Staci Kallish, DO and NTSAD Board Vice President wrote the following lay summary of an article published and shared online. Select PDF to read online article.

• A study recently published demonstrates the development of the fist human model of Sandhoff disease (SD).
• This work was completed by a number of scientists well-known to NTSAD, including Cynthia Tifft, MD, PhD, Richard Proia, PhD, and Miguel Sena-Esteves, PhD and their colleagues and was published March 1st in the Journal of Lipid Research.
• This study used fibroblasts (skin cells) from an infant with SD to create iPS cells (induced pleuripotent stem cells; cells which can them be transformed into other cell types).
• The researchers also used gene-editing technology called CRISPR/Cas9 to correct one of the Sandhoff mutations in some of these cells to create healthy cells.
• They then induced both groups of cells into groups of brain cells called organoids. This allowed them to study early brain development in the SD model compared to an unaffected model.
• As they expected, the researchers saw early ganglioside storage in the cells in the SD organoids, but not in the healthy control organoids. However, they were surprised that they saw cells overgrowing rather than degenerating. The SD organoids became larger than the controls, mimicking the enlarged brain size seen in patients with SD. They also saw changes in expression of other genes in the SD organoids, in genes which control cell maturation, which suggests that having a gangliosiosis may affect brain development in other ways in addition to the build up of storage material.
• Finally, the researchers used gene therapy (similar to the SD gene therapy being studied in SD animal models) to treat the organoids. They saw improvements in SD organoid size and reductions in ganglioside storage after gene therapy treatment. This demonstrates that organoids can be useful models of disease for the study of potential therapies. This also serves as a "proof of principle", the first evidence that gene therapy can correct abnormalities seen in SD in human cells.

Intravenous administration of scAAV9-Hexb normalizes lifespan and prevents pathology in Sandhoff disease mice

Niemir N, Rouvière L, Besse A, Vanier MT, Dmytrus J, Marais T, Astord S, Puech JP, Panasyuk, Cooper JD, Barkats M, Caillaud C.

Adeno-associated virus (AAV) gene therapy has shown much promise for inherited diseases. Most recently, non-invasive delivery routes such as intravenous injection of AAV have been evaluated in a number of inherited diseases. In fact, clinical trials are underway utilizing intravenous AAV gene therapy for MPSIIIA and Spinal Muscular Atrophy. In January of 2018 a paper was published detailing a study evaluating intravenous AAV gene therapy in a mouse model of Sandhoff disease. 

On December 7th a case study was published detailing results of bone marrow transplantation in a juvenile Tay-Sachs patient. The patient initially presented at age 7 with tremors and symptoms progressed to include ataxia, speech stammer, and swallowing problems. At the age of 15 he was diagnosed with juvenile TSD. In light of his deteriorating neurological function, the patient underwent preconditioning with busulfan, a chemotherapy agent, followed by a hematopoietic stem cell transplant (HSCT) from a matched sibling donor, and a post-transplant immunosuppression regimen. To date the patient is 23 years of age and 8 years post-HSCT has retained full donor chimerism (his white blood cells are those from the donor) and normal white blood cell Hexosaminidase A (the enzyme deficient in TSD) levels. The patient has demonstrated stabilization of his neurologic regression with improvement in swallowing dysfunction and no change in the severity of tremor. MRI of the brain at 12 months, 4 years, and 8 years post-HSCT showed no progression compared to pre-transplant scans. 

Karolina M. Stepien • Su Han Lum • J. Edmond Wraith • Christian J. Hendriksz • Heather J. Church • David Priestman • Frances M. Platt • Simon Jones • Ana Jovanovic • Robert Wynn

A new study published December 6th led by Dr. Alessandra Biffi, the director of the gene therapy program at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, details a new promising approach to lentiviral gene therapy. Dr. Biffi is currently evaluating this same approach as a therapy for Tay-Sachs and Sandhoff diseases in a NTSAD-funded study entitled “Proof of concept study of HSC gene therapy for Tay-Sachs disease”.

Alessia Capotondo, Rita Milazzo, Jose M. Garcia-Manteiga, Eleonora Cavalca, Annita Montepeloso, Brian S. Garrison, Marco Peviani, Derrick J. Rossi, Alessandra Biffi

‘‘IS THERE A TREATMENT?’’ are always the first words uttered when a parent or relative of a newly diagnosed child contacts National Tay-Sachs & Allied Diseases Association (NTSAD) upon hearing the devastating news that their loved one was diagnosed with one of the life-limiting diseases supported by NTSAD. The simple answer is always the same: ‘‘There are no treatments.’’ But first we try to inject hope by telling them about the ongoing research, especially in gene therapy, as it has received much NTSAD research grant support for a number of years and has produced promising results in animal models. Investigational new drug (IND)-enabling studies are in process; we remain optimistic for reaching the next major milestone and then hopefully demonstrating efficacy in affected children or adults.

In 2009, NTSAD funded an investigator-sponsored clinical trial at Hospital for Sick Children and NYU for the treatment of late-onset with pyrimethamine (PYR) led by Drs. Joe Clarke and Ed Kolodny. The results were published in 2011. (An open-label Phase I/II clinical trial of pyrimethamine for the treatment of patients). 

The study concluded that leukocyte Hex A activity is enhanced in vivo by treatment with PYR. However, future studies were needed to assess the protocol, including dosage, and perform related biochemical studies. An Israeli team of researchers performed similar studies and recently published their results. 

While they also found that PYR increases HexA activity in LOTS patients, "the observed increase is repeatedly transient and not associated with discernible beneficial neurological or psychiatric effects." 

Clinical report on neurological and cardiac responses after treatment with miglustat and a ketogenic diet in a patient with Sandhoff disease.

Published paper in Science Translational Medicine AAAS 2012 regarding the Long-term follow-up after gene therapy for Canavan Disease. Paola Leone, et al.

A publication on:

Effective gene therapy in an authentic model of Tay-Sachs-related diseases

A publication containing:

Mice Doubly-Deficient in Lysosomal Hexosaminidase A and Neuraminidase 4 Show Epileptic Crises and Rapid Neuronal Loss

A publication written about:

Novel Patient Cell-Based HTS Assay for Identification of Small Molecules for a Lysosomal Storage Disease

A publication on how:

Stem cells act through multiple mechanisms to benefit mice with neurodegenerative metabolic disease

A publication on the:

Late-onset Tay–Sachs disease: Adverse effects of medications and implications for treatment

A publication of the:

Natural History of Infantile GM2 Gangliosidosis

A publication including:

Gene therapy matures in the clinic

A publication including:

h-hexosaminidase lentiviral vectors: transfer into the CNS via systemic administration.

A publication containing:

An open-label Phase I/II clinical trial of pyrimethamine for the treatment of patients affected with chronic GM2 gangliosidosis (Tay–Sachs or Sandhoff variants)

A publication including:

The trigeminal retrograde transfer pathway in the treatment of neurodegeneration

A publication containing:

Combination therapies for lysosomal storage disease: is the whole greater than the sum of its parts?

A publication containing:

N-butyldeoxygalactonojirimycin reduces neonatal brain ganglioside content in a mouse model of GM1 gangliosidosis

A publication containing:

Gene Transfer Corrects Acute GM2, Gangliosidosis—Potential Therapeutic Contribution of Perivascular Enzyme Flow

A list of the lysosomal storage disease research funded projects.