ASH: Gene therapy eases effects of rare Wiskott-Aldrich syndrome

ORLANDO – Genetic modification of autologous stem cells provided sustained clinical benefit with good safety for children with the rare immunodeficiency disorder Wiskott-Aldrich syndrome, an international team of investigators report.

Six of eight children who received infusions of autologous stem cells that had been modified with a lentiviral vector to restore normal expression of the WAS gene had marked reductions in severe infections, fewer hospitalizations, improved hematologic parameters, and more robust immune responses than they had prior to transplant, reported Dr. Francesca Ferrua from the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy.

“Importantly, with regards to safety we did not detect any serious adverse events related to gene therapy in follow up, and we did not observe any evidence of abnormal clonal proliferation after gene therapy,” she said at the American Society of Hematology annual meeting here.

The Wiskott-Aldrich syndrome is an x-linked syndrome caused by mutations in the WAS gene encoding for the WAS protein (WASP), which is involved in regulation of the cytoskeleton. The disorder, which primarily affects males, leads to immunodeficiency, microthrombocytopenia and leukocyte abnormalities. Patients develop severe eczema and other inflammatory disorders, and are at increased risk for autoimmune diseases and malignancies.

The syndrome is estimated to occur in 1-10 per 1 million males worldwide, according to The National Library of Medicine.

Allogeneic hematopoietic stem cell transplantion (HSCT) can be curative for patients with Wiskott-Aldrich syndrome, but the technique is associated with both acute transplant-related complications and long-term morbidities, particularly when there is not a perfect match between donor and recipient, Dr. Ferrua explained.Prior studies using a gamma-retroviral vector under the control of a strong viral promoter showed that gene therapy was feasible in these patients and could result in immunological improvement. The earlier attempts, however, were associated with a high risk of genotoxicity and insertional mutagenesis; seven of nine patients treated in one study developed leukemia.

In their current line of research, Dr. Ferrua and colleagues had previously reported on the use of autologous hematopoietic stem/progenitor cells modified ex vivo to correct the inherent defect in three patients with severe mutations in WAS who had no suitable stem-cell donors.

The researchers collected CD34-positive cells from each patient’s bone marrow and/or mobilized peripheral blood and transduced the cells in the laboratory with a lentivirus modified to promote normal expression of WAS. They then returned the cells to the patients after they underwent a reduced-intensity conditioning regimen using an anti-CD20 monoclonal antibody, busulfan, and fludarabine.

Long-term follow-up

At ASH 2015, Dr. Ferrua reported results on the first 8 patients treated as of October 2015. The patients were treated at a median age of 2.2 years; all are alive after a median of 3.3 years of follow up, with the longest follow up being 5.5 years

All had marked reductions in the annualized estimated rate of severe infections compared with the pre-transplant period.

Of the seven patients followed for more than 1 year, all were able to discontinue prophylaxis for infections, at a median of 13-15 months after gene therapy, and five were able to discontinue immunoglobulin supplementation.

Additionally, four of four patients had evidence of a normal immune response based on the development of specific antibodies after vaccination.

Four patients had resolution of their eczemas, and the other two with eczema had only mild cases.

At a median of 4 months after genetic therapy, none of the patients required platelet transfusions. Out to at least 1 year, there was no evidence of autoimmunity.

Among all patients, there were reductions in the frequency or severity of bleeding, no severe bleeding episodes, no hospitalizations for bleeding and a reduction in the number of hospitalizations for infections.

There were no serious adverse events related to the transplant.

The study was sponsored by IRCCS San Raffaele with support from the Fondazione Telethon and GlaxoSmithKline. Dr. Ferrua reported having no conflicts of interest.

ORLANDO – Genetic modification of autologous stem cells provided sustained clinical benefit with good safety for children with the rare immunodeficiency disorder Wiskott-Aldrich syndrome, an international team of investigators report.

Six of eight children who received infusions of autologous stem cells that had been modified with a lentiviral vector to restore normal expression of the WAS gene had marked reductions in severe infections, fewer hospitalizations, improved hematologic parameters, and more robust immune responses than they had prior to transplant, reported Dr. Francesca Ferrua from the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy.

“Importantly, with regards to safety we did not detect any serious adverse events related to gene therapy in follow up, and we did not observe any evidence of abnormal clonal proliferation after gene therapy,” she said at the American Society of Hematology annual meeting here.

The Wiskott-Aldrich syndrome is an x-linked syndrome caused by mutations in the WAS gene encoding for the WAS protein (WASP), which is involved in regulation of the cytoskeleton. The disorder, which primarily affects males, leads to immunodeficiency, microthrombocytopenia and leukocyte abnormalities. Patients develop severe eczema and other inflammatory disorders, and are at increased risk for autoimmune diseases and malignancies.

The syndrome is estimated to occur in 1-10 per 1 million males worldwide, according to The National Library of Medicine.

Allogeneic hematopoietic stem cell transplantion (HSCT) can be curative for patients with Wiskott-Aldrich syndrome, but the technique is associated with both acute transplant-related complications and long-term morbidities, particularly when there is not a perfect match between donor and recipient, Dr. Ferrua explained.Prior studies using a gamma-retroviral vector under the control of a strong viral promoter showed that gene therapy was feasible in these patients and could result in immunological improvement. The earlier attempts, however, were associated with a high risk of genotoxicity and insertional mutagenesis; seven of nine patients treated in one study developed leukemia.

In their current line of research, Dr. Ferrua and colleagues had previously reported on the use of autologous hematopoietic stem/progenitor cells modified ex vivo to correct the inherent defect in three patients with severe mutations in WAS who had no suitable stem-cell donors.

The researchers collected CD34-positive cells from each patient’s bone marrow and/or mobilized peripheral blood and transduced the cells in the laboratory with a lentivirus modified to promote normal expression of WAS. They then returned the cells to the patients after they underwent a reduced-intensity conditioning regimen using an anti-CD20 monoclonal antibody, busulfan, and fludarabine.

Long-term follow-up

At ASH 2015, Dr. Ferrua reported results on the first 8 patients treated as of October 2015. The patients were treated at a median age of 2.2 years; all are alive after a median of 3.3 years of follow up, with the longest follow up being 5.5 years

All had marked reductions in the annualized estimated rate of severe infections compared with the pre-transplant period.

Of the seven patients followed for more than 1 year, all were able to discontinue prophylaxis for infections, at a median of 13-15 months after gene therapy, and five were able to discontinue immunoglobulin supplementation.

Additionally, four of four patients had evidence of a normal immune response based on the development of specific antibodies after vaccination.

Four patients had resolution of their eczemas, and the other two with eczema had only mild cases.

At a median of 4 months after genetic therapy, none of the patients required platelet transfusions. Out to at least 1 year, there was no evidence of autoimmunity.

Among all patients, there were reductions in the frequency or severity of bleeding, no severe bleeding episodes, no hospitalizations for bleeding and a reduction in the number of hospitalizations for infections.

There were no serious adverse events related to the transplant.

The study was sponsored by IRCCS San Raffaele with support from the Fondazione Telethon and GlaxoSmithKline. Dr. Ferrua reported having no conflicts of interest.

ORLANDO – Genetic modification of autologous stem cells provided sustained clinical benefit with good safety for children with the rare immunodeficiency disorder Wiskott-Aldrich syndrome, an international team of investigators report.

Six of eight children who received infusions of autologous stem cells that had been modified with a lentiviral vector to restore normal expression of the WAS gene had marked reductions in severe infections, fewer hospitalizations, improved hematologic parameters, and more robust immune responses than they had prior to transplant, reported Dr. Francesca Ferrua from the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy.

“Importantly, with regards to safety we did not detect any serious adverse events related to gene therapy in follow up, and we did not observe any evidence of abnormal clonal proliferation after gene therapy,” she said at the American Society of Hematology annual meeting here.

The Wiskott-Aldrich syndrome is an x-linked syndrome caused by mutations in the WAS gene encoding for the WAS protein (WASP), which is involved in regulation of the cytoskeleton. The disorder, which primarily affects males, leads to immunodeficiency, microthrombocytopenia and leukocyte abnormalities. Patients develop severe eczema and other inflammatory disorders, and are at increased risk for autoimmune diseases and malignancies.

The syndrome is estimated to occur in 1-10 per 1 million males worldwide, according to The National Library of Medicine.

Allogeneic hematopoietic stem cell transplantion (HSCT) can be curative for patients with Wiskott-Aldrich syndrome, but the technique is associated with both acute transplant-related complications and long-term morbidities, particularly when there is not a perfect match between donor and recipient, Dr. Ferrua explained.Prior studies using a gamma-retroviral vector under the control of a strong viral promoter showed that gene therapy was feasible in these patients and could result in immunological improvement. The earlier attempts, however, were associated with a high risk of genotoxicity and insertional mutagenesis; seven of nine patients treated in one study developed leukemia.

In their current line of research, Dr. Ferrua and colleagues had previously reported on the use of autologous hematopoietic stem/progenitor cells modified ex vivo to correct the inherent defect in three patients with severe mutations in WAS who had no suitable stem-cell donors.

The researchers collected CD34-positive cells from each patient’s bone marrow and/or mobilized peripheral blood and transduced the cells in the laboratory with a lentivirus modified to promote normal expression of WAS. They then returned the cells to the patients after they underwent a reduced-intensity conditioning regimen using an anti-CD20 monoclonal antibody, busulfan, and fludarabine.

Long-term follow-up

At ASH 2015, Dr. Ferrua reported results on the first 8 patients treated as of October 2015. The patients were treated at a median age of 2.2 years; all are alive after a median of 3.3 years of follow up, with the longest follow up being 5.5 years

All had marked reductions in the annualized estimated rate of severe infections compared with the pre-transplant period.

Of the seven patients followed for more than 1 year, all were able to discontinue prophylaxis for infections, at a median of 13-15 months after gene therapy, and five were able to discontinue immunoglobulin supplementation.

Additionally, four of four patients had evidence of a normal immune response based on the development of specific antibodies after vaccination.

Four patients had resolution of their eczemas, and the other two with eczema had only mild cases.

At a median of 4 months after genetic therapy, none of the patients required platelet transfusions. Out to at least 1 year, there was no evidence of autoimmunity.

Among all patients, there were reductions in the frequency or severity of bleeding, no severe bleeding episodes, no hospitalizations for bleeding and a reduction in the number of hospitalizations for infections.

There were no serious adverse events related to the transplant.

The study was sponsored by IRCCS San Raffaele with support from the Fondazione Telethon and GlaxoSmithKline. Dr. Ferrua reported having no conflicts of interest.