Stem cell transplant without radiation or chemotherapy pre-treatment shows promise

Fuente: http://www.eurekalert.org/pub_releases/2014-12/dci-sct120514.php

Trial reports transplant success in dyskeratosis congenita, a rare bone marrow failure syndrome, following conditioning with immunosuppressive drugs alone.

Suneet Agarwal, M.D., Ph.D., of the Dana-Farber/Boston Children's Cancer and Blood Disorders Center.

Researchers at Dana-Farber/Boston Children's Cancer and Blood Disorders Center report promising outcomes from a clinical trial with patients with a rare form of bone marrow failure who received a hematopoietic stem cell transplant (HSCT) after pre-treatment with immunosuppressive drugs only. This is the first trial reporting successful transplant in dyskeratosis congenita (DC) patients without the use of any radiation or conventional cytotoxic chemotherapy beforehand.

The trial's data were presented by study authors Leslie Lehmann, MD, and Suneet Agarwal, MD, PhD, of Dana-Farber/Boston Children's, at the 56th annual meeting of the American Society of Hematology (abstract #2941). The data suggest that this immunosuppression-only approach could benefit patients with DC--and, perhaps, other bone marrow failure syndromes--who are at high risk of poor transplant outcomes because they cannot tolerate the toxicity of conventional or even reduced-intensity conditioning.

All four participants in the study are alive and well between 10 and 27 months after transplant. None remain dependent on transfusions to maintain blood counts, nor did any experience significant unexpected toxicities or infections during or after transplantation. Were it not for this new regimen, one patient would have been ineligible for transplant due to severe DC-related lung disease.

Conventional transplant conditioning employs radiation and/or high-dose cytotoxic drugs (also known as alkylators) to destroy the bone marrow and blood and immune cells; it also causes widespread cellular damage throughout the body. The process prepares the patient's body to accept the donated stem cells, reducing the risk of rejection and providing a hospitable environment for the new cells to engraft, thrive and produce new blood and immune cells.

In DC and other bone marrow failure syndromes, however, the disease itself already weakens or destroys the patient's bone marrow, raising the question of whether a less toxic approach could effectively condition patients for transplant.

"These data show that it is possible to achieve engraftment within the context of DC using immunosuppression-only conditioning. This experience begs the question of whether we can think more broadly about this approach's applicability for other conditions, something I think is worth considering," Agarwal said.

"Bone marrow failure syndromes are problems of blood and immune cell production," he added. "In theory, then, in some of these conditions it should be possible for healthy donated stem cells to outcompete native cells, without exposing patients to the toxic effects of radiation or alkylating agents."

Eighty percent of patients with DC develop bone marrow failure before reaching age 30. The genetic defects underlying the disease prevent cells from maintaining their telomeres, the caps at the ends of chromosomes that gradually shorten as cells divide and a person ages. As a result, DC patients' hematopoietic stem cells age prematurely and do not divide well. While an HSCT can cure the resulting bone marrow failure, outcomes are often poor, likely because of the toxicity associated with conventional conditioning.

The cellular defects in DC created an opportunity for Agarwal and his collaborators to attempt immunosuppression-only pre-transplant conditioning. Tamping down a patient's immune system, they theorized, would give donor stem cells and their progeny a chance to outcompete the patient's existing cells with a minimal risk of rejection. At the same time, avoiding radiation and alkylators--which cause widespread cellular damage throughout the body--should reduce the risk of long-term HSCT-related complications, such as organ failure and cancer.

###

The research was funded by Boston Children's Hospital's Translational Research Program.

The Dana-Farber/Boston Children's Cancer and Blood Disorders Center--the nation's #1 pediatric cancer program, according to US News & World Report 2014-15--brings together two internationally known research and teaching institutions that have provided comprehensive care for pediatric oncology and hematology patients since 1947. The Harvard Medical School affiliates share a clinical staff that delivers inpatient care and surgery at Boston Children's Hospital, most outpatient care at Dana-Farber Cancer Institute.

Disease decoded: Gene mutation may lead to development of new cancer drugs

Fuente: http://www.eurekalert.org/pub_releases/2014-09/uom-ddg093014.php

The discovery of a gene mutation that causes a rare premature aging disease could lead to the development of drugs that block the rapid, unstoppable cell division that makes cancer so deadly.

Scientists at the University of Michigan and the U-M Health System recently discovered a protein mutation that causes the devastating disease dyskeratosis congenita, in which precious hematopoietic stem cells can't regenerate and make new blood. People with DC age prematurely and are prone to cancer and bone marrow failure.

But the study findings reach far beyond the roughly one in 1 million known DC patients, and could ultimately lead to developing new drugs that prevent cancer from spreading, said Jayakrishnan Nandakumar, assistant professor in the U-M Department of Molecular, Cellular, and Developmental Biology.

The DC-causing mutation occurs in a protein called TPP1. The mutation inhibits TPP1's ability to bind the enzyme telomerase to the ends of chromosomes, which ultimately results in reduced hematopoietic stem cell division. While telomerase is underproduced in DC patients, the opposite is true for cells in cancer patients.

"Telomerase overproduction in cancer cells helps them divide uncontrollably, which is a hallmark of all cancers," Nandakumar said. "Inhibiting telomerase will be an effective way to kill cancer cells."

The findings could lead to the development of gene therapies to repair the mutation and start cell division in DC patients, or drugs to inhibit telomerase and cell division in cancer patients. Both would amount to huge treatment breakthroughs for DC and cancer patients, Nandakumar said.

Nandakumar said that a major step moving forward is to culture DC patient-derived cells and try to repair the TPP1 mutation to see if telomerase function can be restored. Ultimately, the U-M scientist hopes that fixing the TPP1 mutation repairs telomerase function and fuels cell division in the stem cells of DC patients.

"It's conceivable that with the recent advancement in human genome-editing technology, we could, in the not-so-distant future, repair the mutation in hematopoietic stem cells in the bone marrow of DC patients," Nandakumar said.

The findings also reinforce how one tiny change in an amino acid chain can cause devastating health consequences.

"It was surprising to us that just deleting one single amino acid in a protein chain that is 544 amino acids long can result in such a severe disease," Nandakumar said.

###

First author Hande Kocak conducted the research in Nandakumar's lab in the Department of Molecular, Cellular, and Developmental Biology. She is in the Department of Human Genetics at the U-M Medical School. Co-author Dr. Catherine Keegan is Kocak's mentor and has appointments in the departments of Human Genetics and Pediatrics.

The study, "Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1," appears in the journal Genes and Development.

Study: http://bit.ly/1pE6cqJ 

Jayakrishnan Nandakumar: http://bit.ly/1nFwdMf 

Molecular, Cellular, and Developmental Biology: http://www.lsa.umich.edu/mcdb