Novel peptides for the treatment of type 1 and 2 diabetes and their neurological complications

A novel peptide therapeutic AAC2 comprising amino acids with a coumarin-modified side chain that improves glucose control and reduces neurological decline and anxiety through activation of the insulin-insensitive glucose transporter 1 (GLUT1).

The Need

A national study done in 2016 on US adults with diabetes estimated that 0.5% of the population was diagnosed with type 1 diabetes (T1D) (~1.6 million) and 8.5% was diagnosed with type 2 diabetes (T2D) (~27 million). Globally there are ~415 million adults living with diabetes in 2015, with a projected increase to ~642 million by 2040. The global diabetic care market was valued at 22.7 billion USD in 2019, with a forecasted CAGR of 7.9% from 2020-2027 (41.7 billion USD). There are no treatments to prevent diabetes-associated neurological pain or peripheral neuropathy (neurodegeneration in peripheral tissues), nor cognitive dysfunction in diabetes patients who develop resistance to insulin, with potential links to Alzheimer’s Disease. These complications can also lead to dementia, in addition to more well-known issues such as impaired wound healing, amputations of limbs, blindness, and kidney failure. Insulin analogs use can provide protection against hyperglycemia in T1D. These patients, however, remain at high risk for developing cognitive impairment and permanent brain damage. Similar insulin analogs cannot be used to treat insulin-resistant patients, who represent most of the patients with T2D. For those who cannot afford expensive or frequent treatment with insulin, these symptoms progress rapidly towards further complications and death.

The Technology

Researchers at the Ohio State University, led by Dr. Jon Parquette and Dr. Ouliana Ziouzenkova, have developed AAC2, a highly potent short peptide comprising amino acids with a modified coumarin side chain. It exhibits glycemic efficacy in peripheral tissues and the brain. In insulin-resistant mice with T2D, the molecule is stable and safely reduces hyperglycemia, neurological pain, and anxiety. In insulin-deficient mice with T1D, AAC2 improves glucose uptake and prevents death with similar efficacy as insulin. Importantly, AAC2 rescues mice from cognitive decline, preventing brain mass loss and reducing anxiety-related behavior. Glucose uptake efficiency has been tested in cultures of human adipocytes obtained from insulin-resistant patients with morbid obesity as well as endothelial cells comprising the blood brain barrier. Unlike insulin and other current diabetes therapeutics, AAC2 increases glucose uptake via the insulin-independent GLUT1 transporter in nervous tissue (interacting specifically with the leptin receptor (LepR) and activating atypical protein kinase C zeta (PKCς)), which underlies its efficacy for nervous tissue as well as insulin-resistant tissues. Furthermore, since insulin acts through the insulin-dependent GLUT4 transporter in peripheral tissues, AAC2-bound insulin synergistically improves glycemic efficacy performance in the brain, sufficient to rescue cognitive performance. AAC2 is much less expensive than proteins like insulin and corresponding analogs.

Commercial Applications

  • Diabetes and pre-diabetes
  • Neurological complications and neuropathies associated with diabetes
  • Obesity associated with diabetes

Benefits/Advantages

  • A new therapeutic platform for the treatment of diabetes, and especially its neurological complications
  • Minimizes neurological complications that cannot be addressed by other diabetes treatments
  • Effective in insulin-resistant subjects (T2D)
  • May be used by itself or in combination with insulin
  • May be administered in several ways, depending on whether local or systemic treatment is desired
  • May be administered prophylactically or as a treatment
  • Less expensive than insulin and corresponding analogs

Patent Filing(s)

US17/380,536 pending

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