Posted May 22, 2019

Daniel T. Laskowitz, M.D., M.H.S., Duke University

Traumatic brain injury (TBI) has become a signature injury of the Afghanistan and Iraqi conflicts. According to the Department of Defense (DoD) Worldwide Numbers for TBI, 383,947 TBIs of all severities have been reported across the DoD between 2000 and the first quarter of 2018.¹ Delayed medical evaluation and treatment, common in combat scenarios, exacerbate TBIs, resulting in increased neurological damage and a lower quality of life for patients. Currently there are no neuroprotective therapies that improve long-term functional outcomes following TBI, care remains largely supportive. Therefore, development of a prophylactic neuroprotectant to improve outcome after TBI remains an urgent unmet need.

In 1997, Dr. Daniel Laskowitz and fellow researchers first proposed that apolipoprotein E (ApoE), a neuroprotective protein produced in the brain and liver, acted to limit neurodegeneration and reduced neuroinflammation after TBI.^2,3 Furthermore, preclinical studies have demonstrated that a reduction of ApoE after TBI is associated with increased tissue injury and poor functional outcomes.⁴ Although, ApoE is effective in reducing the damaging secondary effects of TBI, the ApoE protein is large and unable to cross the blood-brain barrier (BBB), thus precluding it as a potential prophylactic therapy.

To address the inability of ApoE to cross the BBB, Dr. Laskowitz and his team developed CN-105, a small pentapeptide that is capable of crossing the BBB, and which mimics the action and neuroprotective capabilities of ApoE. With support from a Fiscal Year 2015 Broad Agency Announcement for Extramural Medical Research Award, Dr. Laskowitz and his team at Duke University set out to investigate the optimal therapeutic window and route of administration of prophylactic treatment of CN-105 to effectively reduce secondary neural damage due to inflammatory responses in the brain following TBI. Using a closed head TBI mouse model, which replicates injury to neurons associated with vestibulomotor deficits and long-term neurocognitive defects, Dr. Laskowitz investigated the neuroprotective potential of CN-105 as a prophylactic treatment. Mice that received CN-105 intravenously (IV) 30 minutes before injury showed improved motor function in the Rotarod latency assessment compared to injured mice that had not received CN-105. However, there was a lack of motor function improvement when CN-105 was administered 60 minutes before injury; this was likely a result of the short half-life of CN-105 in mice. To address this limitation, Dr. Laskowitz and his team evaluated the pharmacokinetics of CN-105 which led to changes in dosing regimens and an increase in the bioavailability of CN-105 in the blood stream. Since Service members are commonly engaged in combat for varying lengths of time and prone to TBI for the duration of combat, Dr. Laskowitz evaluated the prophylactic effects of CN-105 when administered both into the peritoneal cavity (intraperitoneal) and IV simultaneously at 3 or 6 hours before injury. Mice that received CN-105 3 or 6 hours before injury both showed improved motor function over a 28-day trial compared to non-treated mice; however, the 3-hour test group displayed the greatest improvement. This suggests, as proof of principle, that CN-105 may be effective in reducing TBI associated functional deficits when administered prophylactically.

Outside of this DoD funding mechanism, CN-105 is currently used in clinical trials, where it has demonstrated an excellent safety profile in patients with acute brain injury and has a high potential for translation into the military TBI population. Furthermore, Dr. Laskowitz has recently joined the Medical Technology Enterprise Consortium which they hope will foster collaborative efforts and facilitate CN-105 translation into TBI populations and ultimately improve quality of life for TBI patients.

References:

¹DoD Worldwide Numbers for TBI. 2018. http://dvbic.dcoe.mil/dod-worldwide-numbers-tbi

² Laskowitz DT, Goel S, Bennett E, Matthew WD. Apolipoprotein E suppresses glial secretion of TNF alpha. J Neuroimmunol 1997 June;76(1-2): 70-4,

³ Lei B, Dawson H,Nnenweber, S, Warner DS, Bennett ER, Vitek MP, McKenna, S, Laskowitz DT. A novel therapeutic derived from apolipoprotein E reduces brain inflammation and improves outcome after closed head injury. Exp Neurol 2005 Mar;192(1):109-16.

⁴Lynch JR, Pineda J, Zhang L, Warner DS, Benveniste H, Laskowitz DT. Apolipoprotein E affects the central nervous system response to injury and the development of cerebral edema. Ann Neurol 2002 Jan;51(1):113-7.

Publication:

Laskowitz D, Wang H, Chen T, Lubkin D, Cantillana V, Ming T, Kernagis D, Zhou G, Macy G, Kolls G, and Dawson H. 2017. Neuroprotective pentapeptide CN-105 is associated with reduced sterile inflammation and improved functional outcomes in a traumatic brain injury murine model. Science Reports. 7:46461.

Link:

Public and Technical Abstracts: Prophylactic Administration of CN-105 Confers Neuroprotection against Acute Brain Injury

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