Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Genetically modified micro-organism – cell – or virus
Reexamination Certificate
2001-08-24
2003-07-22
Mosher, Mary E. (Department: 1648)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Genetically modified micro-organism, cell, or virus
C424S199100, C435S320100, C435S235100
Reexamination Certificate
active
06596269
ABSTRACT:
FIELD OF THE INVENTION
This invention generally pertains to the field of medicine and pain control. In particular, this invention pertains to the surprising discovery that pia mater cells transformed to secrete beta-endorphin will selectively control chronic pain while not significantly affecting basal nociceptive, acute pain, responses.
BACKGROUND OF THE INVENTION
This invention is the surprising discovery of a method of using beta endorphin through genetic engineering to treat chronic pain, while at the same time not significantly affecting the ability to react to acutely painful, potentially dangerous, stimuli. As will be explained below, prior to this invention, there was a great amount of academic debate as to whether beta-endorphin can be used to treat or control chronic pain. Thus, the discovery of beta-endorphin's selective control of chronic pain when secreted by transformed pia mater cells was unpredictable and therapeutically advantageous.
Current analgesic therapies often fall short of therapeutic goals and typically have unacceptable side effects. In many chronic pain syndromes, such as those subsequent to neuropathic injury, pain is not well controlled by any currently available method. Furthermore, most chronic pain treatment regimes affect the patient's ability to perceive acute pain, thus blunting or abrogating necessary protective basal nociceptive responses.
Exogenous opioids, such as morphine, are commonly used to treat chronic pain. Unfortunately, such drugs are addictive and result in side effects, such as nausea and constipation. Such side effects can be reduced by delivery into the subarachnoid space through intrathecal pumps. However, pumps are expensive and invasive, leading to possible risk of infection. Tolerance and dependence to exogenous opioids is also a severe medical and public health problem.
Endogenous opioids as analgesics for the treatment of acute and chronic pain has also been the subject of many studies. There are numerous endogenous opioids, including, e.g., the beta-endorphin peptide family, enkephalins, dynorphins (see, e.g., Cesselin (1995) Fundam. Clin. Pharmacol. 9:409-433). In particular, investigators have focused on the role and use of beta-endorphins as mediators of the body's response to pain.
However, studies have generated conflicting theories as to the role beta-endorphin plays in both acute and chronic pain. Thus, to date, the specific role of beta-endorphin in the physiology and neurotransduction of pain has not been determined.
The vast majority of studies implicate beta-endorphin as an endogenous mediator of acute pain and stress. For example, Dionne (1998) Clin. Pharmacol. Ther. 63:694-701, reported that administration of the analgesic ibuprofen suppresses both acute pain and the plasma beta-endorphin levels seen after oral surgery (tooth extraction). In Kamei (1993) Brain Res. 13:619:76-80, intrathecal administration of beta-endorphin had clear anti-nociceptive effects when acute pain was induced (by heat) in rats (tail-flick response). Tseng (1993) Life Sci. 52:PL211-215; also concluded that beta-endorphin induced anti-nociception in a mouse acute pain (tail-flick response) model. Przewlocki (1987) Pol. J. Pharmacol. Pharm. 39:609-621, reported an enhanced release of beta-endorphin in the brain and pituitary in response to acute stimulation—acute pain precipitated a rapid depletion of beta-endorphin in the hypothalamus and midbrain. Puig (1982) Anesthesiology 57:1-4, is one of several studies implicating beta-endorphin as a mediator of acute post-operative pain. Terenius (1982) Acta Anaesthesiol. Scand. Suppl. 74:21-24, concluded that endorphins do have a protective role in acute pain after finding that the better the pain control (by higher levels of pain killer after major surgery), the lower the level of beta-endorphin in the cerebral spinal fluid (CSF). Furthermore, beta-endorphin release is a response associated with acute stress, see, e.g., Guilleman (1977) Science 197:1367-1369; Milan (1981) Mod. Probl. Pharmacopsychiatry 17:49-67; Mueller (1981) Life Sci. 29:1169-1176; Vermes (1981) Neurosci. Lett. 27:89-93; Akil (1985) Science 227:424-426; Millan (1985) Int. Rev. Neurobiol. 26:1-83; Millan (1987) J. Neurosci. 7:77-87.
There is academic debate as to whether or not beta-endorphin can control chronic pain. Conflicting theories have been presented as to the role of beta-endorphin in chronic pain. Some studies suggest that beta-endorphin is not involved in chronic pain. For example, Calvino (1992) Pain 49:27-32, found no beta-endorphin response when chronic pain was maximum (in a rat arthritis animal model). Dehen (1990) Rev. Neurol. (Paris) 146:155-157, measuring concentrations of beta-endorphin in the CSF in painless subjects and patients with chronic pain, found no significant difference between the two groups. France (1991) Psychosomatics 32:72-77, found no change in CSF beta-endorphin concentrations after successful treatment of pain and resolution of depression in patients suffering chronic neuralgic low back pain/sciatica. Salar (1991). Pharmacol. Res. 23:181-186, found no difference in levels of beta-endorphin the CSF of control subjects versus patients with different types of chronic pain (i.e., suffering from deafferentation pain syndromes). Guieu (1992) Pain 48:83-88, found that no increase in beta-endorphin levels occurred concomitantly with pain relief (induced by vibration).
In contrast, there are only a few references suggesting beta-endorphin may be a potential analgesic for chronic pain. One early reference, in 1978 (Almay (1978) Pain 5:153-162), suggested that beta endorphin may be involved in chronic pain relief; however, they found that patients classified as having mainly organic pain syndromes were found to have significantly lower CSF endorphin levels than patients with predominantly psychogenic pain. Lipman (1991) Psycho-pharmacology 102:112-116, found that increased levels of CSF beta-endorphin were correlated with increased pain relief in chronic pain patients. Young (1993) J. Neurosurg. 79:816-825, found a direct relationship between beta-endorphin release in the brain and alleviation of intractable chronic pain. Baxter, et al., U.S. Pat. No. 4,350,764, which teaches the recombinant synthesis of beta endorphin in bacteria, states as background that beta endorphin was known to be useful in the treatment of intractable pain, such as phantom limb pain, Significantly, none of these references administers beta endorphin to treat chronic pain.
Thus, it is clear that, to date, there is no consensus concerning the role of beta-endorphin for controlling chronic pain or its ability to selectively modulate between these distinct pain types. Also, before this invention, there was no effective method of specifically treating chronic pain while at the same time not significantly affecting basal nociceptive (acutely painful) responses. The present invention resolves this controversy by providing a novel means to treat chronic pain. Thus, the ability to preserve sensitivity to acute pain while successfully treating chronic pain is a surprising discovery.
SUMMARY OF THE INVENTION
The invention provides a method of treating chronic pain by administering beta-endorphin, wherein basal nociceptive responses are not significantly affected. The beta-endorphin can be administered in the form of an expression cassette, such as an expression vector, for recombinant beta endorphin expression in vivo. The expression vector can be, e.g., any viral vector, such as adenovirus, adeno-associated virus (AAV), lentivirus, or herpes virus, or plasmid, or the like. In a preferred embodiment, the viral vector is a recombinant adenoviral vector or an AAV vector. The beta-endorphin-expressing nucleic acid can be administered by any means, including, e.g., aqueous solutions, lipid-cationic delivery systems, and the like.
In one embodiment, the beta-endorphin-expressing nucleic acid (e.g., an expression cassette, such as a recombinant adenovirus or AAV vector) is administered such that it is transduces a tissue
Caudle Robert M.
Finegold Alan A.
Iadarola Michael J.
Mannes Andrew J.
Olah Zoltan
Mosher Mary E.
The United States of America as represented by the Department of
Townsend and Townsend / and Crew LLP
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