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Research to Reverse Diabetic Neuropathy [1]

['This Content Is Not Subject To Review Daily Kos Staff Prior To Publication.']

Date: 2023-10-11  

I have the first level of neuropathy in my toes and feet, tingling but no pins and needles or loss of sensation. So today’s news is just in time for me—two possible ways to reverse neuropathy and restore nerve function, and also a long-term treatment for pain from neuropathy that seems to halt further damage for months.

We noted in A Treatment for Diabetic Neuropathy, about the Proclaim XR Spinal Cord Stimulator implant, that there are multiple mechanisms of neuropathy, causing restriction of blood vessels

These changes are thought to result from a microvascular injury involving small blood vessels that supply nerves (vasa nervorum).

and nerve damage. The critical mechanism is hyperglycemia-induced glycation in which glucose molecules bind to and crosslink proteins.

Elevated levels of glucose within cells cause a non-enzymatic covalent bonding with proteins, which alters their structure and inhibits their function. Some of these glycated proteins have been implicated in the pathology of diabetic neuropathy and other long-term complications of diabetes. There is, however, no agent known that can break down the most common AGE [Advanced glycation end product], glucosepane, which appears 10 to 1,000 times more common in human tissue than any other cross-linking AGE.[51][52]

Right. No agent known YET. We’ll see.

Now this is where the story really starts, years ago.

x Ever heard of glucosepane? It's synthesis may help understand science of aging & #diabetes http://t.co/sR4ux3VTQC pic.twitter.com/XYI2pKjpXZ — Eric Topol (@EricTopol) October 16, 2015

And here is where we have gotten to.

Winsantor’s Topical Pirenzepine Researchers study potentially revolutionary neuropathy treatment In a pilot study of Oxybutinin (a similar “muscarinic antagonist”) done in cooperation with the University of California – San Diego, Dr. Vinik and his team found good results among the study’s 46 patients in terms of nerve regrowth, a reduction in pain and improved quality of life. “We are very excited that we can build on the diabetic neuropathy research that Dr. Vinik pioneered for decades,” Dr. Siraj says, “and be able to investigate pirenzepine as a novel agent to treat neuropathy.” Pirenzepine is not a new drug. It was developed a number of years ago to treat ulcers. It has been reformulated for topical use, and research has shown its potential to regrow nerves in animal and human pilot studies with a very good safety profile, according to the researchers. The new study will involve the topical gel form of Pirenzepine. Once daily for six months, participants will rub the gel on their legs and feet where neuropathy most commonly occurs. The study is seeking to investigate the drug in over 100 participants. To participate in the research, contact the EVMS [Eastern Virginia Medical School] Strelitz Diabetes Center at [757] 446-7933 or by email: DiabetesResearch@evms.edu. That’s if you are local, and can go in for testing. Mt. Sinai Health System, New York: Clinical Trials To Study Two Agents For Painful Peripheral Neuropathy In Diabetes Patients The pirenzepine Phase 2b study is a multicenter, parallel-arm, randomized trial that is open to patients who have diabetes and who both exhibit signs of peripheral neuropathy on exam and present with related pain. The study plans to recruit 260 participants who will be followed for 20 weeks. The primary outcome is pain, but a secondary outcome is treatment of the underlying disease process. There are preliminary data for this therapeutic agent that suggest this type of molecule can increase the density of certain nerve fibers and that it might help nerve regrowth at 20 weeks Ricolinostat Regenacy is poised to deliver the first treatment for peripheral neuropathy. This condition affects more than half of all diabetic adults, approximately 500,000 chemotherapy-treated patients, and an estimated one million individuals with an inherited degenerative nerve condition called Charcot–Marie–Tooth disease type 2 (CMT2). Unlike standard analgesics, the company’s lead compound ricolinostat is a disease-modifying therapy that reverses nerve damage and reduces pain, numbness, and muscle weakness resulting from diabetes, chemotherapy, and Charcot–Marie–Tooth disease. The company’s lead compound ricolinostat is an oral, selective inhibitor of the microtubule-modifying enzyme histone deacetylase 6 (HDAC6). With first-in-class potential, ricolinostat is currently positioned to enter a phase 2 clinical trial for diabetic neuropathic pain. Neurons rely on an internal micro-tubule transport network to supply energy and nutrients to maintain nerve ends in the skin and muscles. When this transport is disrupted by disease nerve cells can malfunction and send random signals, resulting in pain, tingling, muscle spasms, or no signal at all, leading to numbness or paralysis. These are the symptoms of peripheral neuropathy that can result from diabetes, chemotherapy, and mutations. Intracellular transport is regulated by HDAC6—a microtubule-associated deacetylase that plays a significant role in axonal functioning in the nervous system. Inhibition of HDAC6 is a novel approach to restoring nerve function for the treatment of peripheral neuropathies by re-establishing the transport function of microtubules. Phase 1 and 2 clinical trials in 250 cancer patients’ demonstrated ricolinostat’s excellent safety and tolerability profile, particularly when contrasted with the high toxicity of currently marketed, nonspecific pan-HDAC inhibitors such as vorinostat and panobinostat. Regenacy Pharmaceuticals Announces Completion of Enrollment for Phase 2 Study in Diabetic Peripheral Neuropathy & $9.3 Million Series B Financing Helixsmith Engensis Gene therapy for diabetic peripheral neuropathy: A randomized, placebo-controlled phase III study of VM202, a plasmid DNA encoding human hepatocyte growth factor VM202 is a plasmid DNA encoding two isoforms of hepatocyte growth factor (HGF). A previous phase II study in subjects with painful diabetic peripheral neuropathy (DPN) showed significant reductions in pain. A phase III study was conducted to evaluate the safety and efficacy of VM202 in DPN. The trial was conducted in two parts, one for 9 months (DPN 3-1) with 500 subjects (VM202: 336 subjects; and placebo: 164) and a preplanned subset of 101 subjects (VM202: 65 subjects; and placebo: 36) with a noninterventional extension to 12 months (DPN 3-1b). VM202 or placebo was administered to calf muscles on days 0 and 14, and on days 90 and 104. The primary end point in DPN 3-1 was change from baseline in the mean 24-h Numerical Rating Scale (NRS) pain score. In DPN 3-1b, the primary end point was safety, whereas the secondary efficacy end point was change in the mean pain score. VM202 was well-tolerated in both studies without significant adverse events. VM202 failed to meet its efficacy end points in DPN 3-1. In DPN 3-1b, however, VM202 showed significant and clinically meaningful pain reduction versus placebo. Pain reduction in DPN 3-1b was even greater in subjects not receiving gabapentin or pregabalin, confirming an observation noted in the phase II study. In DPN 3-1b, symptomatic relief was maintained for 8 months after the last injection suggesting that VM202 treatment might change disease progression. Despite the perplexing discrepancy between the two studies, the safety and long-lasting pain-relieving effects of VM202 observed in DPN 3-1b warrant another rigorous phase III study. Worldwide Demand Diabetic Peripheral Neuropathy Market Growing at a CAGR of ~6% by 2032 | DelveInsight Not when there is a cure for neuropathy that gets FDA approval. The market will explode to millions of patients in the US, and hundreds of millions worldwide, as fast as production can be ramped up and other countries can complete their approval processes. International Diabetes Federation: Diabetes facts and figures Diabetes around the world in 2021 Approximately 537 million adults (20-79 years) are living with diabetes. The total number of people living with diabetes is projected to rise to 643 million by 2030 and 783 million by 2045. 3 in 4 adults with diabetes live in low- and middle-income countries Yes, I do love living in the future, where both dread diseases and low-income countries are vanishing away, step by step. Note

My thanks to phasmatis for links.

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