Inclusion Criteria:

• Patients with diagnosis of familial or sporadic ALS, defined as meeting the possible, laboratory-supported probable, probable, or definite criteria for a diagnosis of ALS according to the revised World Federation of Neurology El Escorial criteria [Rix Brooks 2000].
• Onset of muscle weakness within 60 months of study entry.
• Patients who have low Slow Inspiratory Vital Capacity (SVC) below that what is predicted for age and sex can be included into the study at the discretion of the investigator as long as they are NOT respiratory insufficient.
• If on any medication (including riluzole), these must have been stable within the previous one month. (See also 'Concomitant Medications' - Section 8).
• Age 18 - 80 years inclusive.
• Male or Female of non-childbearing potential (NCBP) defined as follows:

Pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MlU/ml and oestradiol < 40 pg/ml (<140 pmol/L) is confirmatory]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods in Section 7.1.1, if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.

• Male subjects must agree to use one of the contraception methods listed in Section 7.1.2. This criterion must be followed from the time of the first dose of study medication until the last follow-up visit.
• QTcB < 500 msec or uncorrected QT <600msec (machine or manual overread). If subject has bundle branch block then criteria is QTcB < 530 msec.
• A Body Mass Index that at the discretion of the investigator is acceptable for inclusion into the study.
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

Exclusion Criteria:

• Patients with other neuromuscular disorders (in addition to their ALS diagnosis), unless the investigator determines that such additional disorder will not affect safety or other measures in this study.
• Patients with evidence of dementia or psychiatric illness which, in the investigator's opinion, is likely to prevent them from a full understanding of and/or compliance with the study requirements and procedures.
• Patients with abnormalities detected during the screening evaluations which, in the investigator's medical judgement, are sufficiently significant to exclude them from participation in the study.
• Patients who have participated in a clinical trial involving receipt of a biopharmaceutical product within 6 months prior to the first dosing day.
• Exposure to more than four new investigational products within 12 months prior to the first dosing day.
• The subject has a positive drugs of abuse test at the screening or pre dose visit. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates and benzodiazepines. Subjects who are on any of these drugs by prescription for medical reasons may be considered by the investigator for inclusion if they fulfil other entry criteria.
• The subject has a positive alcohol test at the pre-dose visit. History of regular excessive alcohol consumption within 6 months of the study defined as:
• For European sites: an average weekly intake of > 28 units for males or >21 units for females. One unit is equivalent to 8g of alcohol: a half-pint (~240mL) of beer, 1 glass (125mL) of wine or 1 (25mL) measure of spirits.
• For North American sites: an average weekly intake of >21 drinks for males or >14 drinks for women. One drink is equivalent to 12 g alcohol: 12 ounces (360mL) of beer, 5 ounces (150mL) of wine or 1.5 ounces (45mL) of 80 proof distilled spirits.
• History of sensitivity to GSK1223249, or components thereof, or a history of drugs or other allergies that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
• Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
• Females of childbearing potential, pregnant females as determined by positive serum or urine beta hCG test at screening or prior to dosing, or lactating females.
• Patients who have received any type of vaccination in the last 3 weeks before study drug administration.
• Unwillingness or inability to follow the procedures outlined in the protocol
• Subjects who will undergo muscle biopsies (cohorts 3-optional 5, 6, 7 and 8 will not be eligible for inclusion, if any of the following criteria apply:

Patients with wasted deltoids (MRC score ≤ 2) and patients with normal deltoids (MRC score 5).

Patients who cannot achieve normal coagulation in the peri-operative period and those who may otherwise be at higher risk of bleeding complications