T-cell-restricted intracellular antigen-1 (TIA1) has been recently reported as a novel amyotrophic lateral sclerosis (ALS) related gene, and has already been adopted in a resource frequently used i...

Genervon makes several claims on its website (3) regarding possible mechanisms of GM604 without any supporting data or references. Multiple members of ALSUntangled contacted Genervon by phone and emails in the hope of establishing a dialogue that would allow us to eventually better understand this and several other issues described below; unfortunately, our requests were either never answered (4) or were answered along with the following statement, which prevents us from sharing: ‘This email is sent on behalf of Genervon Biopharmaceuticals, LLC. It may be privileged and contains confidential information intended only for the use of the recipient(s) named above. Use by anyone else is strictly prohibited’ (5). PubMed searches of GM6 and GM604 identified only a single possibly relevant publication (2). In this study, GM604 or vehicle were administered to mice following an experimentally induced stroke and reperfusion. Treatment with GM604 was associated with lower markers of inflammation and apoptosis, reduced stroke size, and improved behavioral outcomes relative to treatment with vehicle. It is not clear that recovery from stroke bears any similarity to neuroprotection in ALS, so this paper cannot be relied upon to provide foundation for a relevant ALS mechanism. This study was funded by Genervon, and one of the authors of this paper is a member of the Genervon leadership team (6), which creates a potential conflict of interest. There may be other unpublished mechanistic data on GM604. The paper on GM604 (2) states ‘Studies with the synthesized GM6 also demonstrated similar trophic effects in a transected femoral nerve rat model. In a zebrafish bioassay, GM6 protected the organism from L-2-hydroxyglutaric acid (LGA), induced oxidative stress and apoptosis in the CNS, and reduced apoptosis by 85% in the midbrain’. However, the only references we can find to support this work are patent applications. Based on all this, ALSUntangled assigns a TOE ‘Mechanism’ grade of D. It should be noted here that various other neurotrophic factors have been tested in ALS, including IGF1 (7), CNTF (8) and BDNF (9)

HBOT involves treating patients with 100% oxygen at pressures several times higher than atmospheric pressure. This is accomplished by placing patients in a sealed, pressurized chamber (2). HBOT was initially used to treat decompression sickness after diving. There are currently 14 approved, evidencebased indications for HBOT including treatment of air embolism, carbon monoxide poisoning, nonhealing wounds (such as diabetic wounds), burns, gangrene, brain abscess, and radiation injury (3). Numerous websites advertise off-label HBOT for a wide variety of other conditions including multiple sclerosis, dementia, stroke and ALS (4,5). Metaanalyses conclude that there is insufficient evidence to support the use of HBOT in multiple sclerosis (6), dementia (7) and stroke (8). The FDA has warned patients against such off-label use (9).

ISSN 2167-8421 print/ISSN 2167-9223 online © 2015 Informa Healthcare DOI: 10.3109/21678421.2015.1024571 into the extremity muscles and the spinal fl uid of the person who donated the fat. No safety or effi cacy outcome measures appear to have been objectively or systematically monitored. This description is similar to what two independent groups reported in their own reviews of PSC in early 2013 (9,10). Over the remainder of 2013, Williams apparently changed his protocol (7). On 20 August 2013 he told us that he had started to use umbilical-derived cells from donors without ALS, was working with “ gene therapy ” , and was testing image guided injections into the spinal cord and nerve roots (7). Our email requests for additional details on these changes have largely gone unanswered (7). With regard to the gene therapy, the PSC website notes a partnership with a company called Neuralgene (6). The Neuralgene website states that they use a virus (AAV) to deliver various genes to various tissues for patients with different diseases (11). For ALS, the website says: ‘ The AAV9 viral vector delivers multiple genes, which include Factor H (a regulator of complement activity), neural growth factors and regulators of TDP-43, to the neural cells ’ (12). The status of Neuralgene ’ s ALS product development program is unclear; animal studies of this gene therapy were reported to begin in May 2013 (12) but the website also claims: ‘ Neuralgene has initiated initial human testing in it ’ s gene therapy for ALS ’ (11). Typically, animal studies would be completed before human testing begins. A PubMed search identifi ed no published studies on Neuralgene protocols in animals or humans and there are no Neuralgene trials listed on ClinicalTrials.gov. Williams is listed as the CEO and director of R & D for Neuralgene (13). On 24 September 2014 Williams wrote: “ We are not doing much with stem cells anymore, mostly just a little orthopedic work ... .we tried aav, vegf, gdnf, igf2, but nothing exciting ” (7). ALSUntangled has been unable to obtain any additional details. According to the PSC website (6) and an email from Williams dated 7 October 2014, some form of MSC treatment is still being offered to patients with ALS (7). ALSUntangled reviews alternative and off-label treatments for patients with ALS (PALS). Here, we examine the treatment offered at Precision Stem Cell, for which we have had more than 1100 requests (1). This is the fi rst review that incorporates our new Table of Evidence (TOE, (2)). Precision Stem Cell (PSC) is a clinic formerly in Gulf Shores, Alabama now in Bogota, Columbia. It is led by Jason Williams, a radiologist (3). He uses imaging techniques such as MRI, CT, fl uoroscopy and ultrasound (4) to insert mesenchymal (meaning loosely packed in a gelatinous ground substance such as fat, umbilical cord or bone marrow) stem cells (MSCs) into patients with various ailments. This is primarily marketed toward athletes as a way to help them recover faster from musculoskeletal injuries (5).

In conclusion, given the lack of demonstrated effectiveness, and the above-documented concerns about product safety and supplier identity and reliability, ALSUntangled does not support the use of mototab for amyotrophic lateral sclerosis or any other motor neuron disease. If Oslo Health Solutions ever contacts us with additional useful information on this product we will gladly publish an addendum to this investigation.

ISSN 1748-2968 print/ISSN 1471-180X online © 2012 Informa Healthcare DOI: 10.3109/17482968.2012.717796 general) cognitive defi cits such as verbal fl uency (4). Whether or not Lyme can cause brain damage in these same regions is controversial; if so, it is exceedingly rare (5). Even if there is overlap in the brain regions affected by ALS and Lyme, a very general coincidence/overlap between two conditions such as this does not mean that they are causally related. The Vaughters fail to mention that 90% of patients with Lyme report or have a specifi c type of rash called erythema migrans (6); PALS rarely, if ever, do. The most common symptoms and signs of nervous system Lyme disease are headache, stiff neck, photosensitivity and fever (from lymphocytic meningitis), reversible facial nerve palsy, eye movement abnormalities, and monoor oligo-radiculopathy that produces dermatomal pain and sensory loss in addition to weakness (5). PALS do not present with headache, stiff neck, photosensitivity, fever or reversible facial weakness, and rarely have eye movement abnormalities, dermatomal pain or sensory loss. Thus, in reality, there is little overlap between the typical clinical picture of ALS and that of nervous system Lyme disease. Very rarely, Lyme has been reported to cause encephalomyelitis and/or polyradiculopathy. If these occurred together they could produce upper and lower motor neuron signs (the hallmark of ALS), but again they should be accompanied by clinical and laboratory features that are not part of ALS such as pain, sensory loss, and focal infl ammatory changes on neuroimaging and/or spinal fl uid (5,7). Secondly, the Vaughters argue that geographic locations and occupations with a high incidence of Lyme disease diagnosed by Centers for Disease Control (CDC) criteria also have a high incidence of ALS. Again, here we see coincidence being accepted as causality. The authors downplay other potential explanations for geographic and occupational clusters of ALS (8). Furthermore, they again fail to mention information that contradicts their hypothesis (including information in some of the very references they cite): the incidence of Lyme The fi rst ALSUntangled, published in 2009, reviewed the possibility of a link between ALS and Lyme disease (1). We found no evidence for an increased frequency of positive Lyme tests in our cohort of 4000 patients with confi rmed diagnoses of ALS. We found no evidence that any of the patients in our cohort with a positive Lyme test had their ALS cured by appropriate treatment for Lyme disease. Nonetheless, rumours of a connection have persisted and a number of “ Lyme literate ” clinics continue to advertise their controversial testing and treatments for patients with ALS (PALS). One source of these persistent rumours appears to be an online manuscript called “ When ALS Is Lyme ” written by Sarah and John Vaughter (2) and available on their marketing website (3). Here, on behalf of PALS who requested it, we review this manuscript.

ISSN 1748-2968 print/ISSN 1471-180X online © 2012 Informa Healthcare DOI: 10.3109/17482968.2012.671629 production. MCT in coconut oil are converted in vivo into ketone bodies. In cultured neurons treated with drugs impairing complex 1 function, the addition of ketone bodies can restore complex 1 function (5). Thus, ingestion of coconut oil, by raising ketone levels, could theoretically help compensate for mitochondrial dysfunction and impaired energy production in patients with ALS. Alternatively, there is growing evidence suggesting that nutritional status (6) and lipid metabolism (7) are important prognostic factors in patients with ALS. Coconut oil could slow ALS progression simply by acting as a high calorie supplement that increases circulating lipids.