News Column

"Compositions Containing Alpha-1-Antitrypsin and Methods for Use" in Patent Application Approval Process

June 19, 2014

By a News Reporter-Staff News Editor at Gene Therapy Weekly -- A patent application by the inventors Flier, Jeffrey (Boston, MA); Koulmanda, Maria (Brookline, MA); Strom, Terry B. (Brookline, MA), filed on November 19, 2013, was made available online on June 5, 2014, according to news reporting originating from Washington, D.C., by NewsRx correspondents (see also The General Hospital Corporation).

This patent application is assigned to The General Hospital Corporation.

The following quote was obtained by the news editors from the background information supplied by the inventors: "Diabetes is a very common disease that develops when the body does not produce enough, or appreciably any, insulin or cannot properly use or respond to insulin. There are two major types of diabetes. Type 1 diabetes is also known as insulin-dependent diabetes mellitus (IDDM) and results from insufficient insulin production. The onset of Type 1 diabetes occurs most often in children, adolescents, or young adults and is regarded as an autoimmune disease. Type 2 diabetes is known as noninsulin-dependent diabetes mellitus (NIDDM) and is the most common form of the disease, accounting for about 90% of all cases of diabetes. In many cases. Type 2 diabetes, in the initial phases, is characterized by a suboptimal response to insulin. Although insulin is produced, the ability of a given amount of insulin needed to effect a given decrease in blood glucose is increased. In Type 2, patients manifest a blunted blood glucose response to insulin, i.e., a state of insulin resistance. The causes of diabetes are not completely known, although both genetic and environmental factors, such as obesity and lack of exercise, increase the risk. There is also a form of diabetes that may develop during pregnancy (gestational diabetes), and a form of autoimmune diabetes that develops in adulthood, which is called latent autoimmune diabetes in adults (LADA) or slowly progressing autoimmune diabetes.

"Type 1 diabetes is treated with insulin, although other treatments have been proposed and transplantation of insulin-producing islet cells from the pancreas has been tested. Non-pharmaceutical intervention is usually prescribed initially for Type 2 diabetes (e.g., diet modification, weight loss, and exercise). If this is not successful, patients are then generally treated with one of three different types of drugs: drugs that stimulate the release of insulin from the pancreas; drugs that increase a patient's sensitivity to insulin; and drugs that directly affect the circulating levels of glucose (e.g., drugs that decrease the production of glucose from the liver or increase its uptake by muscles). More specifically, a patient may be prescribed a sulfonylurea, an .alpha.-glucosidase inhibitor, metformin (Glucophage.TM.), or troglitazone (Rezulin.TM.). In many cases, insulin is also used. After many years of living with type 2 diabetes, some patients manifest exhaustion of the insulin producing apparatus and thereby require insulin therapy.

"Despite the progress in understanding and treating diabetes, none of the current treatment strategies are optimal, and there is a great need for better ways to treat patients who have diabetes or who are at risk of developing diabetes."

In addition to the background information obtained for this patent application, NewsRx journalists also obtained the inventors' summary information for this patent application: "The present invention features, inter alia, methods of treating patients who are insulin resistant. Generally, the methods can be carried out by identifying a patient who is insulin resistant and administering to the patient a therapeutically effective amount of .alpha.1-antitrypsin (AAT; sometimes abbreviated A1AT), which is also referred to as .alpha.1-proteinase inhibitor. For example, one can administer an AAT polypeptide (e.g., a purified or recombinant AAT, such as human AAT) or a homolog, biologically active fragment, or other active mutant thereof. Alternatively, or in addition, one can administer an agent that promotes the expression or activity of an .alpha.1-antitrypsin (e.g., a gene encoding an .alpha.1 antitrypsin). While we describe insulin resistance and the patients amenable to treatment further below, we note here that patients who exhibit insulin resistance are not able to efficiently utilize insulin. Currently available tests can indicate whether a given patient is insulin resistant. For example, in an insulin tolerance test, insulin is administered and blood glucose is measured in response. If blood glucose levels do not fall as expected in response to the administered insulin, the patient is insulin resistant.

"A patient who is insulin resistant can also be a patient who has been diagnosed as having Type 1 diabetes. In this circumstance, the patient is insulin deficient. Insulin production is compromised but it is not abolished. In addition, the patient is also insulin resistant, thereby preventing or impairing the residual mass of insulin producing cells to prevent hyperglycemia. The diagnosis of Type 1 diabetes can be based on one or more findings or indicators, such as hyperglycemia (i.e., a blood glucose level indicative of diabetes) with: (a) hypoinsulinemia; (b) other evidence of pancreatic .beta. cell loss or functional insufficiency; a normal or slightly impaired blood glucose response to insulin; (d) ketoacidosis; or (e) insulin dependence (i.e., a dependence on insulin to obtain blood glucose levels within, or closer to, a normal range (i.e., a range usually observed in healthy or non-diabetic individuals). Patients with Type 1 diabetes must take insulin. Otherwise, their health deteriorates rapidly.

"Our statement that patients who are insulin resistant can have Type 1 diabetes and our statement that these same patients can be hyperglycemic and yet exhibit a normal blood glucose response to insulin may seem contradictory. As noted above, Type 1 diabetes is referred to as insulin-dependent diabetes mellitus because it has been historically understood as a condition that results when the .beta. cells in the pancreatic islets of Langerhans do not produce sufficient insulin to facilitate cellular uptake of glucose from the blood. It remains true that Type 1 diabetes is indicated when blood glucose is elevated and the level of circulating insulin is abnormally low. It is also true that some patients with Type 1 diabetes may respond normally, or nearly normally, when exogenous insulin is administered, while others may also have an insulin resistant state. What our research has indicated, however, is that there is an insulin resistant component in early onset Type 1 diabetes, and insulin resistance may contribute to Type 1 diabetes even in non-obese patients. For example, our studies with new onset type 1 diabetic non-obese diabetic (NOD) mice, the best available model for Type 1 diabetes, show an abnormal insulin tolerance test. This abnormality is seen in concert with reduction in both tyrosyl-phosphorylation of insulin receptor (IR) and the insulin receptor substrate-1 (IRS-1). Normal phosphorylation of both the IR and IRS-1 was restored by treatment with an .alpha.1-antitrypsin (Aralast.TM.) or a TNF-.alpha. antagonist (see FIG. 1). This insulin resistance state is not abolished through normalization of blood glucose levels with intensive insulin therapy, and it is associated with molecular signs of subtle inflammation within fat and muscle, the primary sites for insulin driven disposal of blood glucose.

"Insulin levels are reflected by the level of a protein called C-peptide (for connecting peptide). In the course of producing insulin, the body first produces proinsulin, which is subsequently cleaved into insulin and C-peptide. Thus, in attempting to distinguish patients who have Type 1 diabetes from patients who have Type 2 diabetes, a physician can assess C-peptide. Hypoinsulinemia, as seen in Type 1 diabetes, is reflected by a diminished level of C-peptide in circulating blood.

"Any of the patients described herein can be human patients. In the past, Type 1 diabetes was far more prevalent in young people than Type 2 diabetes. Unfortunately the epidemic of obesity within our culture has led to many young obese individuals with type 2 diabetes. Youngsters with Type 2 diabetes are no longer rare. Moreover, an adult patient can develop late-onset Type 1 diabetes. Nevertheless, a patient's age or, more generally, whether the patient is a child, adolescent, or adult can be taken into consideration in the diagnostic process, as can the patient's family history.

"Other insulin resistant patients are those diagnosed as having Type 2 diabetes. This diagnosis can be based on hyperglycemia with one or more of: (a) a normal or elevated level of insulin; (b) other evidence of pancreatic .beta. cell maintenance; a blunted blood glucose response to insulin; or (d) a family history of Type 2 diabetes. Our methods are applicable to treatment of insulin resistance and do not require frank diabetes. As with Type 1 diabetes, while insulin can be measured directly, a physician can assess insulin production by measuring C-peptide and, in some instances (e.g., where a patient has received exogenous insulin), C-peptide more accurately reflects insulin production. A normal level of insulin (i.e., a level within a range typically observed in healthy and/or non-diabetic patients) is reflected by a normal level of C-peptide (i.e. a level within a range typically observed in healthy and/or non-diabetic patients). Elevated C-peptide reflects elevated insulin. While the presence of normal or elevated levels of insulin indicate but do not prove that an adequate number of .beta. cells are present and functional, one can look for other evidence that these insulin-producing cells are healthy (e.g., one can determine whether the patient is carrying anti-.beta. cell antibodies). An insulin tolerance test can also be useful in diagnosing Type 2 diabetes. When a patient's response to insulin is blunted (i.e., when administered insulin does not bring about the expected reduction in blood glucose), it indicates that the patient's insulin responsive tissues, tissues responsible for insulin driven tissue disposal of blood glucose, are resistant to insulin, as occurs in Type 2 diabetes. The problem is not primarily insulin production, as is the case with Type 1 diabetes. As noted above, we have discovered a degree of insulin resistance in Type 1 diabetes.

"The present methods are also useful in treating patients who are diagnosed as being at risk for developing Type 2 diabetes (e.g., as having a greater than average risk of developing Type 2 diabetes). This diagnosis can be based on one or more of the following findings: (a) impaired glucose tolerance with or without features of metabolic syndrome; (b) normal or impaired glucose tolerance with hyperinsulinemia; or impaired glucose tolerance and a family history of Type 2 diabetes. Impaired glucose tolerance (IGT) is present when a patient has a blood glucose level that is higher than normal, but not high enough for the patient to be considered diabetic. IGT may also be referred to as borderline diabetes, pre-diabetes, or chemical diabetes. A specific population of patients known to be at risk for Type 2 diabetes is the population of female patients who have had gestational diabetes.

"While we tend to use the term 'impaired glucose tolerance' (IGT), one of skill in the art may also refer to patients as having impaired fasting glucose (IFG). The difference stems from the exact test used to diagnose patients (e.g., patients at risk of developing diabetes), and these tests are known in the art and described further below.

"Patients who are diagnosed as having metabolic syndrome exhibit insulin resistance. In fact, metabolic syndrome is also referred to as the insulin resistance syndrome or Syndrome X. As noted above, one can consider the features of metabolic syndrome when determining whether a patient is at risk of developing Type 2 diabetes, as patients who have metabolic syndrome are more likely to develop Type 2 diabetes. Risk for Type 2 diabetes can be assessed without considering these features, however, and, while patients who exhibit features of metabolic syndrome do have a higher risk for diabetes, they also have a higher risk of developing other conditions, such as cardiovascular disease. Thus, one can assess and treat a patient who has metabolic syndrome as described herein, and one can do so with the aim of reducing the patient's risk of developing diabetes or any other undesirable condition associated with metabolic syndrome.

"The features of metabolic syndrome include abdominal obesity, atherogenic dyslipidemia, a prothrombotic state, elevated blood pressure, and elevated levels of inflammatory cytokines. More specifically a patient may be diagnosed as having metabolic syndrome if they have two, three or more of: (a) an elevated waist circumference; (b) elevated triglycerides; reduced high density lipoproteins (HDLs); (d) elevated blood pressure; and (e) elevated fasting glucose.

"The invention also encompasses methods of treating patients who are at risk of developing Type 1 diabetes (e.g., patients who have a greater than average risk of developing Type 1 diabetes) or individuals with new onset Type 1 diabetes and low residual insulin production. These treatment methods can be carried out by identifying a patient who is at risk (e.g., a heightened risk) of developing Type 1 diabetes and administering to the patient a therapeutically effective amount of an .alpha.1-antitrypsin polypeptide or an agent that promotes the expression or activity of .alpha.1-antitrypsin. The patient who has been identified can be a patient who was diagnosed as being at risk of developing Type 1 diabetes on the basis of one or more of the following: (a) having a family history of Type 1 diabetes, with or without impaired glucose tolerance; or (b) having impaired glucose tolerance and evidence of pancreatic .beta. cell loss or functional insufficiency. With respect to family history, a patient has an increased risk of developing Type 1 diabetes when they are a sibling of (e.g., an identical twin of) a patient who has Type 1 diabetes. Evidence of pancreatic .beta. cell loss includes, as it does in the event of making any diabetes-related diagnosis, hypoinsulinemia and/or the presence of anti-.beta. cell antibodies.

"In any of the methods described herein, one can administer a therapeutically effective amount of an .alpha.1-proteinase inhibitor. For example, one can administer an .alpha.1-antitrypsin polypeptide, which may be a full-length .alpha.1-antitrypsin polypeptide (of human or other origin) or a biologically active fragment or mutant thereof al proteinase inhibitors are commercially available for the treatment of AAT deficiencies, and include Aralast.TM. Prolastin.TM., and Zemaira.TM.. As noted, the AAT polypeptide or the biologically active fragment or mutant thereof can be of human origin and can be purified from human tissue or plasma. Alternatively, it can be recombinantly produced. For ease of reading, we do not repeat the phrase 'or a biologically active fragment or mutant thereof' after each reference to AAT. It is to be understood that, whenever a full-length, naturally occurring AAT can be used, a biologically active fragment or other biologically active mutant thereof (e.g., a mutant in which one or more amino acid residues have be substituted) can also be used. Similarly, we do not repeat on each occasion that a naturally occurring polypeptide (e.g., AAT) can be purified from a natural source or recombinantly produced. It is to be understood that both forms may be useful. Similarly, we do not repeatedly specify that the polypeptide can be of human or non-human origin. While there may be advantages to administering a human protein, the invention is not so limited.

"Agents that promote the expression of .alpha.1-antitrypsin include nucleic acid molecules encoding a full-length, naturally occurring .alpha.1-antitrypsin polypeptide or a biologically active fragment or other mutant thereof. The nucleic acid molecules can include regulatory elements such as constitutively active or tissue-specific promoters to facilitate expression of the AAT-encoding sequence. Many suitable vectors, including plasmid and viral vectors are known in the art and can be used to deliver the present nucleic acid molecules to patients. The nucleic acid molecules can also include sequences that serve as reporters or tags or sequences that increase the circulating half-life of an AAT polypeptide to which they are joined (e.g., a portion of an immunoglobulin (e.g., an Fc region) or an albumin (e.g., human albumin).

"Agents that promote the activity of .alpha.1-antitrypsin include agents that promote the secretion of .alpha.1-antitrypsin (e.g., PBA).

"The invention encompasses combination therapies. For example, patients can be treated with an .alpha.1-proteinase inhibitor (e.g., Aralast.TM.) and an anti-inflammatory agent (e.g., an agent that selectively inhibits TNF.alpha. or a moiety within the TNF.alpha. signaling pathway). For example, the agent that inhibits TNF.alpha. can be an anti-TNF.alpha. antibody, which may be a human, humanized, chimeric or single chain antibody. The antibody can also be a polyclonal or monoclonal antibody. Anti-TNF.alpha. antibodies that are currently available and can be used in the methods described herein include adalimumab (Humira.TM.) and infliximab (Remicade.TM.). These antibodies are currently prescribed for the treatment of rheumatoid arthritis or psoriatic arthritis. Other useful antibodies include CDP571, which is a humanized monoclonal anti-TNF.alpha. antibody; D2E7, which is a human anti-TNF monoclonal antibody; and CDP870 (certolizumab pegol), which is an anti-TNF.alpha. pegylated antibody fragment (FAb). CDP870 has been used in clinical trials for the treatment of rheumatoid arthritis and Crohn's disease.

"Alternatively, or in addition, patients can be treated with an .alpha.1-proteinase inhibitor and, as an agent that selectively inhibits a moiety within the TNF.alpha. signaling pathway, a soluble TNF.alpha. receptor antagonist. Useful agents may be soluble and include a sufficient portion of the TNF.alpha. receptor to bind TNF.alpha.. These antagonists can include a heterologous portion (i.e., a non-TNF.alpha. receptor-related portion) that may increase the antagonist's circulating half-life. For example, the antagonists can include an immunoglobulin-like molecule, as is included in etanercept (Enbrel.TM.). Enbrel.TM. per se can also be used. In other embodiments, the heterologous portion of the antagonist can be an albumin (e.g., human serum albumin) or polyethylene glycol. The antagonist can be a PEGylated soluble tumor necrosis factor type I (PEG-sTNF-R1) per se or can include or consist of the p55 portion of the receptor found in this antagonist (see, e.g., Edwards et al., Adv. Drug. Delivery Res. 55:1315-1336, 2003).

"Alternatively, or in addition, patients can be treated with an .alpha.1-proteinase inhibitor and, as an agent that selectively inhibits a moiety within the TNF.alpha. signaling pathway, an inhibitor of TACE (TNF.alpha. converting enzyme).

"Other useful TNF.alpha. inhibitors, any of which, or any combination of which, can be administered in connection with AAT, include agents that selectively inhibit TNF.alpha. expression, such as RNA molecules that mediate RNAi (e.g., a TNF.alpha. selective siRNA or shRNA) and antisense oligonucleotides. More specifically, one can administer a molecule that mediates RNAi (e.g., a short interfering nucleic acid (siNA), a short interfering RNA (siRNA), a double-stranded RNA (dsRNA), or a short hairpin RNA (shRNA) as described in published U.S. Patent Application No. 20050227935, the contents of which are incorporated herein by reference in their entirety. TNF.alpha. expression or activity can also be selectively inhibited by small organic or inorganic compounds (e.g., LMP420; Haraguchi et al., AIDS Res. Ther. 3:8, 2006), thalidomide or a thalidomide analog, or a phosphodiesterase type IV inhibitor. Where small organic compounds and pharmaceuticals such as thalidomide are used, a prodrug may also be used.

"Alternatively, or in addition, patients can be treated with an antagonist of an inflammatory cytokine such as IL-1, IL-6, or IL-8. For example, anakinra (Kineret.TM.) can be used to inhibit IL-1.

"Other agents useful in the present methods (e.g., in combination with an AAT) include agonists of a glucagon-like peptide (GLP) receptor (e.g., GLP-1) or of an exendin receptor. For example, the agonist of the GLP receptor or the agonist of the exendin receptor can be exendin-3, exendin-4, or GLP-1(7-36)-amide.

"Other agents useful in the present methods (e.g. in combination with an AAT) include CD3 antagonists (e.g., an anti-CD3 antibody).

"The number of patients at risk for developing diabetes is substantial. In a cross-section of U.S. adults aged 40 to 74, who were tested during the period 1988 to 1994, 33.8 percent had IFG, 15.4 percent had IGT, and 40.1 percent had pre-diabetes (IGT or IFG or both). Applying these percentages to the 2000 U.S. population, about 35 million adults aged 40 to 74 would have IFG, 16 million would have IGT, and 41 million would have pre-diabetes.

"Other features and advantages of the present invention are described in the drawing, the detailed description, the examples, and the claims.

"All cited patents, patent applications, and references (including references to public sequence database entries) are incorporated by reference in their entireties for all purposes. U.S. Provisional App. No. 60/844,003, filed Sep. 12, 2006, is incorporated by reference in its entirety for all purposes.


"FIG. 1 is a pair of bar graphs representing the results obtained from studies of insulin signaling in skeletal muscle. The upper graph charts insulin receptor (IR) phosphorylation and the lower graph charts insulin receptor substrate-1 (IRS-1) phosphorylation in control, diabetic, and treated animals."

URL and more information on this patent application, see: Flier, Jeffrey; Koulmanda, Maria; Strom, Terry B. Compositions Containing Alpha-1-Antitrypsin and Methods for Use. Filed November 19, 2013 and posted June 5, 2014. Patent URL:

Keywords for this news article include: Antibodies, Biotechnology, Pharmaceuticals, Drugs, Enbrel, Genetics, Pancreas, Arthritis, Bariatrics, Etanercept, Immunology, Proinsulin, Proteomics, Thalidomide, Gene Therapy, Legal Issues, Phthalimides, Therapeutics, Endocrinology, Hyperglycemia, Overnutrition, Bioengineering, Blood Proteins, Immunoproteins.

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Source: Gene Therapy Weekly

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