22 mo odpppto  clinical review

MEDICAL

23clinical review  odpppto mo

19 2011

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EIGHT, six, four, three… John

Forbes’s hopes rose as the number

of lesions fell.Diagnosed with melanoma in

2007, his three operations had

taken more than their pound of flesh, with the last one removing

a 16 inch (41 cm) swathe of skin

from his lower left back.But more lesions kept appear-

ing and last February he wasenrolled in an American phase

III clinical trial for a gene therapy

that had shown success againstthe deadly cancer.

As the weeks rolled by, Mr

Forbes, 59, watched his lesions

disappear. He was declared dis-ease-free in October.

“As these lesions were disap-

pearing, I was going, ‘wow, notonly is it God’s work here but it

is science working beautifully –a new drug coming on that c an

help so many other people and

hopefully save their lives’,” MrForbes says.

OncoVEX, an oncolytic viral

vaccine developed by a small USbiotech company, BioVex, and

now owned by Amgen, created

a stir when the results of its phase

II trial were published in 2009. 1

Administered via intratumour

injection, the vaccine contains

the herpes simplex virus type I,which has been modified to carry

the gene encoding human granu-

locyte-macrophage colony-stim-ulating factor.

It selectively targets and repli-

cates in the tumour cells, destroy-ing them in the process, as well as

stimulating an immune responseto kill cancer cells throughout

the body.

Out of the 50 phase II study

participants with stages IIIc andIV melanoma, 10 had a complete

response and four had a partial

response.According to Amgen, the sci-

entific world is waiting for the

results of the phase III trial,which ended in June, with great

excitement.

“I think most scientists andphysicians don’t really doubt

that there will be a place for

using genetic material deliveredto patients as therapeutic modali-

ties,” says Joe Miletich, Amgen’s

senior vice-president of research

and development.“The problem has always

been finding the most safe and

efficacious way to do it, and thetiming for that. And our hope is

that OncoVEX will be anotherstep on that pathway and that

others will [be encouraged to]

continue.”Decades of research, animal

studies and some widely publi-

cised adverse events are finallycoalescing into success as gene

therapy finally starts to deliver.

Gene therapy clinical trials

for Parkinson’s disease, 2 Leber’scongenital amaurosis,3 haemo-

philia4 and heart failure5 also

prove a portal to the promiseheralded by the human genome

project.

On the genome project’s com-pletion in 2003, scientists hailed

its identification of 20,000–

25,000 human genes as thepivotal moment of a genetic rev-

olution.

Gene therapies were to be thevanguard of a new charge on dis-

ease, whose cause and incidence

doctors would now be able toidentify and predict, as well as

treat.

Viruses are the most common

vectors used to deliver the thera-peutic gene to the target cells, and

these include retroviruses, adeno-viruses, adeno-associated viruses

and herpes simplex viruses.

Since 1990, they have

accounted for two-thirds of vec-tors used in clinical studies but

other delivery systems include

artificially created lipid sphereswith an aqueous core, stem cells

and the direct introduction of 

DNA into the cell.At present, only somatic cells

are targeted for human treat-ment.

Germline gene therapy, with

its potential effect on future gen-erations, remains the subject of 

intense ethical and philosophical

discussion.In 1990, researchers at the

US National Institutes of Health

conducted the first approvedhuman gene therapy trial.

It involved the transfer of the

gene encoding adenosine deami-nase into two patients with severe

combined immunodeficiency.

Ashanti DeSilva, aged four,experienced a partial correction

of her condition.

By the end of that decade, thegene therapy field was riding the

crests and troughs of the new

“whtgogtosfysy,uquosusss”Professor Ian Alexander

Gene therapy holds

huge promise to treat

intractable conditions.

Jane Lyons  separates

the hope from the hype.

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HOPe inajabgene therapy’s next wave

wave of medical research.The number of clinical trials

for gene therapy approved world-

wide had climbed rapidly, fromtwo in 1990 to 116 in 1999, but

in the latter year the first major

adverse event was reported. Jesse Gelsinger, 18, who had a

relatively mild form of ornithinetranscarbamylase deficiency,

died due to vector-associated

toxicity.Hopes rose again in 2000

with what was hailed as a gene-

therapy grand slam.French researchers corrected

a rare form of X-linked severe

combined immunodeficiency(SCID-X1) in 10 children with

the transfer of bone marrow cells

genetically modified by a retrovi-rus vector encoding human  γc.

In collaboration with the

French team, Australian research-ers treated a nine-month-old boy

with SCID-X1 at the Children’s

Hospital, Westmead, NSW, in2002.

They achieved only a partial

immunological reconstitution. 6

However, also in 2002, two

of the French children developed

a leukaemia-like condition.The trial was restarted using

lower doses of modified cells, but

a third child developed a similarcondition in 2005.

Two of the children respondedto chemotherapy but the third

died.

Professor Ian Alexander,the head of the Gene Therapy

Research Unit, an initiative of 

the Children’s Medical ResearchInstitute and the Children’s

Hospital at Westmead, says

such adverse events have led to

a degree of scrutiny not experi-enced by other t herapies.

They have also bred too muchcaution about gene therapies in

regulatory bodies and research-

ers, he says.“The bottom line is that the

clinical trial activity is what is

going to take us forward,” he

says.“You could get concerned

about a theoretical risk, but formany of these patients the dis-

ease that they suffer poses a far

greater one.”And with risk an inescapable

part of clinical research, balanc-

ing it against benefit is the keyto moving forward, Professor

Alexander says.

“Regulatory authorities havea responsibility to protect public

safety, scientists and clinicians

are trying to drive new therapiesforward, and there’s always got

to be a balance struck.”

The development of efficientand safe gene transfer remains

the key focus of the move from

animal models to humans.Professor Alexander, whose

team undertook the SCID-XI

trial in 2002, will be part of thefollow-up multinational phase

I/II study, which will use a dif-ferent gene transfer technology

and is set to begin by the end of 

this year.“There is so much exciting

stuff on the horizon,” he says.

“What we are going to see infive years are very clear, unequiv-

ocal successes.”

Dr Jude Samulski, the pres-ident of the American Society

of Gene and Cell T herapy, says

single-gene defects are where thequickest successes will happen.

“If you have a single-gene

defect, then if you replace it,

chances are you fixed it. If you go

after the complex disorders, likecancer, where multiple things

can contribute to the disease, it’sreally, really tough to say what is

the best approach,” he says.

“The single-gene defects areclearly going to be the play-

ing field where this technology

will get perfected and move for-wards.”

And as the field moves onto

the front foot, it will hopefullytake with it the lessons learnt

from its time in the corner, saysDr Samulski.

“I think our communityfailed completely to put in per-

spective what happens in our

world and what happens dailyin the other [research] commu-

nities,” he says.

“Look at any study on smallmolecules for chemotherapy and

there are hundreds and hundreds

of failures that result in death.”Striking the balance between

hype and hope has been another

lesson, Dr Samulski says.“If you oversell something,

you are going to be held to it.

And I think that was true in the

early days: people were so excitedabout the potential that they

oversold everything.”

He believes such premature

hype has also stymied corporateinvestment in gene therapy.

“I think our first opportunityfor that has come and gone with

the overselling, and I think the

second one is going to be scruti-nised a little bit longer, like kick-

ing the tyres on a car, before

people jump in with both feet tomake this a reality.”

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