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New! - Gene Therapy Clinical Trial update (1 year post therapy informal reports)

GSK Collaboration (Oct 2010)

Gene Therapy with HSCT Phase I/II Clinical Trial (March 2010)

Gene Therapy Clinical Trial update - January 2012

We have been told by the researchers that all of the the trial participants are all doing well. Enrollment for the trial has been slower than expected.

Also, we have been informally told by trial participants the following apparently good news. It is premature to draw any scientific or statistically valid conclusions, but the insight is worth considering:

• Patient 1 is approximately 18 months post-transplant and one parent told another that he was making improvement in motor skills and speech (as observed last summer on his anniversary date)
• Patient 2 will be one year post transplant on February 17th. He is "a normal 2-year old" according to mom but they are awaiting 4 more months which is the date his older sibling had onset of notable symptoms (he is not showing any early signs).
• Patient 3 will be one year post transplant approx. February 24th
• There are two other who have been transplanted - we do not know those dates.

Again, it is premature to draw any conslusions - but we remain encouraged by this therapy.

Telethon & San Raffaele Announce GSK Collaboration

Oct 2010, GlaxoSmithKline PLC (GSK), Fondazione Telethon and Fondazione San Raffaele today announced a new strategic alliance to research and develop novel treatments to address rare genetic disorders, using gene therapy carried out on stem cells taken from the patient's bone marrow (ex vivo). The alliance capitalises on research performed at the San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), a joint venture between Fondazione Telethon and Fondazione San Raffaele established since 1995.

Fondazione Telethon will receive an upfront 10 million euro payment from GSK and is eligible to receive further payments upon successful completion of a number of predetermined development milestones.

GSK will co-develop with Fondazione Telethon and Fondazione San Raffaele, six further applications of ex vivo stem cell therapy, the first of these will be metachromatic leukodystrophy (MLD). Read the press release here.

Gene Therapy with HSCT Phase I/II Clinical Trial - Now Recruiting!

A Gene Therapy with HSCT Phase I/II Clinical Trial started recruiting in late March 2010. The protocol uses the patien'ts own genetically modified hematopoietic stem cells to increase ARSA production to 10-15x the normal rate. This super-production in the blood is to offset the reduced number of cells that typically cross the blood brain barrier.

Gene therapy is based on the principle that every illness caused by gene defect can be cured by inserting, through viral vectors, a functional copy of the gene in the sick cells of the patient. In the case of the MLD, it is problematic to insert the functional gene in the sick cells of the central and peripheral nervous system for the inaccessibility of these organs. It is, however, possible, by using appropriate gene transfer systems, to correct in a stable way hematopoietic cells that can transport then the functional enzyme to the affected nervous system.

What is ex vivo gene therapy? Replacing faults in stem cells has been practiced for more than 40 years, in the form of donor haematopoetic stem cell (HSC) transplants (bone marrow transplants). However such transplants rely on stem cells taken from an immune matched, or closely related, donor, which is not always available. There is always a risk of graft rejection but this is particularly high when matched donors cannot be found. This ex vivo gene therapy transfers the corrected gene to the patient's own stem cells. The patient's own HSCs are harvested from their body, 'healthy' copies of the gene are inserted into the cell using a modified viral vector and the cells are re-introduced to the patient.

Because the technique uses the patient's own cells there is much less risk of immune rejection compared to a bone marrow transplant. The reintroduction process is similar to the historical transplantation of hematopoietic cells from healthy donors, but since it uses the patient's own cells - an autologous transplant - it is hoped to be a less risky and more effective alternative.

Click here to see a video interview with Dr. Allesandra Biffi, Principal Investigator for the Clinical Trial.

Trial Status - July 2010
One pre-symptomatic late infantile has been transplanted to date. He is progressing well but it is too soon to know if there are any indications of efficacy..

Trial Center
The study will take place in Milano (Milan) Italy. 8 MLD patients are being recruited. The study is a Phase I /I I with a requirement from the Italian authorities to show efficacy.

The recruitment of the patients is international. All costs of patients and families participating in the study will be paid by HSR-TIGET.

Inclusion Criteria

• Late infantile MLD in pre-symptomatic phase (usually identified because of an older affected sibling)

• Early juvenile MLD in pre-symptomatic phase or within the first 6 months from the onset of the symptoms.

• (Presumably) no prior therapies

Trial Period & Follow Up
The post-transplant follow-up will be performed at regular intervals for 3 years with 5 more years of formal post-trial study.

Protocol Summary

• Bone marrow extraction from the patient of the patient

• Isolation of the stem cells to be submitted to gene transfer

• Manipulation of the stem cells ARSA production capability with the lentiviral vector

• Minimal patient conditioning with Busulfan (GVHD is greatly reduced due to re-implantation of patient's own cells)

• Re-infusion of the manipulated stem cells

Efficacy
Primary efficacy end points are an improvement or stability in the motor performances assessed by the "Gross Motor Function Measure, GMFM" 24 months after the treatment, in comparison to the scores obtained in a cohort of untreated patients of peer age, and a significant increase of the ARSA activity in the patients' hematopoietic cells measured 24 months after the treatment, in comparison to the pre-treatment values.

Principal Investigators

• Dr. Alessandra Biffi, Project Leader at HSR-TIGET & Staff Pediatrician in Pediatric Immunohematology and Bone Marrow Transplant Unit at HSR.+39-02-2643-4678/4681 FAX:+39-02-2643-4668 biffi.alessandra@hsr.it

• Dr. Maria Sessa, Project Leader at HSR-TIGET & Staff Neurologist at HSR (also a member of the MLD Foundation's Medical & Scientific Advisory Board). +39-02-2643-2755 FAX:+39-02-26432951 sessa.maria@hsr.it

HSR-TIGET ... San Raffaele Institute
HSR-TIGET was funded in 1995 as joint- venture among the Scientific Institute San Raffaele and the Telethon Foundation for the research and treatment of rare genetic diseases. Main goal of the Institute is to be a center of excellence in all the phases of the research from basic to clinical gene and cellular therapy, from the experimentation of new therapeutic strategies in the animal models of disease up to their clinical testing in the patients.

Quick Links

October 18, 2010 GlaxoSmithKline, Fondazione Telethon and Fondazione San Raffaele announce a new strategic alliance ... including an upfront 10 million euro payment.

July 20, 2010 Trial Update from San Raffaele

March 24, 2010 - Now recruiting! ... Approval was received from the Italian authorities.

Click here to see a video interview with Dr. Allesandar Biffi, Principal Investigator for the Clinical Trial.

March 4, 2010 Trial Document from San Raffaele

Dr. Sessa Video overview of the Gene Therapy research from a 2009 MLD Family Conference™