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Antisense Gene Therapy Trials Underway in Patients With CML

Antisense Gene Therapy Trials Underway in Patients With CML

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 cells.

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 cell lines.

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 normal hematopoiesis.

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 efficacy.

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 response.

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