Responding to the need for more efficacious and less toxic treatments
for chronic myelogenous leukemia (CML), researchers at the University
of Pennsylvania are exploring a novel form of gene therapy. By
interfering with the transmission of a crucial message, they hope
to prevent malignant cell growth without affecting normal hematopoietic
The strategy relies on blocking the "sense" sequence
of a particular gene's messenger RNA (mRNA), using a complementary
"antisense" sequence to prevent translation and/or enhance
degradation, said Selina Luger, MD, assistant professor in the
Hematology-Oncology Division, University of Pennsylvania Medical
Center, Philadelphia. In this way, she said, the malignant cell
is deprived of the necessary encoded protein.
The strategy differs from conventional gene therapy because the
genetic constitution of a given cell is not altered, Dr. Luger
said at the 13th annual symposium of the Chemotherapy Foundation.
Furthermore, she emphasized, since it does not rely on retroviral
vectors, a potential source of toxicity is eliminated.
Dr. Luger explained that since every gene has its own sense sequence,
the antisense sequence must be custom- designed for a given gene.
The c-myb proto-oncogene has been identified as preferentially
expressed in primitive hematopoietic tissues and leukemic tumor
Purging Bone Marrow
Using LR3001, a specific antisense oligodeoxynucleotide, disrupts
c-myb, Dr. Luger said. In vitro, it has been shown to decrease
proliferation of CML cell colonies at doses that still allow for
Based on these preclinical findings, her group has begun a protocol
of autologous bone marrow transplantation in patients with chronic
or accelerated phase CML. In an attempt to eliminate the malignant
clone from the autograft without systemic exposure, LR3001 is
used ex vivo to purge the marrow.
The protocol is open to patients under age 65 with normal hepatic,
renal, and cardiac function. To date, eight patients have been
treated, with encouraging results.
Infusional Antisense Therapy
Because unmodified oligonucleotide is susceptible to nuclease
attack, its use in vivo would not be possible, Dr. Luger said.
LR3001 has been chemically modified to prevent nuclease digestion
and therefore increase in vivo stability while maintaining therapeutic
A phase I clinical trial has been initiated employing the modified
form of LR3001 as an infusional agent. The trial seeks to determine
the maximally tolerated dose and dose-limiting toxicity of LR3001,
as well as to assess pharmacokinetics and pharmacodynamics. The
trial is open to patients with accelerated phase CML or blast
crisis, refractory or relapsed acute leukemia, and those with
myelodysplasia with excess blasts.
The modified LR3001 is being administered as a 24-hour continuous
IV infusion over 7 days. Depending on response, patients may receive
additional cycles every 28 days.
The trial is still in its earliest stages. Thus far, Dr. Luger
reported, no significant toxicities have developed at any of the
five dose levels. It is too soon, she said, to assess clinical