Our ApproachOne gene can
span a spectrum
of diseases

Learn how one gene can unlock a new era in the treatment of multiple inherited disorders.

Our gene therapies are investigational and have not been approved by FDA or any other regulatory agency. Their safety and efficacy are being studied in clinical trials.

Gene therapy to address lysosomal disorders

Lysosomal disorders are a group of 50 diverse disorders caused by alterations to genes that operate cellular recycling centers called lysosomes. Lysosomes use digestive enzymes to break down toxic substrates, digest bacteria that invade the cell and recycle worn-out cell components. These are sometimes referred to as “housekeeping” enzymes.1 Genetic alterations that disable or eliminate these enzymes cause toxic buildup that damages cells and organs throughout the body, often including the central nervous system (CNS), and can lead to a wide range of symptoms.

The treatment of lysosomal disorders varies widely depending on how severely a given genetic change affects a person’s ability to recycle cellular waste and the symptoms that result. Gene therapy gives us the opportunity to develop a single dose therapy to address the specific altered gene that causes lysosomal disorders.

GBA gene and Gaucher disease

One of the genes AVROBIO is focused on restoring is the GBA gene. There are almost 500 disease-related genetic variations in the GBA gene, associated with a variety of disorders.2 AVROBIO’s focus is on Gaucher disease.

The GBA gene contains instructions for making a protein known as glucocerebrosidase, or GCase (see figure below). In the absence of fully functional GCase, fatty acids can build up to toxic levels in the cells of the spleen, liver, lung, bone marrow and CNS, causing Gaucher disease.3 The specific GBA gene variant a person inherits influences the type of Gaucher disease they are diagnosed with, the symptoms they experience and their severity.2

Individuals with Gaucher disease experience a wide variety of signs and symptoms.4 To learn more about the three subtypes of Gaucher disease and associated symptoms, visit Understanding Gaucher Disease.

Unaffected GBA Gene

A normal GBA gene will produce a fully functioning GCase enzyme that is involved in the normal process of successfully breaking down toxic substrate in cells.

Affected GBA Gene

In Gaucher disease, the variant GBA gene results in either a non-functioning protein or no protein made, and prevents toxic substrate in cells being broken down. Buildup of toxic substrate can lead to a variety of symptoms throughout the body, including the brain.

A normal GBA gene will produce a fully functioning GCase enzyme that is involved in the normal process of successfully breaking down toxic substrate in cells.

In Gaucher disease, the variant GBA gene results in either a non-functioning protein or no protein made, and prevents toxic substrate in cells being broken down. Buildup of toxic substrate can lead to a variety of symptoms throughout the body, including the brain.

Targeting GBA with hematopoietic stem cell (HSC) gene therapy

AVROBIO uses hematopoietic stem cell (HSC) gene therapy to target the root cause of genetic disorders by introducing a functional copy of the affected gene into the patient’s own HSCs, with the goal of durably expressing the therapeutic protein throughout the body, including the CNS. This is especially important for lysosomal disorders with CNS manifestations, like Gaucher disease, Hunter syndrome and Pompe disease.

We apply this approach in our Gaucher disease program by introducing a functional copy of the GBA gene into the patient’s HSCs, or blood stem cells. These genetically modified blood stem cells are designed to generate a wide variety of cells that travel throughout the body. All of these daughter cells are expected to carry the functional gene necessary to produce the therapeutic GCase enzyme needed for healthy cellular function.

Current Gaucher disease standard of care, known as enzyme replacement therapy (ERT), does not treat the root genetic cause of disease, but supplements the missing GCase enzyme. ERT does not cross the blood-brain barrier (BBB) to break down fatty acids in the CNS or improve clinical symptoms in the brain. In contrast, HSC gene therapy is designed to produce corrected monocytes, a cell type which can cross the BBB to enter the brain and spinal cord, and generate cells that are expected to produce the needed therapeutic protein throughout the body. Learn more about how HSC gene therapy reaches the whole body.

A comprehensive approach to lysosomal disorders

Beyond the GBA gene, AVROBIO is using HSC gene therapy to target a number of other genes that cause lysosomal disorders. For each of these disorders, genetic variations cause accumulation of toxins in cells and tissues, leading to a wide range of systemic and CNS disease manifestations.

IDS gene – Hunter syndrome

Neuronopathic mucopolysaccharidosis type II (nMPS II), or Hunter syndrome, is caused by changes in the IDS gene, which lead to a deficiency in the lysosomal enzyme iduronate-2-sulfatase (IDS). The enzyme IDS is required to break down large sugar molecules called glycosaminoglycans.7 Hunter syndrome can lead to severe cognitive deficits, as well as complications in skeletal and connective tissue and respiratory and cardiac systems.

GAA gene – Pompe Disease

Pompe disease is caused by changes in the GAA gene, which makes a protein called acid alpha-glucosidase.6 This genetic change leads to toxic buildup of glycogen in lysosomes, which can lead to muscular disorders in addition to respiratory issues and loss of neuromuscular control. Up to 300 genetic variations can lead to Pompe disease, with varying age of onset and severity.6

References
  1. NORD. Lysosomal Storage Disorders. https://rarediseases.org/rare-diseases/lysosomal-storage-disorders/ Accessed: October 12, 2022.
  2. Do, J., McKinney, C., Sharma, P. et al. Glucocerebrosidase and its relevance to Parkinson disease. Mol Neurodegeneration 14, 36 (2019). https://doi.org/10.1186/s13024-019-0336-2.
  3. NORD. Gaucher disease. https://rarediseases.org/rare-diseases/gaucher-disease/ Accessed: August 24, 2022.
  4. National Institutes of Health Genetic and Rare Diseases Information Center. Gaucher disease. https://rarediseases.info.nih.gov/diseases/8233/gaucher-disease. Accessed: August 1, 2022.
  5. Medline Plus. CTNS Gene. https://medlineplus.gov/genetics/gene/ctns/ Accessed: August 24, 2022.
  6. National Institutes of Neurological Disorders and Stroke. Pompe disease. https://www.ninds.nih.gov/health-information/disorders/pompe-disease Accessed: August 24, 2022.
  7. Medline Plus. Mucopolysaccharidosis type II. https://medlineplus.gov/ency/article/001203.htm Accessed: August 24, 2022.

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