'State Of The Science' Review Of Genetic Medicine Published By Weill Cornell Exp

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'State Of The Science' Review Of Genetic Medicine Published By Weill

Cornell Experts

http://www.medicalnewstoday.com/medicalnews.php?newsid=40770

In an article published in the April issue of the prestigious Nature

Reviews Genetics, two experts at the Weill Medical College of Cornell

University sum up the achievements, challenges and promise of a

burgeoning field: genetic medicine.

" There have been some real success stories since the human genome was

sequenced in 2001, but some disappointments, too, and real hurdles

yet to be overcome, " says co-author Dr. G. Crystal, the Bruce

Webster Professor of Internal Medicine and Chairman of the Department

of Genetic Medicine at Weill Cornell Medical College.

" However, the purpose of this paper is to highlight the nearly

limitless potential of this technology, which is still in its

infancy, " he says.

Co-author Dr. O'Connor, Assistant Research Professor of

Genetic Medicine at Weill Cornell, agrees with that assessment.

" There are, and will be, roadblocks along the way, both biological

and social. But the pace of discovery suggests that all of these

challenges can be met, " he says.

The article, entitled " Genetic Medicines: Treatment Strategies for

Hereditary Disorders, " focuses on the treatment of " monogenic "

disorders -- the over 1,800 inherited illnesses linked to aberrations

in a single gene.

" On paper, a gene therapy 'fix' for these disorders appears simple:

Introduce a 'healthy' form of the dysfunctional gene, or even a

portion of that gene, to the disease site, to correct the problem, "

Dr. Crystal explains.

" Unfortunately, it's rarely, if ever, proved that simple. "

The article enumerates a number of promising gene therapy approaches,

each with its strengths -- and its Achilles' heel. They include:

Gene transfer using viral vectors. Getting a gene and its promoter to

breach the outer membrane of target cells has always been a tough

challenge. But harmless adenoviruses have proven useful vehicles for

penetrating cells and depositing piggybacked genes.

" Trouble is, host immune responses have limited the expression of

adenovirus-delivered genes, " Dr. O'Connor explains.

So, researchers have turned to simpler viral vectors, such as adeno-

associated viruses (AAVs). " These are capable of delivering longer

gene expression, but there's been a trade-off in terms of the amount

of genetic cargo they can carry and the magnitude of expression

levels, " Dr. O'Connor says.

Then there are the retroviruses (such as MMLV) which go one step

further, permanently integrating bits of DNA into the host cell's

genome.

" That's a lot more long-lasting because expression continues as the

cells divide; there's not that dilution of effect, " Dr. Crystal

explains.

But retrovirus-delivered gene therapy has one big disadvantage here,

too: Integration boosts the risk for " mutagenesis " -- cancer-linked

mutations in the cell's genome.

In one of the first gene therapy trials, a majority of children with

the monogenic immune disorder X-linked SCID were effectively cured by

MMLV-delivered genes. Unfortunately, a minority later developed life-

threatening leukemias linked to the therapy's mutagenic potential.

" We believe, however, that if you could identify spots on the

chromosome where integration was safe, this risk of mutagenesis could

be minimized, " Dr. Crystal says.

RNA-modification therapies. Ribonucleic acid (RNA) is the

intermediary player that helps turn instructions encoded in DNA into

the active proteins that drive cell function. Suppressing or

stimulating RNA should be another way of " fixing " genetic disorders.

One RNA-directed technology in development involves the use

of " antisense oligonucleotides " (ASOs), compounds that can decrease

production of an unwanted or overly expressed protein. Keeping ASOs

stable within cells, without compromising their ability to target

specific defects, has been a challenge, however.

Then there's RNAi, where the " I " stands for " interference. "

Essentially, this technology involves harnessing a natural process

whereby specific molecules silence RNA activity. Here, as with other

gene therapies, effective delivery across the cellular membrane has

proven challenging, and the molecules' short half-lives mean effects

have been transient.

" On the other hand, experiments that delivered RNAi with a viral

vector have proven promising in mouse models of Huntington's disease,

helping to slow progression, " Dr. O'Connor says.

Other innovations include trans-splicing -- substituting a " healthy "

piece of a gene in a spot normally occupied by dysfunctional DNA,

rather than replacing the whole gene.

" One strategy of trans-splicing was pioneered in our lab here at

Weill Cornell, and has proven promising in animal models for

hemophilia and cystic fibrosis, " Dr. Crystal says.

Finally, the experts noted that ribozymes -- RNA with enzymatic

activity -- might also be used to fix gummed-up cellular machinery,

although problems with delivery and stability have plagued this

approach as well.

Embryonic stem cells. Beyond the political and ethical issues

connected to this hot-button technology, therapy involving embryonic

stem cells -- which can differentiate into any cell type in the body -

- does have biological hurdles to overcome, as well.

" There are potential rejection issues, although most scientists

believe those can be overcome, " Dr. O'Connor says.

However, because of their incredible plasticity, the potential for

these cells is nearly limitless. Numerous studies have already shown

they can be efficiently directed to differentiate into specific cell

types.

" In the future, we should be able to use embryonic stem cells to help

regenerate diseased organs, " Dr. Crystal says. " While current

restrictions here in the U.S. limit this research, it's important

that we as scientists educate the public as to the uniqueness of

these cells and their therapeutic potential. "

So, where does all this leave the future of genetic medicine? For

every naysayer who doubts gene therapy's potential, there are scores

who see today's setbacks as just speed bumps on the road to success.

" Remember, drug development is always a 10-to-15-year process,

whatever the theory behind it, " Dr. O'Connor observes. " And just in

the last decade we've seen enormous leaps forward, such as faster

high-throughput screens, hapmap technologies and other advances. It's

our belief that even more astonishing advances are yet to come that

will turn the dream of genetic medicine into a reality for patients

at the bedside. "

Joan and Sanford I. Weill Medical College of Cornell University

http://www.nyp.org