already discussing future strategies withseveral pharmaceutical companies.

Meanwhile, the fundamental researchwork continues. The next steps includeresolving the known single-gene antibi-otic polypeptides to the smallest possiblesequence and elucidating the structureof each of these polypeptide antibioticswith their targets. ‘These polypeptideantibiotics might be rational design toolsfor pharmaceutical companies to developdrugs that inhibit essential bacterial enzymes,’ predicts Young.

Overcoming resistanceThe possibility of developing several newclasses of antibiotic is crucial as well asexciting. ‘The need to define new targetsfor antimicrobial agents and to developinnovative strategies is clearly urgent,’says Charles Stratton, Director of Clinical

Microbiology, Vanderbilt UniversitySchool of Medicine (Nashville, TN, USA).In the past decade, the spread of multi-ple antibiotic resistance has become amajor threat to the continued efficacyand use of current antibiotics. Strattonfinds the approach of Bernhardt and colleagues of great interest. ‘The mainadvantage of proteins produced byphages is that they target the cell wall, astructure that does not exist in humancells,’ he says. He highlights the exampleof penicillin, the first antibiotic to be discovered. ‘Penicillin is a β-lactam antibiotic and, although resistance to itis now a huge problem worldwide, it has proved to be one of the safest anti-biotics because it targets peptidoglycan.Bacteriophage proteins that target differ-ent steps in cell-wall biosynthesis couldbe equally safe, but this premise must

be proven,’ he stresses. However, if itdoes prove correct, bacteriophages andthe proteins they produce could becomea major source of new antimicrobialagents.

Young agrees, and points out thatphage proteins could have an added attraction: ‘In principle, one could easilymodify polypeptide antibiotics by chang-ing the encoding DNA sequence. It isalso possible to actually select randomchanges in a polypeptide that wouldovercome resistance, using the powerfultools of bacterial molecular genetics. Butthat really is looking into the future,’ heconcludes.

Reference1 Bernhardt, T.G. et al. (2001) A protein

antibiotic in the phage Qβ virion: Diversityin lysis targets. Science 292, 2326–2329

Milking nature for Alzheimer’streatmentJoanna Owens, Joanna.Owens@drugdiscoverytoday.com

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A new drug derived from mammals’first-milk could provide an effective newtreatment for Alzheimer’s disease (AD).An interim report has recommendedthat ReGen Therapeutics (London, UK)be allowed to progress to the end-pointof its 90-patient, multi-centre, double-blind, placebo-controlled clinical studyof the efficacy of Colostrinin™ for treatingAD.

The international steering committeeof the trial, carried out in Poland, foundthat there were no adverse reactions re-lated to Colostrinin and an encouragingtrend of efficacy in patients treated withthe drug compared with the placebo

group. The committee also recommendedthat a further 18 patients should be enrolled to increase the statistical powerof the trial.

The cost of ADAD is an increasingly common, progres-sive neurodegenerative disease for whichthere is no cure. The disease slowly destroys the brain, impairing cognitivefunctions such as memory, abstractthinking and language function, andcauses other symptoms such as attentiondeficit, depression, anxiety and agita-tion. The pharmaceutical industry is,therefore, under pressure to develop

therapies for AD, which inflicts substan-tial emotional and financial costs to families, businesses and governments.

AD neurodegeneration is typified bythe presence of amyloid plaques, tautangles and loss of neurons1. The plaquesconsist of amyloid β (Aβ) deposits, whichare formed as a result of the abnormalcleavage of amyloid precursor protein(APP)2. Tau tangles are caused by an over-production of the tau protein1, which,upon release from the cell, becomesheavily phosphorylated and glycated3,4,and thus more insoluble. It is thoughtthat both of these pathogenic processescould be a result of oxidative stress1,3,4.

Colostrinin and cognitionColostrinin is a proline-rich polypeptideconstituent of colostrum – the milk pro-duced by mammals after giving birth,which provides the newborn with innateimmunity against infection. Because ofits immunomodulatory properties, stud-ies were undertaken by Josef Lisowskiand colleagues (Institute of Immunologyand Experimental Therapy, Wroclaw,Poland) to determine whether Colostrinincould be used to correct immune disorders. During these studies, the researchers noticed that volunteersshowed improvements in cognitive abil-ities and mood. This prompted the groupto investigate Colostrinin as a potentialtreatment for AD.

In the past few years, Colostrinin hasbeen found to improve learning andmemory in rats5, and a Colostrinin deriva-tive was shown to retard the progress ofAD and delay the loss of long-termmemory in aged rats6. Furthermore, in46 AD patients given either 100 µg oral Colostrinin, commercially available selenium supplements or placebo over aone-year trial, eight of 15 Colostrinin-treated patients showed an improve-ment in the disease, and stabilization ofthe disease was observed in the remain-ing seven patients7 (as measured by mini mental-state examination; MMSE).Importantly, the drug was found to haveonly a few mild and transient side effectssuch as anxiety, stimulation, insomniaand tiredness.

Mechanism of actionThere are several mechanisms by whichColostrinin might stabilize AD. First,Colostrinin has been shown to inducethe secretion of cytokines, such as inter-feron-γ (IFN-γ)8 and tumour necrosis fac-tor-α (TNF-α)9, which have been shownto inhibit amyloid plaque formation10.Second, in studies by ReGen, Colostrininwas found to reduce the intracellular ox-idation of a fluorescent substrate (fluo-rescein) as determined by a reduction influorescence intensity, demonstrating

that Colostrinin is an anti-oxidant thatcan scavenge free radicals. Third, re-searchers at ReGen found that in leukocyte cultures, treatment with eitherwhole Colostrinin or its constituent peptides for six days caused increasedproliferation and adhesiveness (Fig. 1)when compared with untreated con-trols. Interestingly, such an increase inproliferation and adhesiveness is essen-tial because AD causes a massive loss ofneurons and, therefore, by increasing theadhesiveness of cells it might eventually

be possible to reattach neurons andmake them function. More importantly,scientists at ReGen demonstrated thatColostrinin, or its constituent peptides,can induce morphological changes: PC12nerve progenitor cells were found to dif-ferentiate after treatment (Fig. 2), intoepithelial, fibroblastoid or nerve-typecells.

Marian Kruzel, Senior Scientific Advisorat ReGen, has been studying milk proteins and peptides for a long time. He said: ‘I am interested in the whey

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Figure 1. Fluorescence micrograph images of human leukocyte proliferation. Treatmentwith either whole Colostrinin, or its constituent peptides (referred to here as peptide 2and peptide 10), for six days, caused increased proliferation and adhesiveness comparedwith untreated cultures. (a) Treatment with peptide 2, (b) treatment with Colostrinin, (c)treatment with peptide 10, (d) negative control. The arrows indicate increasedproliferation and regions of cell aggregation (clumping).

Figure 2. Differentiation of PC12 nerve progenitor cells after treatment with Colostrinin.This three-dimensional fluorescence image shows (a) control PC12 cell; and (b) afibroblastoid differentiating cell after treatment with Colostrinin™.

Patients with advanced lymphomascould be treated with measles vaccine inthe future. Researchers at the MayoClinic (Rochester, MN, USA) have shownthat a strain of measles virus used in vaccines causes regression of humanlymphoma tumours in immunodeficientmice1.

The idea that viruses can be used tofight cancer is not new. Sporadic reportshave appeared in the literature through-out the past century, but interest intensi-fied in the late 1990s with the advent ofgene therapy. Several types of virus have

shown promise in preclinical studies, andsome clinical studies are already underway. For example, a Phase II trial of intratumoural injections of ONYX-015 (a genetically modified adenovirus) com-bined with standard chemotherapydrugs to treat recurrent head and neckcancer2 has shown substantial benefitsover chemotherapy alone.

Cytopathic effectsThe Mayo team is concentrating on themeasles virus (MV), specifically on a live,attenuated vaccine derived from the

non-pathogenic Edmonston-B strain(MV-Ed). This has been used worldwidefor more than 30 years and is safe andeasily available.

Mayo researchers have previouslyfound that cell death can be inducedwith MV-derived fusogenic membrane-glycoproteins (FMGs) known as F and H.These glycoproteins cause the infectedcell to fuse with others to form large,multinucleated bodies that die in a non-apoptotic process involving nuclearfusion3. FMGs kill tumour cells more effi-ciently than suicide genes of the type

proteins because of their immunomodu-latory function in humans and animals. I have established an international net-work of scientists (France, New Zealand,Poland and USA) working on lactoferrin,one of the major proteins in colostrumand mature milk.’ He continued:‘Colostrinin, as a proline-rich polypep-tide complex, has its own beauty,because of the variety of biological activ-ities associated with the complex. It isextremely exciting to work with a product that has the potential to treat a variety of, as yet, untreatable disorders.’

ReGen is now recruiting the extra 18patients required for the second phase ofits clinical trial, and now aims to opti-mize and validate the dosage form andcontinue to develop the science and in-tellectual property of Colostrinin-basedtherapies. Jerzy Georgiades, ChiefScientific Officer at ReGen, revealed thatthe second phase of the trial might becarried out in Poland in parallel withother European countries, including theUK. He added that the same parameters

(mainly MMSE) will be used to evaluateefficacy, but within a larger population.

Kruzel believes that further researchinto Colostrinin will address its applica-bility not only to AD, but to other neurodegenerative and neoplastic disor-ders.

Although ReGen scientists are focus-ing their research primarily on the treat-ment of AD, they are also looking to findpreventive measures. Kruzel concludesthat: ‘Nothing is more rewarding thanthe improvement in patients treatedwith your experimental drug; we arelooking forward to the positive clinicalresults from our current studies inPoland.’

References1 Geodert, M. (1993) Protein and the

neurofibrillary pathology of Alzheimer’sdisease. Trends Neurosci. 16, 460–465

2 Rozenmiller, J.M. et al. (1992) Activatedmicroglia and cerebral amyloid deposits inAlzheimer’s disease. Res. Immunol. 163,646–649

3 Yan, S.D. et al. (1995) Non-enzymaticallyglycated tau in Alzheimer’s disease induces

neuronal oxidant stress resulting in cytokinegene expression and release of amyloidpeptide. Nat. Med. 1, 693–699

4 Wan, S.D. (1994) The presence of glycatedtau in Alzheimer’s disease: a mechanism forinduction of oxidant stress. Proc. Natl. Acad.Sci. U. S. A. 91, 7787–7791

5 Popik, P. et al. (1999) Colostrinin, apolypeptide isolated from early milk,facilitates learning and memory in rats.Pharmacol. Biochem. Behav. 64, 183–189

6 Popik, P. et al. (2001) Cognitive effects ofColostral–Val nonapeptide in aged rats.Behav. Brain Res. 118, 201–208

7 Leszek, J. et al. (1999) Colostrinin™: aproline-rich polypeptide (PRP) complexisolated from ovine colostrum for treatmentof Alzheimer’s disease. A double-blind,placebo-controlled study. Arch. Immunol.Ther. Exp. 47, 377–385

8 Ringheim, G.E. et al. (1996) Transcriptionalinhibition of the α-amyloid precursor proteinby interferon γ. Biochem. Biophys. Res.Commun. 224, 246–251

9 Barger, S.W. et al. (1995) Tumor necrosisfactors α and β protect neurons againstamyloid β peptide toxicity. Proc. Natl. Acad.Sci. U. S. A. 92, 9328–9332

10 Inglot, A.D. et al. (1995) Colostrinin™: aproline-rich polypeptide from ovinecolostrum is a modest cytokine inducer inhuman leukocytes. Arch. Immunol. Ther. Exp.44, 215–223

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Measles vaccine could treat lymphomaJo Whelan, Freelance writer