Profilaksa DVT kod velikih ortopedskih operacija - Depol ...

ARTHRITIS GENE THERAPY
Christopher Evans, Harvard Medical School, Boston, United States
20 - 22 September 2012, Opatija, Croatia
Localizing therapeutics to joints in a sustained fashion is extremely difficult because of the rapid rate of egress of
both small and large molecules - intra-articular dwell times are usually measured in hours whereas the diseases are
chronic. Gene transfer to the joint is the only technology that can overcome this limitation in a clinically reasonable
fashion. A variety of vectors and trans-genes have been used in pre-clinical models, establishing unequivocal
proof of principle in both rheumatoid arthritis (RA) and osteoarthritis (OA). There have been four clinical trials for
RA and two for OA. Only one of these has progressed to Phase II.
The first human trial used a retrovirus to deliver the interleukin-1 receptor antagonist (IL-1Ra) cDNA in an ex vivo
fashion into the metacarpophalangeal joints of nine subjects with RA. No safety issues were identified in this
succesful Phase I trial. In a subsequent German study involving just two subjects, there was a remarkable clinical
response in one of the patients. A different approach using adeno-associated virus (AAV) carrying etanercept
cDNA progressed to Phase II, but was marred by the death of one subject; nevertheless, the FDA allowed this trial
to continue to completion. No statistically significant improvement was noted, however.
Phase I trials for the treatment of OA have been completed successfully in the USA and Korea. This protocol uses allografted
chondrocytes that have been transduced with retrovirus to over-express transforming growth factor-β1.
Phase II studies are underway. Our group is trying to initiate a Phase I trial in OA, using AAV to deliver IL-1Ra cDNA.
Although the science and technology behind these studies are sound, progress in clinical implementation is limited
by the high translational costs and the restrictive regulatory environment.
Oral
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