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Mission Statement: The United Leukodystrophy Foundation is dedicated to helping children and adults who have Leukodystrophy and assisting the family members, professionals and support services that serve them. The ULF is committed to the identification, treatment and cure of all leukodystrophies through programs of education, advocacy, research and service.

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Milan, July 20, 2010

Dear colleague,

The present letter is to update you on our clinical experimentation of gene therapy for the treatment of Metachromatic Leukodystrophy (MLD), currently active in the San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), in Milan. The study was recently approved (on March 2010) by the Italian Regulatory Authorities and is currently open to patients’ recruitment.

The clinical experimentation has as objective the evaluation of the effectiveness and the safety of the treatment in study (gene therapy based on hematopoietic stem cells and lentiviral vectors) in a cohort of 8 MLD patients.

The first patient, with a molecular familiar history compatible with a diagnosis of late infantile MLD, has been recently treated being in a pre-symptomatic stage of his disease.  Thus far, we can report a favorable outcome of the transplant procedure with a good bone marrow recovery and the short-term safety of both the conditioning regimen and stem cell transduction with lentiviral vectors. Only the long-term follow up would allow assessing the efficacy of the treatment in preventing and/or attenuating disease associated symptoms.

In the hope to be able to offer a hope of benefit to the patients and their families, we confide in Your precious collaboration for the recruitment of the patients for this clinical trial and we remain to disposition for any explanation at the following addresses:

Dr. Alessandra Biffi

Tel: +39-02-2643-4678/4681; Fax: +39-02-2643-4668; biffi.alessandra@hsr.it;  

Dr. Maria Sessa

Tel: +39-02-2643-2755; Fax: +39-02-2643-2951; sessa.maria@hsr.it

Gene therapy:

Gene therapy is based on the principle that every illness caused by an alteration of a known gene 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. With the purpose to realize this, we have drawn a gene therapy strategy based on the transplantation of hematopoietic stem cells transduced with a lentiviral vector containing the human normal Arylsulfatase A (ARSA) gene, able to generate by their differentiated progeny a permanent source of the functional enzyme for the affected tissues. Such strategy, for many aspects similar to the transplantation of hematopoietic cells from healthy donors, is set as a less risky and more effective alternative to allogeneic transplantation thanks to the use of autologous, patient's cells genetically corrected by means of lentiviral vectors (which allow an above-physiological expression of the enzyme in the hematopoietic cells).

The safety and the effectiveness of this approach have been shown in the preclinical model of the disease, in which we documented the prevention and the correction of the signs and symptoms of the pathology following the treatment. To the light of such results, we have therefore implemented a clinical protocol for the transfer of such therapeutic strategy to MLD patients.

The clinical protocol:

This research is conducted within the Fondazione Centro San Raffaele del Monte Tabor in Milan, in the Pediatric Clinical Research Unit of HSR-TIGET and in the Pediatric Immunohematology and Bone Marrow Transplant Unit at HSR.

Study promoter is the Fondazione Centro San Raffaele del Monte Tabor, in the person of the HSR-TIGET Director Prof. Luigi Naldini. The main financial sponsor is the Italian Telethon Foundation.

The plan of treatment consists of four phases:

•  Bone marrow explant of the patient with isolation of the stem cells to be submitted to gene transfer;

•  Manipulation of the cells and gene transfer with the lentiviral vector;

•  Patient's conditioning, based on the alkylating agent Busulfan;

•  Re-infusion of the manipulated stem cells.

Besides the safety end points of the treatment (related to the conditioning regimen and to the use of the lentiviral vectors), we will evaluate as primary efficacy end points an improvement / 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.

The follow-up post-treatment will be performed in the three years following the gene therapy, and an additional follow-up is anticipated for the 5 following years at the end of the study, according to the Italian Regulation (D.M. 2 March 2004)).

The physicians responsible of the study are:

Dr. Alessandra Biffii (Principal Investigator; Project leader at HSR-TIGET & Staff Pediatrician in the Pediatric Immunohematology and Bone Marrow Transplant Unit at HSR); 

Dr. Maria Sessa (Principal Investigator; Project Leader at HSR-TIGET & Staff Neurologist in the Nuerology Department at HSR);

Dr. Attilio Rovelli (Co-Principal Investigator; Director of the Bone Marrow Transplantation Center of the Pediatric Department, San Gerardo Hospital, Monza);

Prof. Luig iNaldini (Co-Principal Investigator; Director of HSR-TIGET) Prof. Maria Grazia Roncarolo (Co-Principal Investigator and Director of the Pediatric Immunohematology and Bone Marrow Transplant Unit at HSR; HSR Scientific Director).

The study is single center, in open, not randomized, perspective, comparative with a non-contemporary population of controls from us studied within a clinical study of natural history of the disease. As expected from the criterions for experimentation in pediatric patients, the study is a Phase I / II, therefore facing the evaluation not only of the safety but also of the effectiveness of the treatment.

The recruitment of the patients is international. The costs of the study are entirely to load of the HSR-TIGET.

The study foresee the enrollment of patients in the pediatric age affected from MLD, diagnosed through dosing of ARSA enzymatic activity and/or genetic analysis, that fullfil the following characteristics:

• Late infantile MLD in pre-symptomatic phase (in presence of a case index in the family);

• Early juvenile MLD in pre-symptomatic (in presence of a case index in the family) phase or within the first 6 months from the onset of the symptoms.

The Institute

The HSR-TIGET (http://www.fondazionesanraffaele.it) 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. Particularly remarkable effort is related to the development of protocols of gene therapy based on the use of hematopoietic stem cells. The therapeutic success from us obtained in the treatment of a serious form of congenital immunodeficiency (ADA-SCID) represents today the most convincing demonstration of the effectiveness and safety of such approach.

Dr. Alessandra Biffi

Prof. Lugi Naldini

Dr. Maria Sessa

Prof. Maria Grazia Roncarolo

Dr. Attilio Rovelli

San Raffaele Telethon Institute for Gene Therapy

San Raffaele Scientific Institute

Via Olgettina, 58,

20132 Milano, Italy

Natural History Study of Krabbe Disease underway in the US

Posted May 6, 2010

Title of study

A Longitudinal Observational Study That Will Evaluate Prospectively Clinical and Surrogate Parameters That Are Affected in Infant Patients With Globoid Cell Leukodystrophy (Krabbe Disease).
The study can be found on www.clinicaltrials.gov

Aim of the study

To be able to compare the benefits experienced by infants with globoid cell leukodystrophy, who receive a possible future treatment, to those untreated, a better understanding of the natural course of infantile GLD is necessary. The current literature contains only case studies of individual or small groups of GLD patients. A longitudinal study of a larger population of patients with infantile GLD has yet to be performed. This protocol is a 1.5 years longitudinal observational study to capture natural history data in patients with infantile GLD. This data will provide information on the range and diversity of clinical disease parameters that can in the future be used to evaluate treatment effects.

Contact Investigator in the US

Dr. Maria Escolar MD (Principal Investigator)
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States, 27517
Telephone: 001-919-966-4465
Maria_Escolar@med.unc.edu

Study sponsor

Zymenex A/S
Roskildevej 12 C
3400 Hilleroed
Denmark
www.zymenex.com

Description of the Disease

Infantile globoid cell leukodystrophy (GLD, or Krabbe disease) is a rare, inherited degenerative disorder of the central and peripheral nervous systems. It is characterized by the presence of globoid cells (multinucleated cells), the breakdown of the nerve's protective myelin coating, and destruction of brain cells. Globoid cell leukodystrophy is one of a group of genetic disorders called the leukodystrophies. These disorders impair the growth or development of the myelin sheath, and causes severe degeneration of mental and motor skills. Myelin, which lends its color to the "white matter" of the brain, is a complex substance made up of a number of different glucoproteins and glucolipids, the most important of which is galactocerebroside. Each of the leukodystrophies affects one of these substances. Globoid cell leukodystrophy is caused by a deficiency of galactocerebroside ß-galactosidase (GALC), an essential enzyme for myelin metabolism. The disease most often affects infants, with onset before the age of 6 months, but can occur in adolescence or adulthood. Symptoms include irritability, unexplained fever, limb stiffness (hypertonia), seizures, feeding difficulties, vomiting, and slowing of mental and motor development. Other symptoms include muscle weakness, spasticity, deafness, and blindness.

There is no cure for globoid cell leukodystrophy. Generally, treatment for the disorder is symptomatic and supportive.

Infantile globoid cell leukodystrophy is generally fatal before age 2 years. Patients with juvenile- or adult-onset disease generally have a milder course of the disease and live significantly longer.

Globoid cell leukodystrophy is a autosomal recessive disorder with a wide geographic distribution. The incidence in the United States is estimated as 1 in 100.000 births. However, the incidence appears to be higher in the Scandinavian countries. 32 Swedish cases were reported during the period from 1953 through 1967 with calculated incidence at 1.9 per 100,000 births.

March 11, 2010

Lovastatin in X-linked adrenoleukodystrophy

Marc Engelen, M.D. & Stephan Kemp, Ph.D

New England Journal of Medicine 2010 Jan 21;362(3):276-277.

In 1998 it was reported in the New England Journal of Medicine that the cholesterol reducing agent lovastatin reduced very long-chain fatty acids (VLCFA) in blood from patients with X-linked adrenoleukodystrophy. Since the publication many X-ALD patients worldwide are using lovastatin with the hope that it will have a positive effect on the clinical outcome. In the following years, other researchers raised doubt on the beneficial effect of lovastatin on VLCFA. A subsequent study with simvastatin (a structurally related statin) in patients with childhood cerebral ALD showed no effect on VLCFA. And treatment of X-ALD mice had no effect on VLCFA levels in brain and adrenal.

To resolve whether lovastatin can truly reduce plasma VLCFA in patients with X-ALD, a randomized double-blind placebo controlled cross-over trial was carried out. Fourteen patients with the adrenomyeloneuropathy (AMN) phenotype participated in the trial. Patients were treated with lovastatin for 6 months and 6 months with a placebo, or vice versa. Neither the patients nor the researchers knew who was using what kind of medication during the treatment period. At the end of the trial the samples and data were analyzed.

As expected, treatment with lovastatin reduced plasma cholesterol levels. The plasma VLCFA levels reduced by about 20%, but they remained between 2 and 3 times above the normal level. In addition, VLCFA levels in red and white blood cells remained unchanged after lovastatin treatment. Since VLCFA are virtually water insoluble, most of the VLCFA in blood are transported as cholesterol-esters in lipoprotein particles like LDL. No effect on VLCFA levels was observed in these particles.

The authors conclude that lovastatin leads to a small decrease in VLCFA levels in plasma which has to be considered a non-specific result of the LDL-cholesterol decrease. Physicians should not prescribe lovastatin as a VLCFA lowering therapy to patients with X-ALD, since evidence does not support it.

Milan, March 04, 2010

San Raffaele Telethon Institute For Gene Therapy (HSR-TIGET)

Metachromatic Leukodystrophy (MLD)

This announcement is to inform you about the forthcoming opening of a clinical experimentation of gene therapy for the treatment of Metachromatic Leukodystrophy (MLD) in our San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), in Milan.

The HSR-TIGET (http://www.fondazionesanraffaele.it) was funded in 1995 as joint venture among the Scientific Institute of 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.  Particularly remarkable effort is related to the development of protocols of gene therapy based on the use of hematopoietic stem cells. The therapeutic success for us obtained in the treatment of a serious form of congenital immunodeficiency (ADA-SCID) represents today the most convincing demonstration of the effectiveness and safety of such approach.

Gene therapy is based on the principle that every illness caused by an alteration of a known gene 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. With the purpose to realize this, we have drawn a gene therapy strategy based on the transplantation of hematopoietic stem cells transduced with a lentiviral vector containing the human normal Arylsulfatase A (ARSA) gene, able to generate by their differentiated progeny a permanent source of the functional enzyme for the affected tissues. Such strategy, for many aspects similar to the transplantation of hematopoietic cells from healthy donors, is set as a less risky and more effective alternative to allogeneic transplantation thanks to the use of autologous, patient’s cells genetically corrected by means of lentiviral vectors (which allow an above physiological expression of the enzyme in the hematopoietic cells.

The safety and the effectiveness of this approach have been shown in the preclinical model of the disease, in which we documented the prevention and the correction of the signs and symptoms of the pathology following the treatment. To the light of such results, we have therefore implemented a clinical protocol for the transfer of such therapeutic strategy to MLD patients.

The clinical experimentation, already approved by the Institutional Ethical Committee and waiting final authorization from the Italian Competent Authorities (expected by March 20, 2010), has as objective the evaluation of the effectiveness and the safety of the treatment in study in a cohort of 8 MLD patients.

The study is single center, in open, not randomized, perspective, comparative with a non-contemporary population of controls from us studied within a clinical study of natural history of the disease. As expected from the criterions for experimentation in pediatric patients, the study is a Phase I / II, therefore facing the evaluation not only of the safety but also of the effectiveness of the treatment. On the base of such indication, the inclusion criteria and the end points of the study have been defined.  The recruitment of the patients is international. The costs of the study are entirely to load of the HSR-TIGET.

The study will include patients in the pediatric age affected from MLD, diagnosed through dosing of ARSA enzymatic activity and/or genetic analysis that fulfill the following characteristics:

The plan of treatment consists of four phases:

Besides the safety end points of the treatment (related to the conditioning regimen and to the use of the lentiviral vectors), we will evaluate as primary efficacy end points an improvement / 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.

The follow-up post-treatment will be performed in the three years following the gene therapy, and an additional follow-up is anticipated for the 5 following years at the end of the study, according to the Italian Regulation (D.M. 2 March 2004).

This research will be developed within the Fondazione Centro San Raffaele del Monte Tabor in Milan, in the Pediatric Clinical Research Unit of HSR-TIGET and in the Pediatric Immunohematology and Bone Marrow Transplant Unit at HSR.

Study promoter is the Fondazione Centro San Raffaele del Monte Tabor, in the person of the HSR-TIGET Director Prof. Lugi Naldini. The main financial sponsor is the Italian Telethon Foundation.

The physicians responsible of the study are:

Dr. Alessandra Biffi (Principal Investigator: Project leader at HSR-TIGET & Staff Pediatrician in the Pediatric Immunohematology and Bone Marrow Transplant Unit at HSR);

Dr. Maria Sessa (Principal Investigator; Project Leader at HSR-TIGET & Staff Neurologist in the Neurology Department at HSR)

Dr. Attilio Rovelli (Co-Principal Investigator; Director of the Bone Marrow Transplantation Center of the Pediatric Department, San Gerardo Hopsital, Monza); Prof. Luigi Naldini (Co-Principal Investigator and Director of the Pediatric Immunohematology and Bone Marrow Transplant Unit at HSR; HSR Scientific Director)

San Raffaele Telethon Institute for Gene Therapy

San Raffaele Scientific Institute

Via Olgettina, 58

20132 Milano, Italy

Dr. Alessandra Biffi: 39-02-2643-4678/4681, biffi.alessandra@hsr.it

Dr. Maria Sessa: 39-02-2643-2755, Sessa.maria@hsr.it

Shire HGT Metachromatic Leukodystrophy (MLD) Program Update

19 February 2010

Shire HGT had planned to initiate a Phase 2/3 study with intravenous (IV) enzyme replacement therapy (ERT) for treatment of MLD in 2009.  However, clinical data from the ongoing Phase 1/2 extension study, collected on an ongoing basis over the last few years, demonstrates that the IV route of administration is not succeeding. Therefore, Shire has decided to suspend further development of an IV formulation of arylsulfatase A (ASA) derived from CHO cells, also known as HGT-1111.  Shire plans to share these clinical data publicly at an upcoming scientific meeting and is working closely with the clinical investigators caring for participants continuing to receive HGT-1111 to evaluate next steps for these patients.

Going forward Shire believes that direct delivery to the central nervous system (CNS) offers the best chance for development of a successful treatment for MLD.  Shire plans to develop HGT-1110, a formulation of ASA derived from human cells and compatible with direct CNS delivery for MLD patients. This human cell line has been used successfully by Shire for the development of other ERTs for Hunter syndrome, Fabry disease, and type 1 Gaucher disease.  Shire’s CNS platform was recently advanced with the initiation of a Phase 1/2 trial using direct delivery of idursulfase to the CNS in Hunter patients.  Development of the HGT-1110 formulation suitable for direct delivery to the CNS is ongoing, and preclinical studies are planned for 2010.  

Shire is committed to the MLD community.  We continue to work diligently to bring a much-needed therapy to patients and their families.

For any questions or clarification, please contact:

North America:

Lisa Marie Sturk, Ph.D.

Senior Medical Science Liaison

Mobile:                  +1.617.852.3696

Toll-Free Fax:       +1.866.532.6770

Email:  lmsturk@shire.com

ROW:

Steve Moloney, MD

Senior European Medical Director

Tel:      + 44 (0) 1256 894508

Fax:     + 44 (0) 1256 894405

Mobile: + 44 (0) 7770 814107

Email: smoloney@shire.com

Global Medical Information:

Tiffany Crump, RPh

Medical Communications Manager

Tel:         +1.484.595.8850

Fax:        +1.484.595.8493

Email: TCrump@shire.com  

VISIT OUR:  LEUKODYSTROPHY SUPPORT COMMUNITY

The ULF has always encouraged a sense of family, support, belonging and communication. To further extend that philosophy, the ULF has partnered with the online community network Team Inspire to provide a mechanism for patients, caregivers and physicians to communicate in a common online forum for Leukodystrophy support. 

The Inspire community breaches a wide range of health related communities and felt that the ULF was a good fit for the community. The Inspire community provides several mechanisms for communicating with the members. There are blog pages where individuals can post their daily thoughts. There are discussion topics that members can start and get into a dialog with other members. There is also individual messaging capability to send messages to a single community member.  

We feel that the Inspire community is another positive step in that direction and we encourage everyone who can, to join the ULF Inspire community. Membership is completely free and it only takes a few moments to sign up and become a member. 

We hope that this will allow for a wider communication network and foster even more communication outside of ULF meetings and other conferences. Click the link above or on the left to get started now.