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HKU leads the Asia's first genetically modified hematopoietic stem cell transplantation for late juvenile metachromatic leukodystrophy patient (MLD)

20 May 2015

Dr Lian Qizhou (Third from the right), Assistant Professor of the Department of Ophthalmology and Department of Medicine of Li Ka Shing Faculty of Medicine, HKU and his team, Professor Zhuo Jiacai (First left), Clinical Professor and Head of the Division of Haematology at the Second People’s Hospital of Shenzhen (The First Affiliated Hospital of Shenzhen University) and patient Miss Liao Yu-an (Second left) and her mother Ariel Lee Pi-ju (Third from the left) took a group photo together.

A stem cell research team at the Li Ka Shing Faculty of Medicine, The University of Hong Kong (HKU) has led the first genetically modified hematopoietic stem cell transplantation in Asia for a Taiwanese juvenile with the fatal inherited disorder metachromatic leukodystrophy (MLD), through close collaboration with researchers from The Second People’s Hospital of Shenzhen (The First Affiliated Hospital of Shenzhen University), Mainland China, and the National Taiwan University Hospital (NTUH), Taiwan.  MLD is a devastating lysosomal storage disease caused by a deficiency of arylsulfatase A (ARSA).  Without this enzyme, sulfatides are not broken down and accumulate in the white matter of the brain and nervous system, causing destruction of the myelin sheath, or demyelination.  Early results of transplantation are very encouraging and the team has successfully saved the life of the patient with advanced-stage MLD.

Significance of the transplantation

Dr Lian Qizhou, Assistant Professor of the Department of Ophthalmology and Department of Medicine of Li Ka Shing Faculty of Medicine, HKU, leads the whole project and his team has genetically modified the patient’s hematopoietic stem cells for transplantation.  Dr Lian said, “We have always believed that genetically modified stem cell transplantation offers the best chance of success in the rescue of such an incurable genetic defect.  After months of careful preparation, we are very excited to have performed the first transplantation in a late juvenile patient with advanced-stage MLD.  The collaborative teams are delighted with how smoothly the treatment has progressed and particularly excited about the amazing early results.  There is evidence that the patient with this previously incurable condition can gain some improvement and disease progress can be arrested, the cognitive and mobility functions have been improved too.”

The collaborator, Professor Zhuo Jiacai, Clinical Professor and Head of the Division of Haematology at the Second People’s Hospital of Shenzhen (The First Affiliated Hospital of Shenzhen University) said, “Before stem cell transplantation, the patient required chemotherapy, termed Busulfan-based conditioning, to remove original bone marrow cells and generate space for gene corrected-stem cell growth.  This procedure potentially introduced the risk of multiple lesions including the neural system.  By careful titration of therapy, the conditioning treatment was well tolerated and the patient made a rapid recovery following transplantation without obvious side-effects.”

About hematopoietic stem cell gene transplantation (HSCGT)

The MLD patient underwent hematopoietic stem cell gene transplantation (HSCGT) and it brings several benefits.  First, genetically modified hematopoietic stem cells which express high levels of ARSA become a quantitatively more effective source of functional enzyme than normal donor cells when transplanted into patients.  The transplanted cells move to brain and secrete enough functional ARSA enzyme that is taken up by the recipient neural cells that are ARSA-deficient. Second, autologous transplantation is associated with significantly reduced transplant-related morbidity, avoiding the risk of severe immune rejection.  HSCGT strategy could therefore represent a significant advance over conventional allogeneic HSCT.

Safety is the major concern of this approach because viral vectors integrate into the host genome and may bring risk to cause mutagenesis of cancer-related genes or oncogenes.  The new generation of modified self-inactive lentiviral-based HSCGT has dramatically increased safety with no evidence of increased risk of cancer in clinical trials after more than 5 years of follow-up.  Subsequent to recent clinical trials conducted in Italy only in late infants with early onset MLD, the operation performed by HKU and collaborative partners is the first successful case on a late juvenile patient who had progressed to a middle stage of MLD.  This has extended the application of this new technology for MLD treatment.

“We have also developed sensitive molecular tools to retrieve vector integration sites with high efficiency, allowing us to retrieve several thousands of integrants per patient and monitor the engrafted gene-corrected stem cells and their daughter cells.  Moreover, it will be important to monitor long term and demonstrate that the effects of gene therapy are sustained,” said Dr Lian.

Details of the transplantation

There were three steps in the whole transplantation procedure.  First, a batch of hematopoietic stem cells was collected for backup use.  Second, another batch of patient’s HSCs was collected and transduced with lentiviral-mediated functional genes of ARSA.  The gene-corrected HSC was frozen down and samples were examined to ensure they were functional and ARSA enzyme activity elevated, with no other contaminants.  Finally, following a conditioning regimen, the gene-corrected cells were re-infused back to the patient.  Unlike the team of Italy who transplanted stem cells back to patients immediately following gene modification, the HKU team first froze down the genetically modified stem cells and performed a series of quality control checks before releasing cells to the patient.  This permitted more time to check the critical parameters of stem cells and gene functions, thus reducing the risk of transplantation failure or severe complications.  The patient’s blood system was fully engrafted and a high level of ARSA enzyme was detected following transplantation.  To date after 8 months of transplantation, the patient’s condition remains stable and satisfactory progress is being made with rehabilitation.

About the Treated Juvenile MLD patient

The patient (a Chinese female juvenile from Taiwan, now aged 18) presented with drowsiness and a decline in memory, mobility, writing and speech in 2010 at her age of 13 years old.  She was wrongly diagnosed and treated for attention deficit disorder for more than 2 years.  In October 2012, she was finally diagnosed in Taiwan with MLD, confirmed by low ARSA activity with ARSA gene mutations, MRI imaging and clinical signs.  Supportive treatments failed to arrest progress of the disease.  Prior to stem cell-gene transplantation, she was unable to walk up and down the stairs, unable to manage personal hygiene and experienced episodic seizures, severe constipation and occasional urinary incontinence.  In September 2014, the hematopoietic stem cell gene transplantation was performed.  Early results indicate stabilisation of the disease.  Her mobility and balance, capacity of hygiene management and ability to write have improved, constipation and urinary problems have resolved, and no seizures have been recorded.

Current treatments for MLD

MLD is a devastating lysosomal storage disease caused by a deficiency of arylsulfatase A (ARSA).  There is no cure for MLD and until recently, management for most patients with MLD was confined to supportive care.  Several treatment options are now being developed and are at clinical trial stage.  Most are enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT).  Enzyme replacement therapy (ERT) with functional ARSA has been challenged because ARSA is a high molecular weight protein that is unable to penetrate the blood–brain barrier (BBB).  Hematopoietic stem cells cross the BBB in MLD patients and differentiate to microglial cells.  The donor microglial cells are able to secrete limited ARSA enzyme that is taken up by the recipient neural cells.  Hematopoietic stem cell transplantation (HSCT) can benefit selected subsets of patients with some lysosomal storage diseases, but results have been poor in MLD, highlighting the need for innovative therapeutic approaches in this field.

For more information about MLD and the research team, please refer to the attached factsheet.

For photos and powerpoint presentation, please click the below link：
http://www.med.hku.hk/v1/news-and-events/press-releases

A stem cell research team at the Li Ka Shing Faculty of Medicine, The University of Hong Kong (HKU) has led the first genetically modified hematopoietic stem cell transplantation in Asia for a Taiwanese juvenile with the fatal inherited disorder metachromatic leukodystrophy (MLD), through close collaboration with researchers from The Second People’s Hospital of Shenzhen (The First Affiliated Hospital of Shenzhen University), Mainland China, and the National Taiwan University Hospital (NTUH), Taiwan. (From left) Professor Zhuo Jiacai, Clinical Professor and Head of the Division of Haematology at the Second People’s Hospital of Shenzhen (The First Affiliated Hospital of Shenzhen University) and Dr Lian Qizhou, Assistant Professor of the Department of Ophthalmology and Department of Medicine of Li Ka Shing Faculty of Medicine, HKU attended the press conference.

In September 2014, Liao Yu-an received the hematopoietic stem cell gene transplantation.  Early results indicate stabilisation of the disease.  Her mobility and balance, capacity of hygiene management and ability to write have improved, constipation and urinary problems have resolved, and no seizures have been recorded.