A familial case of MYH9 gene mutation associated with multiple functional and structural platelet abnormalities ...
When Genetics Pulls A Fast One, Gender Identification Can Become Complicated
The spectrum of information that can be obtained by prenatal testing is wide and rapidly increasing. Many mutations, or "abnormalities," are inconsequential, while others are significant. Genetic counseling combined with noninvasive prenatal screening (NIPS) can be helpful.
Consider this a sort of Public Service Announcement about the nuances of prenatal testing (and, in an odd way, about the selection of individual pronouns).
I became interested in anomalies of the human sex chromosomes, X and Y, as a medical student, when I had a patient with a rare genetic condition that gave rise to a syndrome called "androgen insensitivity" or "testicular feminization." It is caused by either of two types of mutations on the X chromosome. (Recall that females are generally XX, while males are XY.)
So, while normally, people with one X and one Y chromosome in every somatic cell (and who are designated "XY") would be males, the mutations distort development. One mutation causes a deficiency of the receptor for the hormone dihydrotestosterone (DHT), which promotes male characteristics; in the other, the receptor is apparently present, but the receptor-DHT complex is inactive. Thus, in either case, the hormone cannot perform its normal actions, which would give rise to a male-appearing fetus, so the fetus is phenotypically a female.
My patient was genetically male (XY), but because of the mutation, his cells were unable to respond to DHT in utero, the result of which was the birth of a person who became a normal-appearing woman with adequate breast development, normal female external genitalia but a vagina of less than normal depth, absent uterus, sparse pubic and axillary hair, and the absence of menstrual periods.
(This situation adds a new wrinkle to current confusion about appropriate pronouns.)
Some form of testicular feminization occurs in about one out of 20,000 births and can be incomplete (giving rise to various sexual ambiguities) or complete (the genetic male appears to be a woman). Even many physicians have never heard of it, so I was surprised to see a case of it depicted several years ago on the British TV series, "Call the Midwife." There is a description of the episode here.
Testicular feminization is the kind of abnormality that can be detected by prenatal genetic tests, which raises various medical, ethical, and moral issues -- such as whether to abort the fetus -- because there is currently no treatment for it.
Far more common are variations in sex chromosomes where people have an extra or missing entire X or Y. These are the most frequent chromosomal anomalies, occurring in approximately one in 400 births. However, most people affected are unaware that they have them, because the anomalies are not life-disrupting and, unlike testicular feminization, seldom give rise to telltale characteristics, signs, or symptoms.
Thus, because of the confusion and anxiety that can ensue when a person (or parent) learns of the genetic anomaly, perhaps knowing about the diagnosis might be worse than the "disease" itself.
The first noninvasive prenatal screening (NIPS) appeared just over a decade ago. The first-trimester blood tests that became available in 2011 to detect Down syndrome have vastly expanded their repertoire, gradually adding more conditions, including atypical numbers of sex chromosomes, to their panel.
In 2020, the American College of Obstetricians and Gynecologists endorsed conducting noninvasive prenatal screening during all pregnancies. Their website describes the categories of genetic disorders that are possible:
Aneuploidy is a condition in which there are missing or extra chromosomes. In a trisomy, there is an extra chromosome. In a monosomy, a chromosome is missing. Inherited disorders that are caused by changes in genes are called mutations. These include sickle cell disease, cystic fibrosis, Tay-Sachs disease, and many others.
Testicular feminization is in the category of abnormalities caused by mutations.
Although parents-to-be might think the test is intended primarily to rule out Down syndrome or more severe abnormalities, as noted above, other findings might be detected, many of them inconsequential. Even so, the finding of sex chromosome abnormalities often precipitates a decision to terminate the pregnancy, particularly in younger couples.
In view of the complexity and importance of the information derived from prenatal testing, parents-to-be would be wise to obtain genetic counseling to provide information about how genetic abnormalities might affect them and their family, if at all. The genetic counselor or other qualified healthcare professional collects personal and family health history, which is used to estimate how likely it is that the fetus has a serious genetic condition and to recommend which genetic tests might be appropriate.
This is truly a situation in which, as the saying goes, knowledge is power. Expectant parents should obtain counseling to learn what the future may hold.
IN8bio Presents Positive Data Demonstrating Durable 1-year Complete Remission In 100% Of Evaluable Patients In Phase 1 Trial Of INB-100
NEW YORK, June 13, 2024 (GLOBE NEWSWIRE) -- IN8bio, Inc. (Nasdaq: INAB), a clinical-stage biopharmaceutical company developing innovative gamma-delta T cell therapies, presents updated data from its Phase 1 trial of INB-100 at the European Hematology Association (EHA) 2024 Hybrid Congress.
The data from INB-100 demonstrated that 100% of evaluable leukemia patients (n=10) remained alive, progression-free, and in durable CR through one year as of May 31, 2024. Historically, published data demonstrated that up to ~50% of patients with hematologic malignancies undergoing HSCT with reduced intensity conditioning (RIC) relapse by one year and often succumb to the disease shortly thereafter. Two of the patients treated with INB-100 remain alive and relapse free for over three and a half years, and a third patient is now nearing three years. Furthermore, INB-100 has demonstrated for the first time, the in vivo expansion and persistence of a haplo-matched allogeneic, or donor-derived, cellular therapy at 365 days, with blood levels of gamma-delta T cells surpassing levels previously associated with greater survival.
The complete responses to date, combined with a favorable safety and risk profile demonstrating no dose limiting toxicities (DLTs), no cytokine release syndrome (CRS), no neurotoxicity or immune effector cell-associated neurotoxicity syndrome (ICANS) and a lack of serious infections is encouraging for the treatment of hematological malignancies. One patient died of idiopathic pulmonary fibrosis, a known toxicity of transplants, without evidence of progression. Additionally, two patients with TP53 mutations, including one patient with Ph-acute lymphocytic leukemia (ALL) treated with seven prior treatment regimens and a patient with MDS/MPN syndrome, relapsed but remain alive. Leukemic relapse is the leading cause of death in patients undergoing HSCT, making relapse prevention a critical unmet need.
The trial has been expanded to enroll an additional ten patients at Dose Level 2 (DL2), the recommended Phase 2 dose. Enrollment and treatment of patients into the expansion cohort is ongoing, with updated data expected in late 2024 and 2025. IN8bio expects to discuss plans for a potential registrational trial for this indication with the U.S. Food and Drug Administration (FDA) in a Type B meeting this summer.
"These data demonstrate the potential of allogeneic INB-100 gamma-delta T cells to provide durable relapse-free periods for patients with high-risk or relapsed AML and other hematologic malignancies undergoing HSCT," said Trishna Goswami, MD, Chief Medical Officer of IN8bio. "100% of evaluable patients remain in complete remission at one year of follow-up. In this trial, the first three patients were high-risk or relapsed AML patients with complex cytogenetics, including trisomy of chromosome 8 and deletion of chromosome 7. All three patients are alive and progression free with one lost-to-follow-up at 42.4 months after they relocated away from the study site and out of state. Achieving these outcomes despite giving patients a RIC regimen, which carries a higher risk of relapse, in an older population with a median age of 68 is very encouraging. We look forward to advancing our novel gamma-delta T cell therapy for patients who need additional options."
"The emerging safety, efficacy and durability profile of this novel gamma-delta T cell therapy supports its potential to improve relapse free survival for patients with blood cancers following allogeneic stem cell transplantation," said Dr. Joseph P. McGuirk, Schutte-Speas Professor of Hematology-Oncology, Division Director, Hematologic Malignancies and Cellular Therapeutics, and Medical Director, Blood and Marrow Transplant, at The University of Kansas Cancer Center. "Approximately 25% of patients relapse within the first 100 days, and nearly half by one year post stem cell transplant, which remains the primary cause of treatment failure and mortality. The results of this clinical trial are very encouraging and hold promise that a novel cellular therapy using donor-derived gamma-delta T cells may prevent relapse, resulting in improved relapse-free survival for patients with hematologic malignancies."
Conference Call DetailsIN8bio will host a conference call and webcast today, Thursday, June 13, 2024, at 4:15 pm ET to review the updated clinical data from the EHA presentation. The webcast can be accessed by clicking this link and can also be accessed on the Events & Presentations page of the Company's website. To participate in the live call, please register using this link. It is recommended that participants register at least 15 minutes in advance of the call. Once registered, participants will be informed of the dial-in number and will be provided a unique PIN.
About the INB-100 Phase 1 TrialThe Phase 1 clinical trial (NCT03533816) is an investigator-sponsored dose-escalation trial of allogeneic derived, gamma-delta T cells from matched related donors that have been expanded and activated ex vivo and administered systemically to patients with leukemia following HSCT approximately 15 to 30 days post engraftment. The single-institution clinical trial is being conducted at The University of Kansas Cancer Center (KUCC). The primary endpoints of this trial include safety and tolerability, and secondary endpoints include rates of GvHD, relapse rate and overall survival.
About IN8bioIN8bio is a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of gamma-delta T cell product candidates for solid and liquid tumors. Gamma-delta T cells are a specialized population of T cells that possess unique properties, including the ability to differentiate between healthy and diseased tissue. IN8bio's DeltEx platform employs allogeneic, autologous, iPSC and genetically modified approaches to develop cell therapies designed to effectively identify and eradicate tumor cells.
IN8bio has initiated a Phase 2 trial of INB-400 in GBM at multiple centers across the United States and has two ongoing Phase 1 trials in solid and hematological tumors, including INB-200 for GBM and INB-100 for patients with hematologic malignancies undergoing transplantation. IN8bio also has a broad portfolio of preclinical programs focused on addressing other hematological and solid tumor cancers. For more information about IN8bio and its programs, please visit www.IN8bio.Com.
Forward Looking StatementsThis press release may contain forward-looking statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements may be identified by words such as "aims," "anticipates," "believes," "could," "estimates," "expects," "forecasts," "goal," "intends," "may," "plans," "possible," "potential," "seeks," "will" and variations of these words or similar expressions that are intended to identify forward-looking statements, although not all forward-looking statements contain these words. Forward-looking statements in this press release include, but are not limited to, statements regarding the potential of allogeneic INB-100 gamma-delta T cells to provide durable relapse-free periods for patients with high-risk or relapsed AML and other hematologic malignancies undergoing HSCT; the ability of IN8bio to continue advancing its novel gamma-delta T cell therapy; the potential of INB-100 to improve the relapse free survival for patients with blood cancers undergoing stem cell transplantation; the potential activity and safety data of INB-100; IN8bio's plans regarding interactions with regulatory agencies, including the FDA; and IN8bio's ability to achieve anticipated milestones, including expected data readouts from its trials, enrollment of additional patients in its clinical trials, and advancement of clinical development plans. IN8bio may not actually achieve the plans, intentions, or expectations disclosed in these forward-looking statements, and you should not place undue reliance on these forward-looking statements. Actual results or events could differ materially from the plans, intentions, and expectations disclosed in these forward-looking statements as a result of various factors, including: uncertainties inherent in the initiation and completion of preclinical studies and clinical trials and clinical development of IN8bio's product candidates, including patient enrollment and follow-up and IN8bio's ability to meet anticipated deadlines and milestones; the risk that IN8bio may not realize the intended benefits of its DeltEx platform; availability and timing of results from preclinical studies and clinical trials; whether the outcomes of preclinical studies will be predictive of clinical trial results; whether initial or interim results from a clinical trial will be predictive of the final results of the trial or the results of future trials; the risk that trials and studies may be delayed and may not have satisfactory outcomes; potential adverse effects arising from the testing or use of IN8bio's product candidates; uncertainties related to regulatory approvals to conduct trials or to market products; IN8bio's reliance on third parties, including licensors and clinical research organizations; and other important factors, any of which could cause actual results to differ from those contained in the forward-looking statements, that are described in greater detail in the section entitled "Risk Factors" in our Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on May 9, 2024, as well as in other filings IN8bio may make with the SEC in the future. Any forward-looking statements contained in this press release speak only as of the date hereof, and IN8bio expressly disclaims any obligation to update any forward-looking statements contained herein, whether because of any new information, future events, changed circumstances, or otherwise, except as otherwise required by law.
Corporate ContactIN8bio, Inc.Glenn Schulman, PharmD, MPH203.494.7411gdschulman@IN8bio.Com
InvestorsMeru AdvisorsLee M. Sternlstern@meruadvisors.Com
MediaKimberly HaKKH Advisors917.291.5744kimberly.Ha@kkhadvisors.Com
The First Neanderthal With Down Syndrome Shines Light On The Origin Of Human Compassion
The analysis of a fossil the size of a thumb found in the Spanish city of Valencia in the 1980s has made it possible to identify the first case of Down syndrome among Neanderthals, our evolutionary first cousins, who disappeared about 40,000 years ago for unknown reasons. The remains were that of a six-year-old boy. According to the scientists who identified and analyzed the remains, this finding demonstrates that the Neanderthals also took care of the weakest members of their community without expecting anything in return, an altruism that was thought to be exclusive to our species, Homo sapiens.
One of the features that differentiate Homo sapiens from Neanderthals is the petrosal, a dense cranial bone located behind the ears. Subtle differences in the architecture of this bone are related to changes in the auditory system. When the petrosal bone of a child individual was found years ago in Cova Negra, a Neanderthal site near the Spanish town of Xàtiva, it was thought that to belong to another of the Neanderthal children that had already been located in this cave.
The remains were analyzed by Ignacio Martínez and Mercedes Conde-Valverde, experts in the auditory differences of sapiens and Neanderthals, who used computerized axial tomography to analyze the fossil. The surprise was immediate: the bone had marks of congenital malformations that are normally associated with Down syndrome.
It's not known if the child from Cova Negra was a boy or girl, but researchers do know that the injuries to their inner ear probably left them deaf and with hardly any balance. According to the researchers, who published their findings in Science Advances, it is impossible for the child to have survived without the care not only of their mother, but also other members of their family.
It has been debated for decades whether any other human species is capable of the kind of altruism that's seen in caring for the weak or sick without expecting anything in return. There are hardly any known cases. But in 2016 researchers published the case of a chimpanzee born with Down syndrome. The offspring survived almost two years thanks to the care of its mother and older sister. When the latter died, the mother could not take care of her sick daughter and she passed away.
In our own species, the oldest cases of Down syndrome date back some 5,000 years, according to a study published in February based on DNA analysis. None of the children identified survived more than 16 months, although several of the children found in the Iberian Peninsula were buried with honors.
Fragment of the petrosal bone found in Cova Negra (Valencia).S. A.The Cova Negra child is the first case of Down syndrome among Neanderthals. Although the bone has not been dated yet, the site where it was found dates back between 270,000 and 146,000 years ago. These were Neanderthals, the native human species of Europe, who lived in small clans and led a nomadic life in search of game. Despite the harshness of this existence, the Cova Negra child survived to the age of six. A gap of time later, in 1929, the life expectancy of children with this condition was only nine years, the authors of the study point out. Today, thanks to medical advances, as well as better social protections for this community, people with Down syndrome have a life expectancy of around 60 years in developed countries, the researchers add.
"This discovery is a bombshell," says Juan Luis Arsuaga, co-director of the Atapuerca archaeological site and co-author of the study. "It shows that trisomy [the cause of Down syndrome, characterized by three copies of chromosome 21] existed at any time. But above all, it invites us to think about this child, who was cared for by an entire family and who survived for years. It is clear that this type of altruism is not exclusive to our species," he says. "Neanderthals greatly appreciated their children, and we know this precisely because many children's remains have been found in Cova Negra that we think received burials."
Archaeologist and midwife Patxuka de Miguel, one of the authors of the study on the first cases of Down syndrome among sapiens, describes the new research as "excellent." "I don't know if the group that lived in Cova Negra was aware of the importance of each person who was born in the group, but I believe that in all societies in which survival is based on this collaboration, no one was superfluous. In the case of the Neanderthal population, it is increasingly assumed that they had knowledge about the use of resources for some pathologies, a symbolic world of their own and took care of people with sequelae of serious pathologies who survived for a long time after their suffering," she says.
Edgard Camarós, archaeologist at the University of Santiago de Compostela in Spain, believes that this is an "exceptional" find. "It opens a whole window to the archeology of caregiving; something very interesting to understand our evolution. It is true that this is a single case, and the diagnosis is based solely on a scan. I understand that it would also require genetic studies, especially to find that mutation on chromosome 21, which is what would confirm Down syndrome," he details.
Miguel Botella, a doctor and paleopathologist from the University of Granada in Spain, highlights: "Although the complexity of their behaviors was already known, this is a new approach of interest because it is a child. However, the ascription of the ear pathology to a possible Down syndrome should be treated with extreme caution, as it is by no means exclusive to Down syndrome," he adds.
Chris Stringer, paleoanthropologist at the Natural History Museum in London, points out: "Although the severity [of this condition] may vary greatly in affected individuals today, the degree of pathological alteration suggests that this child was severely disabled and would have required considerable social support from others until the time of his death," he explains. This study "adds another element to our view of the humanity of Neanderthals, capable of deep and lasting care for their own," he concludes.
Sign up for our weekly newsletter to get more English-language news coverage from EL PAÍS USA Edition
Comments
Post a Comment