men were randomly assigned 3doses of either RTS,S/AS02 (the treatmentgroup) or rabies vaccine (the control

group). 250 men (131 in the treatmentgroup and 119 in the control group) re-ceived 3 doses of vaccine and were observedfor 15 weeks. The authors report that P. falci-parum infections occurred significantly ear-lier in the control group than the treatmentgroup. The overall malaria vaccine efficacywas 34%. Vaccination induced strong anti-body and T-cell responses against a P. falci-parum antigen. 158 men that received afourth dose the next year, and the overallvaccine effectiveness increased to 47%.The investigators conclude that RTS,S/AS02is safe and is the first pre-erythrocytic vac-cine to show significant protection againstnatural P. falciparum infection.

By Kristine Novak

Research News about 200 genes more highly expressedthan in conventional ALL. These genes in-cluded members of the HOX gene family—many of which are regulated by MLL.Conventional ALL samples expressed high

levels of lymphoid-spe-cific genes, whereasMLL cells expressedgenes primarily associ-ated with hematopoi-etic progenitors. Basedon this expression pro-file, the authors pro-pose that MLL is causedby the arrest of an ear-

lier hematopoietic progenitor. This is con-sistent with studies showing that MLLexpression occurs in hematopoietic prog-enitors before full lineage commitment.The authors state that MLL should be con-sidered a distinct disease from ALL. Thesefindings might explain why children withMLL do not respond to standard ALLchemotherapy.

Who’s down with APP?A unique axonal membrane compartment has been identified that contains the

Alzheimer disease–associated proteins amyloid precursor protein (APP), β-secretase andpresenilin-1, providing long-sought information into how these proteins might function to-gether in normal and diseased neurons. APP is proteolytically processed by β- and γ-secre-tases, which might be encoded by the presenilin genes, to generate amyloid-β. Amyloid-βhas been found to accumulate in the brains of Alzheimer disease patients, so the secretasesthat process APP have been considered disease-causing culprits. However, it has been diffi-cult to colocalize the proteases and substrates in the same neuronal membrane compart-ment. In the 6 December of Nature, Kamal et al. identify an axonal membranecompartment that contains APP, β-secretase and presenilin-1, and show that APP under-goes proteolytic processing into amyloid-β here. The compartment is transported along theaxon by the microtubule motor kinesin-1, which directly binds APP. The authors show thataxonal transport of β-secretase and presenilin-1 is decreased in APP-null mice. Cleavage ofAPP also liberated kinesin-1 from the membrane. These results suggest that APP functionsas a kinesin-1 membrane receptor, mediating the axonal transport of β-secretase and pre-senilin-1. The authors propose that increases in APP cleavage could cause kinesin-1 releasefrom vesicles, vesicle stalling and amyloid-β deposition in neurons.

Bacterial tumor invasionAlthough many drugs are effective in

killing rapidly dividing cancer cells, it isdifficult to deliver these drugs to the poorlyvascularized, hypoxic regions inside largetumors. In the 27 November issue of PNAS,Dang et al. report an ‘inside-out’ therapy todestroy the oxygen-deprived necrotic areasof tumors—using bacteria. Dang et al. at-tempted to take advantage of the fact thathypoxic tissues exist only in tumors andnot in normal tissues by treating tumorswith the anaerobic cytolytic bacteriaClostridium novyi. They report that intra-venously administered C. novyi spores,along with conventional chemotherapeu-tic agents, can destroy colorectal tumors ina mouse xenograft model. Treatment withchemotherapy alone slowed, but did notstop, tumor growth. Combination bacteri-olytic therapy, however, caused the tumorsto become black necrotic masses thatshrank and disappeared, whereas sur-rounding normal tissue remained intact.More than three-quarters of the tumorstreated, including very large tumors, werecompletely destroyed within 24 hours, andapproximately half the mice were curedwith no evidence of tumor regrowth.Future experiments are required to answersafety questions.

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