New Research Paves the Way for Therapeutics for APBD

What the Research Showed Is Encouraging

APBD is caused by mutations in a single gene, GBE1 (the glycogen branching enzyme gene). This gene helps the body build glycogen, a form of glucose that is easily stored by the body. In healthy individuals, a single glycogen molecule can store as many as 55,000 glucose molecules in multiple chains that branch off its center. Glucose molecules can be rapidly broken off the chains when needed for energy or added back on for storage of excess glucose. In APBD—which is a form of Glycogen Storage Disease Type IV—the mutated gene instead results in a large amount of glycogen that is oddly shaped, with very long chains that contain fewer branches. This form cannot be easily used by the body and tends to build up, forming abnormal clumps called polyglucosan bodies. Over the long term, these polyglucosan bodies can damage cells, particularly those of the nervous system.

The Glycogen Synthase (GYS1) Gene

The researchers targeted the synthesis of glycogen in the body, theorizing that reducing glycogen would also reduce the number of damaging polyglucosan bodies. Two genes that make two proteins were studied. The first was the glycogen synthase (GYS1) gene, which helps build the long, linear chains in glycogen. The researchers hoped that by reducing glycogen synthase, they could correct the ratio between long, linear chains and branched chains in glycogen, thereby preventing deformed glycogen from being made. This rationale was supported by previous laboratory research in neurons that showed that inhibiting glycogen synthase does indeed lower polyglucosan bodies.

The Protein Phosphatase 1 Regulatory Subunit 3C (PPP1R3C) Gene

The second gene studied helps activate glycogen synthase and is called protein phosphatase 1 regulatory subunit 3C or PPP1R3C. The rationale behind targeting PPP1R3C was quite similar to the rationale behind targeting glycogen synthase. If glycogen synthase activity could be reduced, levels of elongated glycogen chains in the disease could also be reduced.

We all carry two copies of almost every gene in the body. The researchers knocked out only one copy of the glycogen synthase gene, because research has shown that mice with no glycogen synthase gene at all usually do not survive birth. For PPP1R3C, they bred mice deficient in either one or both copies of the gene and studied both sets of those mice.

The results were impressive. The APBD mice lost body weight, appeared hunched, had poor balance, and altered movement. They also had a shortened lifespan of approximately 12 months of age. In comparison, APBD mice deficient in one copy of glycogen synthase had normal body weights, balance abilities, activity levels, and walking patterns. These APBD mice deficient in glycogen synthase lived as long as normal healthy mice in the study—the full 24 months of the study. Similarly, the APBD mice that were deficient in one or two copies of PPP1R3C showed improved body weight, less hunching, and normal activity and walking. The APBD mice that were deficient in one copy of PPP1R3C lived only slightly longer than the APBD mice, but the mice deficient in both copies of the PPP1R3C gene lived until 22 months of age—a great improvement over the APBD mice, but still not a normal lifespan.

When brain, muscle, heart, and liver tissue were examined, the glycogen synthase-deficient APBD mice had fewer polyglucosan bodies in all those tissues. The PPP1R3C-deficient mice did well also—whether they had one or both copies of the gene knocked out. They showed lower levels of polyglucosan bodies in the brain, and lower levels of glycogen itself in muscle and the liver, compared to untreated APBD mice. Evidence of damage to neurons was also reduced.

Indeed, 1,700 FDA-approved compounds have been screened to find the ones that are able to reduce glycogen synthase activity and polyglucosan accumulation in APBD fibroblasts. This high throughput screening was accomplished by H. Orhan Akman, PhD at Columbia University Medical Center. Research has shown that guaiacol, 2-ethoxy phenol, and terpin are potential candidates, and they are being explored as therapies for APBD.

Research Applications Beyond APBD

This research extends earlier findings in another Glycogen Storage Disease, Lafora disease, which is a primary research interest of Dr. Minassian’s, and whose laboratory discovered the genes responsible for that disorder. Several mouse studies have shown that targeting these same two proteins helps protect against Lafora disease. The researchers highlight that these new findings have relevance to individuals suffering from other forms of Glycogen Storage Disease Type IV, and still other diseases in which polyglucosan bodies accumulate.